Publications by authors named "Lori A Knackstedt"

37 Publications

MC-100093, a novel β-lactam GLT-1 enhancer devoid of antimicrobial properties attenuates cocaine relapse in rats.

J Pharmacol Exp Ther 2021 May 13. Epub 2021 May 13.

School of Pharmacy, Temple University, United States.

Cocaine use disorder (CUD) currently lacks FDA-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens following cocaine self-administration and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine-seeking. The beta-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. While ceftriaxone shows promise for treating CUD, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1 enhancing effects of ceftriaxone but displayed superior drug-like properties. Here we describe a new monocyclic beta-lactam, MC-100093, as a potent up-regulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested and to determine physiochemical, pharmacokinetic and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine-seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs, however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine-seeking without reducing food-seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.
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http://dx.doi.org/10.1124/jpet.121.000532DOI Listing
May 2021

Effects of ceftriaxone on ethanol drinking and GLT-1 expression in ethanol dependence and relapse drinking.

Alcohol 2021 May 16;92:1-9. Epub 2021 Jan 16.

Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States; Ralph A. Johnson Veterans Administration Medical Center, Charleston, SC, United States.

Repeated cycles of chronic intermittent ethanol (CIE) exposure increase voluntary consumption of alcohol (ethanol) in mice. Previous reports from our laboratory show that CIE increases extracellular glutamate in the nucleus accumbens (NAc) and that manipulating accumbal glutamate concentrations will alter ethanol drinking, indicating that glutamate homeostasis plays a crucial role in ethanol drinking in this model. A number of studies have shown that ceftriaxone increases GLT-1 expression, the major glutamate transporter, and that treatment with this antibiotic reduces ethanol drinking. The present studies examined the effects of ceftriaxone on ethanol drinking and GLT-1 in a mouse model of ethanol dependence and relapse drinking. The results show that ceftriaxone did not influence drinking at any dose in either ethanol-dependent or non-dependent mice. Further, ceftriaxone did not increase GLT-1 expression in the accumbens core or shell, with the exception of the ethanol-dependent mice receiving the highest dose of ceftriaxone. Interestingly, ethanol-dependent mice treated with only vehicle displayed reduced expression of GLT-1 in the accumbens shell and of the presynaptic mGlu2 receptor in the accumbens core. The reduced expression of the major glutamate transporter (GLT-1), as well as a receptor that regulates glutamate release (mGlu2), may help explain, at least in part, increased glutamatergic transmission in this model of ethanol dependence and relapse drinking.
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http://dx.doi.org/10.1016/j.alcohol.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026658PMC
May 2021

Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters.

Pharmacol Ther 2021 May 9;221:107797. Epub 2021 Jan 9.

Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smętna 12, PL 31-343 Kraków, Poland.

Glutamate transmission is an important mediator of the development of substance use disorders, particularly with regard to relapse. The present review summarizes the changes in glutamate levels in the reward system (the prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, and ventral tegmental area) observed in preclinical studies at different stages of cocaine exposure and withdrawal as well as after reinstatement of cocaine-seeking behavior. We also summarize changes in the glutamate transporters xCT and GLT-1 and metabotropic glutamate receptors mGlu2/3, mGlu1, and mGlu5 based on preclinical and clinical studies with an emphasis on their role in cocaine-seeking. Glutamate transporters, such as GLT-1 and x, play a key role in maintaining glutamate homeostasis. In preclinical models, agents reversing cocaine-induced decreases in GLT-1 and xc- in the nucleus accumbens attenuate relapse. Very recent studies indicate that other mechanisms of action, such as reversing the mGlu2 receptor downregulation, contribute to these compounds' anti-relapse efficacy. In preclinical models, antagonism of mGlu5 receptors and stimulation of mGlu2/3 autoreceptors decrease relapse. Therefore, analysis of the above glutamatergic adaptations seems to be crucial because, so far, there are no prognostic biomarkers that can forecast relapse vulnerability in clinical practice, which would be helpful in alleviating or suppressing this phenomenon. Moreover, these receptor sites can be molecular targets for the development of effective medication for cocaine use disorder.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107797DOI Listing
May 2021

Glutamate homeostasis and dopamine signaling: Implications for psychostimulant addiction behavior.

Neurochem Int 2021 03 5;144:104896. Epub 2020 Nov 5.

Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA. Electronic address:

Cocaine, amphetamine, and methamphetamine abuse disorders are serious worldwide health problems. To date, there are no FDA-approved medications for the treatment of these disorders. Elucidation of the biochemical underpinnings contributing to psychostimulant addiction is critical for the development of effective therapies. Excitatory signaling and glutamate homeostasis are well known pathophysiological substrates underlying addiction-related behaviors spanning multiple types of psychostimulants. To alleviate relapse behavior to psychostimulants, considerable interest has focused on GLT-1, the major glutamate transporter in the brain. While many brain regions are implicated in addiction behavior, this review focuses on two regions well known for their role in mediating the effects of cocaine and amphetamines, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). In addition, because many investigators have utilized Cre-driver lines to selectively control gene expression in defined cell populations relevant for psychostimulant addiction, we discuss potential off-target effects of Cre-recombinase that should be considered in the design and interpretation of such experiments.
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http://dx.doi.org/10.1016/j.neuint.2020.104896DOI Listing
March 2021

A Rat Model of Cocaine-Alcohol Polysubstance Use Reveals Altered Cocaine Seeking and Glutamate Levels in the Nucleus Accumbens.

Front Neurosci 2020 18;14:877. Epub 2020 Aug 18.

Psychology Department, University of Florida, Gainesville, FL, United States.

Preclinical models of cocaine use disorder are widely utilized to identify neuroadaptations underlying cocaine seeking and to screen medications to reduce seeking. However, while the majority of cocaine users engage in poly-substance use (PSU), a minority of preclinical studies employ PSU models. We previously reported that when rats consume alcohol after daily intravenous cocaine self-administration, nucleus accumbens (NA) core basal glutamate levels are reduced below those of rats that consumed only cocaine, and do not increase during cue + cocaine-primed reinstatement of cocaine-seeking. Here we used the same model of sequential cocaine and alcohol self-administration to test the hypothesis that a similar pattern of glutamate changes would be observed in the NA core prior to and during a cocaine-primed reinstatement test. Rats underwent intravenous cocaine self-administration followed by access to unsweetened alcohol in the home cage for 12 days. Rats underwent a minimum of 12 daily extinction sessions prior to a cocaine-primed reinstatement test conducted during microdialysis procedures. Contrary to our previous work using the same model, here we found that access to alcohol increased cocaine intake and increased responding during early extinction training. We found that as in our previous work, cocaine + alcohol-consuming rats displayed basal glutamate levels below those of rats that self-administered only cocaine. During the cocaine-primed reinstatement test, rats that consumed only cocaine displayed increased glutamate efflux in the NA core while those that consumed cocaine + alcohol did not. These results indicate that preclinical models of PSU should be utilized to develop experimental therapeutics for the reduction of cocaine seeking.
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http://dx.doi.org/10.3389/fnins.2020.00877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488193PMC
August 2020

Hypothalamic-pituitary-adrenal axis activity in post-traumatic stress disorder and cocaine use disorder.

Stress 2020 11 24;23(6):638-650. Epub 2020 Aug 24.

Psychology Department, University of Florida, Gainesville, FL, USA.

Post-traumatic stress disorder (PTSD) is often comorbid with cocaine use disorder (CUD), but little is known about hypothalamic-pituitary-adrenal (HPA) axis function in PTSD + CUD. Here we review the clinical and pre-clinical literature of PTSD and CUD with the goal of generating hypotheses about HPA axis activity in comorbid PTSD + CUD. Low glucocorticoid (CORT) levels immediately after trauma exposure are associated with PTSD. CORT administered within 12 h of trauma exposure reduces later PTSD symptoms. Weeks-years after trauma, meta-analyses find lower CORT levels in patients with PTSD relative to never-traumatized controls; the same is found in a pre-clinical model of PTSD. In rodents, reduced basal CORT levels are consistently found after chronic cocaine self-administration. Conversely, increased CORT levels are found in CUD patients during the first 2 weeks of cocaine abstinence. There is evidence for CORT hyper-suppression after dexamethasone, high glucocorticoid receptor (GR) number pre-trauma, and increased GR translocation to the nucleus in PTSD. Hyper-suppression of HPA axis activity after dexamethasone suggests that PTSD individuals may have increased anterior pituitary GR. Given evidence for decreased anterior pituitary GR in rats that self-administer cocaine, PTSD + CUD individuals may have normal GR density and low basal CORT levels during late abstinence. Future studies should aim to reconcile the differences in pre-clinical and clinical basal CORT levels during cocaine and assess HPA axis function in both rodent models of CUD that consider stress-susceptibility and in PTSD + CUD individuals. Although additional studies are necessary, individuals with PTSD + CUD may benefit from behavioral and psychopharmacological treatments to normalize HPA axis activity. LAY SUMMARY Post-traumatic stress disorder (PTSD) is often comorbid with cocaine use disorder (CUD), but little is known about the hypothalamic-pituitary-adrenal (HPA) axis function in PTSD + CUD. The current review provides a synthesis of available clinical and pre-clinical data on PTSD and CUD with the goal of generating hypotheses about HPA axis activity in comorbid PTSD + CUD. While this review finds ample evidence supporting aberrant HPA axis activity in both PTSD and CUD, it suggests that more research is needed to understand the unique changes HPA axis activity in PTSD + CUD, as well as the bidirectional relationship between stress-susceptibility and motivation to seek cocaine.
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http://dx.doi.org/10.1080/10253890.2020.1803824DOI Listing
November 2020

Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cue-induced cocaine seeking.

Addict Biol 2021 03 18;26(2):e12928. Epub 2020 Jun 18.

Department of Psychology, University of Florida, Gainesville, Florida, USA.

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed cocaine seeking but NA core glutamate efflux still increases. Here, we sought to determine if the same would occur when cocaine seeking is prompted by both context and discrete cues (cue-induced seeking) after cocaine abstinence. Male rats self-administered intravenous cocaine accompanied by drug-associated cues (light + tone) for 2 h/day for 14 days. Rats then experienced abstinence with daily handling but no extinction training for 2 weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a cue-induced cocaine seeking test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both cue-induced cocaine seeking and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when cocaine seeking is induced by drug-associated cues, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.
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http://dx.doi.org/10.1111/adb.12928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746580PMC
March 2021

Molecular changes evoked by the beta-lactam antibiotic ceftriaxone across rodent models of substance use disorder and neurological disease.

Neurosci Biobehav Rev 2020 08 30;115:116-130. Epub 2020 May 30.

Department of Psychology, University of Florida, 945 Center Dr., Gainesville, FL, 32611, USA; Center for Addiction Research and Education, University of Florida, Gainesville, FL, 32611, USA. Electronic address:

Ceftriaxone is a beta-lactam antibiotic that increases the expression of the major glutamate transporter, GLT-1. As such, ceftriaxone ameliorates symptoms across multiple rodent models of neurological diseases and substance use disorders. However, the mechanism behind GLT-1 upregulation is unknown. The present review synthesizes this literature in order to identify commonalities in molecular changes. We find that ceftriaxone (200 mg/kg for at least two days) consistently restores GLT-1 expression in multiple rodent models of neurological disease, especially when GLT-1 is decreased in the disease model. The same dose given to healthy/drug-naive rodents does not reliably upregulate GLT-1 in any brain region except the hippocampus. Increased GLT-1 expression does not consistently arise from transcriptional regulation, and is likely to be due to trafficking changes. In addition to altered transporter expression, ceftriaxone ameliorates neuropathologies (e.g. tau, amyloid beta, cell death) and aberrant protein expression associated with a number of neurological disease models. Taken together, these results indicate that ceftriaxone remains a strong candidate for treatment of multiple disorders in the clinic.
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http://dx.doi.org/10.1016/j.neubiorev.2020.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483567PMC
August 2020

Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats.

Psychopharmacology (Berl) 2020 Jul 7;237(7):2007-2018. Epub 2020 May 7.

Department of Psychology, University of Florida, 114 Psychology, 945 Center Dr, Gainesville, FL, 32611-2250, USA.

Rationale: The beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement.

Aims: Here, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core.

Methods: Male and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing.

Results: mGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement.

Conclusions: These results indicate that ceftriaxone's effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.
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http://dx.doi.org/10.1007/s00213-020-05514-yDOI Listing
July 2020

Sequential cocaine-alcohol self-administration produces adaptations in rat nucleus accumbens core glutamate homeostasis that are distinct from those produced by cocaine self-administration alone.

Neuropsychopharmacology 2020 02 2;45(3):441-450. Epub 2019 Jul 2.

Psychology Department, University of Florida, Gainesville, FL, USA.

There are currently no FDA-approved medications to reduce cocaine relapse. The majority of preclinical studies aimed at identifying the neurobiology underlying relapse involve the self-administration of cocaine alone, whereas many, if not a majority, of cocaine users engage in polysubstance use. Here we developed a rat model of sequential cocaine and alcohol self-administration to test the hypothesis that this combination produces distinct neuroadaptations relative to those produced by cocaine alone. Male rats underwent intravenous cocaine self-administration (2 h/day) followed by 6 h access to unsweetened alcohol (20% v/v) for 12 days. After extinction training, we assessed surface expression of the glutamate transporter GLT-1 and glutamate efflux in the nucleus accumbens (NA) core during the reinstatement of cocaine-seeking. We also tested the ability of ceftriaxone to attenuate the reinstatement of cocaine-seeking and assessed reinstatement-induced Fos expression in several regions critical for reinstatement. Alcohol consumption did not alter cocaine intake, nor did access to cocaine alter alcohol consumption. However, we noted significant changes in glutamate homeostasis in the NA core of cocaine + alcohol rats relative to rats consuming cocaine alone, such as increased surface GLT-1 expression and a lack of increase in glutamate efflux during reinstatement of cocaine-seeking. A history of cocaine + alcohol also altered patterns of reinstatement-induced Fos expression. These changes likely account for the inability of ceftriaxone to attenuate cocaine relapse in cocaine + alcohol rats, while it does so in rats consuming only cocaine. As such glutamate neuroadaptations are targeted by medications to reduce cocaine relapse, preclinical models should consider polysubstance use.
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http://dx.doi.org/10.1038/s41386-019-0452-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969168PMC
February 2020

The effects of Pavlovian cue extinction and ceftriaxone on cocaine relapse after abstinence.

Drug Alcohol Depend 2019 04 13;197:83-86. Epub 2019 Feb 13.

Department of Psychology, University of Florida, Gainesville, FL, 32603, USA. Electronic address:

Background: Cocaine use disorder is a significant public health problem and currently no medications are FDA-approved to reduce cocaine relapse. Drug-associated cues are reported to elicit craving and cocaine-seeking in humans. Repeated, non-reinforced presentations of drug-associated cues (cue extinction) have been proposed to reduce the ability of such cues to prompt drug-seeking. In rodent models of cocaine relapse, cue extinction reduces cocaine relapse when such extinction occurs in the same context as cocaine self-administration, which is not akin to the manner in which treatment would occur in humans. Here we sought to determine whether cue extinction outside of the cocaine self-administration context would reduce relapse in the drug context. We also hypothesized that ceftriaxone, an antibiotic consistently shown to attenuate cocaine relapse in rats, would enhance the relapse-preventing effects of cue extinction.

Methods: Rats self-administered intravenous cocaine for 12 days followed by 20-21 days of abstinence. Immediately preceding the relapse test, rats either underwent 6 single daily cue extinction sessions (1 h/day) outside the self-administration context or no extinction with daily handling. Rats also received vehicle or ceftriaxone (200 mg/kg IP) on those six days.

Results: Ceftriaxone attenuated cued relapse relative to vehicle-treated rats, but there was no additive effect of cue extinction on cocaine-seeking. Cue extinction alone did not attenuate relapse.

Conclusions: Thus, in agreement with work in humans, when cue extinction is conducted outside the drug-associated context it does not reduce the risk of relapse alone. Ceftriaxone remains a strong possibility for medication to reduce cocaine relapse in humans.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440847PMC
April 2019

The effects of clavulanic acid and amoxicillin on cue-primed reinstatement of cocaine seeking.

Behav Neurosci 2019 Apr 4;133(2):247-254. Epub 2019 Feb 4.

Department of Psychology, University of Florida.

Research using the cocaine self-administration and reinstatement animal model of relapse finds that the beta-lactam antibiotic, ceftriaxone, attenuates cocaine-primed reinstatement of cocaine seeking and upregulates two proteins that regulate glutamate release and reuptake (xCT and GLT-1, respectively) in the nucleus accumbens core (NAc). We tested three compounds with beta-lactam rings for their ability to attenuate cue-primed reinstatement and increase GLT-1 and xCT expression in the NAc and prefrontal cortex (PFC). Rats self-administered intravenous cocaine for 1 hr/day for 7 days then 6 hrs/day for 10 days. Cue-primed reinstatement tests began after 8-9 days of extinction training. Rats received oral vehicle, clavulanic acid (CA), amoxicillin (AMX), or CA + AMX (Augmentin; AUG) for 5 days prior to testing. Only AMX-treated rats demonstrated a reduction of cocaine-seeking that trended toward significance, warranting future investigation of a wider range of doses. In the NAc, GLT-1a expression was reduced in vehicle-treated rats relative to cocaine-naïve controls and was not restored by AMX or AUG. CA-treated rats reinstated more than vehicle-treated rats and exhibited GLT-1a and xCT expression intermediate between cocaine-naïve controls and vehicle-treated cocaine rats. In agreement with our previous work, cocaine did not decrease PFC GLT-1a expression. Cocaine reduced xCT expression in the PFC that was unchanged by any of the three compounds. These results indicate that AMX may be another beta-lactam that attenuates cocaine relapse. Furthermore, the upregulation of both GLT-1 and xCT in the NAc may be needed to attenuate cocaine seeking. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508097PMC
April 2019

A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors.

Transl Psychiatry 2018 10 5;8(1):209. Epub 2018 Oct 5.

Psychology Department, University of Florida, Gainesville, FL, 32611, USA.

PTSD is highly comorbid with cocaine use disorder (CUD), and cocaine users with PTSD + CUD are more resistant to treatment. Here we sought to develop a rat model of PTSD + CUD in order to identify the neurobiological changes underlying such comorbidity and screen potential medications for reducing cocaine seeking in the PTSD population. We utilized a predator scent stress model of PTSD, wherein rats received a single exposure to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). One week after TMT exposure, stress-susceptible (susceptible), intermediate, and resilient phenotypes were detected and were consistent with behavioral, corticosterone, and gene expression profiles 3 weeks post TMT. We assessed phenotypic differences in cocaine self-administration, extinction, and cue-primed reinstatement. Susceptible rats exhibited deficits in extinction learning and increased cue-primed reinstatement that was not prevented by Ceftriaxone, an antibiotic that consistently attenuates the reinstatement of cocaine seeking. TMT-exposed resilient rats displayed increased mGlu5 gene expression in the amygdala and medial prefrontal cortex and did not display the enhanced cocaine seeking observed in susceptible rats. Combined treatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1 H-pyrazol-5-yl)benzamide (CDPPB), fear extinction, and ceftriaxone prevented the reinstatement of cocaine seeking in susceptible rats with fear extinction an important mediating condition. These results highlight the need for animal models of PTSD to consider stress-responsivity, as only a subset of trauma-exposed individuals develop PTSD and these individuals likely exhibit distinct neurobiological changes compared with trauma-exposed populations who are resilient to stress. This work further identifies glutamate homeostasis and mGlu5 as a target for treating relapse in comorbid PTSD-cocaine addiction.
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http://dx.doi.org/10.1038/s41398-018-0265-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173705PMC
October 2018

Impairments in reversal learning following short access to cocaine self-administration.

Drug Alcohol Depend 2018 11 25;192:239-244. Epub 2018 Sep 25.

Department of Psychology, University of Florida, 945 Center Dr., Gainesville, FL, 32611, United States.

Background: Cocaine use disorder is characterized by compulsive drug-seeking that persists long into abstinence. Work using rodent models of cocaine addiction has found evidence for reversal learning deficits 21 days after non-contingent cocaine administration and 60 days after self-administration. Here we sought to determine if a deficit in reversal learning is present 3-4 weeks after cessation of cocaine self-administration, when relapse to cocaine-seeking is robust. Conversely, we hypothesized that reversal learning training would protect against relapse, similar to other forms of environmental enrichment.

Methods: Male rats underwent short access (ShA, 2 h/10d) or long access (LgA, 1 h/7d then 6 h/10d) cocaine self-administration, followed by 21-29 days of abstinence. During abstinence, a subset of rats underwent training in a plus-maze that required an egocentric strategy to earn a sucrose reward. Following response acquisition and retention, the ability to reverse the spatial navigation strategy was tested.

Results: Total trials to criteria and total errors made did not differ between the groups during response acquisition, retention, or reversal. On the first reversal test, ShA rats performed better than LgA and control rats. ShA rats' performance worsened over time. There were no effects of cognitive training or length of cocaine access on context-primed relapse of cocaine-seeking.

Conclusions: The present data indicate that perhaps LgA cocaine self-administration does not produce adaptations to regions mediating context-primed relapse as it does for cocaine and cocaine-associated cue-induced reinstatement of drug-seeking. A time-dependent deficit in reversal learning was found only in ShA rats. Reversal learning training did not protect against cocaine relapse.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200584PMC
November 2018

The importance of considering polysubstance use: lessons from cocaine research.

Drug Alcohol Depend 2018 11 1;192:16-28. Epub 2018 Sep 1.

Department of Psychology, University of Florida, 945 Center Dr., P.O. Box 112250, Gainesville, FL 32611, USA; Center for Addiction Research and Education, Gainesville, FL 32611, USA. Electronic address:

Background: Polysubstance use (PSU) is prevalent among individuals with substance use disorders, but the vast majority of preclinical substance use research has focused on individual substances in isolation. Cocaine has been prevalent in the repertoire of persons who use more than one illicit substance.

Methods: We conducted a meta-analysis combining results from literature searches and secondary data analyses to estimate the prevalence of simultaneous and concurrent cocaine + alcohol and cocaine + cannabis use among cocaine users. We next summarized the small body of literature on behavioral, cognitive and neurobiological consequences of cocaine PSU across species, with a focus on alcohol and cannabis. Finally, we used systematic literature searches to assess the extent to which human and animal studies on the neurobiological consequences of cocaine include PSU subjects.

Results: The estimated prevalence of simultaneous and concurrent alcohol use among human cocaine users was 74% and 77%, respectively. The estimated prevalence of simultaneous and concurrent cannabis use among cocaine users was 38% and 64%, respectively. Consumption of alcohol or cannabis with cocaine enhances subjective responses to cocaine, concomitant with changes in cocaine metabolism that increase blood cocaine levels, and, in the case of alcohol, produce the psychoactive metabolite cocaethylene. There is also consistent evidence for neurobiological effects of cocaine + alcohol combinations. However, animal PSU research with cocaine lags behind human research.

Conclusion: Based on the prevalence and known consequences of PSU, consideration of PSU in both human and animal research is vital for understanding patterns of substance use.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450360PMC
November 2018

Dose-dependent reduction in cocaine-induced locomotion by Clozapine-N-Oxide in rats with a history of cocaine self-administration.

Neurosci Lett 2018 05 20;674:132-135. Epub 2018 Mar 20.

Psychology Department, University of Florida, Gainesville FL 32611, United States; Center for Addiction Research and Education, University of Florida, Gainesville, FL 32611, United States. Electronic address:

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are novel tools for the dissection of circuitry mediating behavior and neural function. Designer receptors based on the muscarinic M3 and M4 subtypes were designed to be activated by clozapine-N-oxide (CNO), a ligand previously shown to be an inert metabolite of clozapine. However, recent work in rats has shown that CNO is reverse metabolized to its parent compound. Furthermore, CNO administration (5 mg/kg IP) attenuates amphetamine-induced locomotion and the evoked dopamine response that accompanies it. As these systems are routinely used to probe the neurocircuitry underlying cocaine-seeking behavior, here we sought to determine whether CNO would have similar effects on cocaine-induced locomotion in rats with a history of cocaine self-administration. In order for muscarinic-based DREADDs to be utilized for the dissection of circuitry underlying behavioral responses to cocaine, the doses of CNO administered to induce DREADD signaling must themselves have no effect on cocaine-induced behavior. Male Sprague-Dawley rats self-administered cocaine (0.35 mg/infusion) for 12 days, followed by 14-21 days of instrumental extinction training. Rats then underwent locomotor testing. CNO (0, 3, or 5 mg/kg) was injected (utilizing a within-subjects design), followed 20 min later by cocaine (10 mg/kg IP). Locomotion was monitored for the following 120 min. We found that the 5, but not the 3 mg/kg, dose of CNO reduced cocaine-induced locomotion. Thus, studies utilizing DREAADs to probe cocaine-induced behavior should consider these findings when choosing a dose of CNO and include non-DREADD CNO controls.
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http://dx.doi.org/10.1016/j.neulet.2018.03.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899660PMC
May 2018

Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement.

Neuropharmacology 2018 06 20;135:297-307. Epub 2018 Mar 20.

Psychology Department, University of Florida, Gainesville, FL, United States; Center for Addiction Research and Education, University of Florida, Gainesville, FL, United States.

Cocaine use disorder is a chronically relapsing disease without FDA-approved treatments. Using a rodent model of cocaine relapse, we and others have previously demonstrated that the beta-lactam antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Ceftriaxone restores cocaine-induced deficits in both system xc- and GLT-1 expression and function in the nucleus accumbens core (NAc). We recently demonstrated that restoration of GLT-1 expression in the NAc is necessary for ceftriaxone to attenuate reinstatement of cocaine-seeking. Here we used an adeno-associated virus (AAV) to overexpress GLT-1a in the NAc to investigate whether such restoration is sufficient to attenuate cue- and cocaine-primed reinstatement. Rats self-administered cocaine for two weeks and received injections of either AAV-GFAP-GLT-1a or AAV-GFAP-eGFP in the NAc following the last day of self-administration. Rats then underwent three weeks of extinction training (during which time transduction and expression occurred) before undergoing a cue- or cocaine-primed reinstatement test. Microdialysis for the quantification of glutamate efflux in the NAc was conducted during the cocaine-primed test. Rats that received AAV-GFAP-GLT-1a reinstated cue-primed cocaine-seeking in a similar manner as rats that received the control AAV-GFAP-eGFP. Upregulation of GLT-1a attenuated glutamate efflux during a cocaine-primed reinstatement test, but was not sufficient to attenuate reinstatement. We confirmed that GLT-1a upregulation resulted in functional upregulation of glutamate transport and expression, without affecting sodium-independent glutamate uptake, indicating system xc-was not altered. These results indicate that upregulation of NAc GLT-1 transporters alone is not sufficient to prevent the reinstatement of cocaine-seeking and implicate additional mechanisms in regulating glutamate efflux.
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http://dx.doi.org/10.1016/j.neuropharm.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383073PMC
June 2018

The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens.

Psychopharmacology (Berl) 2018 03 2;235(3):837-848. Epub 2017 Dec 2.

Department of Psychology, University of Florida, 114 Psychology, 945 Center Dr, Gainesville, FL, 32611-2250, USA.

Rationale: Effective pharmacological treatments to prevent cocaine relapse remain elusive. In male rats, ceftriaxone attenuates the reinstatement of cocaine-seeking while increasing glutamate transporter-1 (GLT-1) and xCT expression in the nucleus accumbens core (NAc). Despite reported sex differences in cocaine relapse, these effects have not yet been confirmed in female rats.

Objective: We investigated the effects of ceftriaxone on cue-primed reinstatement and cocaine-induced alterations in glutamatergic proteins in the NAc of female rats. Potential interactions between estrous phase and treatment were also assessed.

Method: Male and female rats self-administered cocaine in the presence of discrete cues for 12 days, followed by 2-3 weeks of extinction. Ceftriaxone or vehicle was administered daily for a minimum of 6 days immediately preceding a cue-primed reinstatement test.

Results: Total cocaine intake was greater in females than in males, but reinstatement behavior was similar. Ceftriaxone attenuated reinstatement in both sexes and was accompanied by increased expression of GLT-1a and xCT in the NAc. However, ceftriaxone attenuated reinstatement only when females were tested during met-, di-, and proestrus phases and not during estrus. A significant increase in AMPA receptor subunit GluA1 surface expression was also observed during estrus, potentially influencing reinstatement.

Conclusion: These findings extend the beneficial effects of ceftriaxone on persistent cocaine-seeking from males to females, increasing its potential as a pharmacological treatment for preventing relapse. The effects of estrus on GluA1 expression and reinstatement observed here indicate that females may need additional interventions during some phases of the menstrual cycle.
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http://dx.doi.org/10.1007/s00213-017-4802-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893281PMC
March 2018

Ceftriaxone reduces alcohol intake in outbred rats while upregulating xCT in the nucleus accumbens core.

Pharmacol Biochem Behav 2017 08 4;159:18-23. Epub 2017 Jul 4.

Psychology Department, University of Florida, Gainesville, FL, United States.

Alcohol addiction is a chronic disease characterized by an inability to regulate drinking. A critical brain region involved in alcohol consumption is the nucleus accumbens (NA). Glutamate transmission in this region regulates alcohol consumption and relapse to alcohol-seeking. Across multiple alcohol-administration rodent models, basal extracellular glutamate levels are increased in the NA during early withdrawal. Glutamate transporter 1 (GLT-1) and system x-, containing the subunit xCT, regulate NA glutamate levels. Ceftriaxone (Cef) increases expression and function of both transporters following extinction from cocaine self-administration and here we sought to determine if Cef would similarly decrease alcohol consumption while increasing xCT and GLT-1 in the NA core. We used the intermittent access to alcohol (IAA) paradigm to induce drinking in outbred Sprague-Dawley rats; this paradigm permits rats access to alcohol (20%v/v) for 24-h without water deprivation, followed by 24-h of abstinence. Following 17 24-h drinking sessions, Cef treatment (200mg/kg IP) was initiated and continued for 5days while a control group received vehicle (0.9% saline IP). Alcohol consumption was assessed for two 24-h periods during Cef and two 24-h periods after cessation of Cef treatment. In a separate cohort of rats, Cef's ability to alter blood alcohol levels (BALs) after a non-contingent alcohol injection (1g/kg) was assessed. We found that Cef decreased alcohol consumption during the period of Cef treatment and on the two days following injections, and this was accompanied by an increase in NA core xCT expression. Furthermore, a history of alcohol consumption did not alter xCT and GLT-1 expression relative to alcohol-naïve controls. Cef did not alter BALs, indicating that the reduction in alcohol consumption was not caused by altered alcohol clearance. These results indicate that while Cef reduces alcohol consumption in outbred rats, its ability to do so is not associated with an increase in GLT-1 expression.
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http://dx.doi.org/10.1016/j.pbb.2017.07.001DOI Listing
August 2017

Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression.

J Neurosci 2017 06 11;37(24):5809-5821. Epub 2017 May 11.

Psychology Department, University of Florida, Gainesville, Florida 32611,

Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1 and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased the expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism, and their coregulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for coregulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as being a key mediator of AMPA receptor expression in the NAc. Ceftriaxone attenuates the reinstatement of cocaine, alcohol, and heroin seeking. The mechanism of action of this behavioral effect has been attributed to glutamate transporter 1 (GLT-1) and xCT (a catalytic subunit of Sxc)/Sxc upregulation in the nucleus accumbens core. Here we used an antisense strategy to knock down GLT-1 or xCT in the nucleus accumbens core and examined the behavioral and molecular consequences. While upregulation of both xCT and GLT-1 are essential to the ability of ceftriaxone to attenuate cue-induced reinstatement of cocaine seeking, each protein uniquely affects the expression of other glutamate receptor and transporter proteins. We also report that reducing basal glutamate levels through the manipulation of xCT expression increases the surface expression of AMPA receptor subunits, providing insight to the mechanism by which cocaine alters AMPA surface expression.
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http://dx.doi.org/10.1523/JNEUROSCI.3717-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473201PMC
June 2017

Alcohol consumption increases basal extracellular glutamate in the nucleus accumbens core of Sprague-Dawley rats without increasing spontaneous glutamate release.

Eur J Neurosci 2016 07 6;44(2):1896-905. Epub 2016 Jun 6.

Psychology Department, University of Florida, PO Box 112250, Gainesville, FL, 332611, USA.

Glutamate neurotransmission in the nucleus accumbens core (NAc) mediates ethanol consumption. Previous studies using non-contingent and voluntary alcohol administration in inbred rodents have reported increased basal extracellular glutamate levels in the NAc. Here, we assessed basal glutamate levels in the NAc following intermittent alcohol consumption in male Sprague-Dawley rats that had access to ethanol for 7 weeks on alternating days. We found increased basal NAc glutamate at 24 h withdrawal from ethanol and thus sought to identify the source of this glutamate. To do so, we employed a combination of microdialysis, slice electrophysiology and western blotting. Reverse dialysis of the voltage-gated sodium channel blocker tetrodotoxin did not affect glutamate levels in either group. Electrophysiological recordings in slices made after 24 h withdrawal revealed a decrease in spontaneous excitatory postsynaptic current (sEPSC) frequency relative to controls, with no change in sEPSC amplitude. No change in metabotropic glutamate receptor 2/3 (mGlu2/3) function was detected as bath application of the mGlu2/3 agonist LY379268 decreased spontaneous and miniature EPSC frequency in slices from both control and ethanol-consuming rats. The increase in basal glutamate was not associated with changes in the surface expression of GLT-1, however, a decrease in slope of the no-net-flux dialysis function was observed following ethanol consumption, indicating a potential decrease in glutamate reuptake. Taken together, these findings indicate that the increase in basal extracellular glutamate occurring after chronic ethanol consumption is not mediated by an increase in action potential-dependent glutamate release or a failure of mGlu2/3 autoreceptors to regulate such release.
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http://dx.doi.org/10.1111/ejn.13284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620661PMC
July 2016

Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats.

Stress 2016 07 3;19(4):406-18. Epub 2016 Jun 3.

a Department of Psychology , University of Florida , Gainesville , FL , USA ;

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.
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http://dx.doi.org/10.1080/10253890.2016.1189898DOI Listing
July 2016

mGlu5 Receptors and Relapse to Cocaine-Seeking: The Role of Receptor Trafficking in Postrelapse Extinction Learning Deficits.

Neural Plast 2016 10;2016:9312508. Epub 2016 Jan 10.

Psychology Department, University of Florida, Gainesville, FL 32611, USA.

We have previously demonstrated that MTEP, an allosteric antagonist of mGlu5, infused into the nucleus accumbens attenuates relapse after abstinence from cocaine self-administration. MTEP infused into the dorsolateral striatum (dlSTR) does not alter relapse but has long-lasting effects on subsequent extinction learning. Here we tested whether systemic MTEP would prevent relapse after abstinence or alter extinction learning. We also investigated the mechanism of action by which intra-dlSTR MTEP on test day alters extinction on subsequent days. Animals self-administered cocaine for 12 days followed by abstinence for 20-21 days. MTEP (0.5-5 mg/kg IP) was administered prior to placement into the operant chamber for a context-primed relapse test. A separate group of animals received intra-dlSTR MTEP prior to the relapse test and were sacrificed day later. Systemic administration of MTEP attenuated abstinent-relapse without significantly affecting extinction learning. Surface biotinylation analysis of protein expression in the dlSTR revealed that, in cocaine animals, intra-dlSTR MTEP administration decreased mGlu5 surface expression and prevented changes in Arc and GluA1/GluA2 observed in their vehicle counterparts. Thus, blockade of mGlu5 receptors may be utilized in future treatment strategies for relapse prevention in humans, although the effects of chronic blockade on extinction learning should be further evaluated.
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http://dx.doi.org/10.1155/2016/9312508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736983PMC
December 2016

Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

Eur Neuropsychopharmacol 2016 Feb 10;26(2):186-194. Epub 2015 Dec 10.

Psychology Department, University of Florida, Gainesville, FL, United States. Electronic address:

Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux.
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http://dx.doi.org/10.1016/j.euroneuro.2015.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762719PMC
February 2016

Ceftriaxone and cefazolin attenuate the cue-primed reinstatement of alcohol-seeking.

Front Pharmacol 2015 10;6:44. Epub 2015 Mar 10.

Department of Neuroscience, Medical University of South Carolina Charleston, SC, USA.

Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone.
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http://dx.doi.org/10.3389/fphar.2015.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354333PMC
March 2015

Repeated cycles of chronic intermittent ethanol exposure increases basal glutamate in the nucleus accumbens of mice without affecting glutamate transport.

Front Pharmacol 2015 23;6:27. Epub 2015 Feb 23.

Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina , Charleston, SC, USA ; Department of Neurosciences, Medical University of South Carolina , Charleston, SC, USA ; Ralph H. Johnson VA Medical Center , Charleston, SC, USA.

Repeated cycles of chronic intermittent ethanol (CIE) exposure increase voluntary consumption of ethanol in mice. Previous work has shown that extracellular glutamate in the nucleus accumbens (NAc) is significantly elevated in ethanol-dependent mice and that pharmacologically manipulating glutamate concentrations in the NAc will alter ethanol drinking, indicating that glutamate homeostasis plays a crucial role in ethanol drinking in this model. The present studies were designed to measure extracellular glutamate at a time point in which mice would ordinarily be allowed voluntary access to ethanol in the CIE model and, additionally, to measure glutamate transport capacity in the NAc at the same time point. Extracellular glutamate was measured using quantitative microdialysis procedures. Glutamate transport capacity was measured under Na(+)-dependent and Na(+)-independent conditions to determine whether the function of excitatory amino acid transporters (also known as system XAG) or of system Xc (-) (glial cysteine-glutamate exchanger) was influenced by CIE exposure. The results of the quantitative microdialysis experiment confirm increased extracellular glutamate (approximately twofold) in the NAc of CIE exposed mice (i.e., ethanol-dependent) compared to non-dependent mice in the NAc, consistent with earlier work. However, the increase in extracellular glutamate was not due to altered transporter function in the NAc of ethanol-dependent mice, because neither Na(+)-dependent nor Na(+)-independent glutamate transport was significantly altered by CIE exposure. These findings point to the possibility that hyperexcitability of cortical-striatal pathways underlies the increases in extracellular glutamate found in the ethanol-dependent mice.
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http://dx.doi.org/10.3389/fphar.2015.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337330PMC
March 2015

Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.

Addict Biol 2015 Mar 25;20(2):316-23. Epub 2014 Feb 25.

Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA; Department of Psychology, University of North Carolina, Chapel Hill, NC, USA.

Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.
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http://dx.doi.org/10.1111/adb.12127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437505PMC
March 2015

Addicted to palatable foods: comparing the neurobiology of Bulimia Nervosa to that of drug addiction.

Psychopharmacology (Berl) 2014 May 6;231(9):1897-912. Epub 2014 Feb 6.

Department of Psychology, University of Florida, P.O. Box 112250, Gainesville, FL, 32611-2250, USA.

Rationale: Bulimia nervosa (BN) is highly comorbid with substance abuse and shares common phenotypic and genetic predispositions with drug addiction. Although treatments for the two disorders are similar, controversy remains about whether BN should be classified as addiction.

Objectives: Here, we review the animal and human literature with the goal of assessing whether BN and drug addiction share a common neurobiology.

Results: Similar neurobiological features are present following administration of drugs and bingeing on palatable food, especially sugar. Specifically, both disorders involve increases in extracellular dopamine (DA), D1 binding, D3 messenger RNA (mRNA), and ΔFosB in the nucleus accumbens (NAc). Animal models of BN reveal increases in ventral tegmental area (VTA) DA and enzymes involved in DA synthesis that resemble changes observed after exposure to addictive drugs. Additionally, alterations in the expression of glutamate receptors and prefrontal cortex activity present in human BN or following sugar bingeing in animals are comparable to the effects of addictive drugs. The two disorders differ in regards to alterations in NAc D2 binding, VTA DAT mRNA expression, and the efficacy of drugs targeting glutamate to treat these disorders.

Conclusions: Although additional empirical studies are necessary, the synthesis of the two bodies of research presented here suggests that BN shares many neurobiological features with drug addiction. While few Food and Drug Administration-approved options currently exist for the treatment of drug addiction, pharmacotherapies developed in the future, which target the glutamate, DA, and opioid systems, may be beneficial for the treatment of both BN and drug addiction.
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http://dx.doi.org/10.1007/s00213-014-3461-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484591PMC
May 2014

The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning.

Addict Biol 2014 Jan 27;19(1):87-101. Epub 2013 May 27.

Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.

Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7-10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration.
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http://dx.doi.org/10.1111/adb.12061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762937PMC
January 2014

Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training.

J Neurosci 2012 Sep;32(36):12406-10

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

Decreased basal glutamate levels are observed in the rat nucleus accumbens (NA) core following cocaine self-administration. This disruption of glutamate homeostasis arises from a reduction in the export of glutamate via system x(C)(-) and is accompanied by a decrease in expression of xCT, the catalytic subunit of system x(C)(-). A second hallmark of disrupted homeostasis is a decrease in expression and function of the major glutamate transporter, GLT-1. We have previously shown that chronic treatment with the antibiotic ceftriaxone restores xCT and GLT-1 expression following cocaine self-administration and attenuates both cue- and cocaine-primed reinstatement. Here we used a (3)H-glutamate uptake assay and microdialysis to test the hypothesis that ceftriaxone restores the function of both GLT-1 and xCT (glutamate reuptake and export, respectively) in the NA core following cocaine self-administration. We also used electrophysiology to investigate the ability of ceftriaxone to normalize measures of synaptic plasticity following cocaine. We found that 5 d of ceftriaxone treatment following cocaine self-administration restores basal glutamate levels in the accumbens core, likely through an upregulation of system x(C)(-) function. We also found that ceftriaxone restores glutamate reuptake and attenuates the increase in synaptically released glutamate that accompanies cocaine-primed reinstatement. Ceftriaxone also reversed the cocaine-induced synaptic potentiation in the accumbens core, evidenced by normalized spontaneous EPSC amplitude and frequency and evoked EPSC amplitude. These data indicate that ceftriaxone normalizes multiple aspects of glutamate homeostasis following cocaine self-administration and thus holds the potential to reduce relapse in human cocaine addicts.
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http://dx.doi.org/10.1523/JNEUROSCI.1976-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465971PMC
September 2012