Publications by authors named "Nathan S Pentkowski"

35 Publications

Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology.

Neurosci Biobehav Rev 2021 May 9;127:647-658. Epub 2021 May 9.

Department of Psychology, University of New Mexico, Albuquerque, NM, 87109, Mexico. Electronic address:

Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.005DOI Listing
May 2021

Chemogenetic inhibition of ventral hippocampal CaMKIIα-expressing neurons attenuates anxiety- but not fear-like defensive behaviors in male Long-Evans hooded rats.

Neurosci Lett 2021 04 26;751:135777. Epub 2021 Feb 26.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States. Electronic address:

Previous research has implicated the ventral pole of the hippocampus in regulating anxiety. However, most rat studies examining the specific contribution of the ventral hippocampus have utilized techniques that have nonspecific effects and/or create nonreversible damage to the region. The present study sought to characterize the role of ventral hippocampal CaMKIIα-expressing neurons in modulating anxiety- and fear-like behavior during exposure to a variety of threatening stimuli. Five weeks prior to testing, adult male Long-Evans hooded rats received ventral hippocampal viral-vector infusions expressing either AAV8-CaMKIIα-hM4D-mCherry (DREADD) or AAV8-CaMKIIα-EGFP (GFP). DREADD transfection allowed for the specific, noninvasive and temporary inhibition of the ventral hippocampus (vHC) immediately before threat presentation. Rats were evaluated for behaviors congruent with anxiety- or fear-like defensive states during testing in the elevated plus-maze (EPM) and light-dark test (LDT), or post footshock freezing and footshock-induced contextual freezing, respectively. Analyses revealed a significant effect of vHC inhibition that was dependent on the type of threat exposure. Specifically, DREADD-induced silencing of vHC neurons reduced anxiety-like behavior in the EPM and LDT, without reliably affecting footshock-induced fear. These data add to a growing literature implicating the vHC as a key region involved in controlling the expression of anxiety in rodents, primates and humans.
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http://dx.doi.org/10.1016/j.neulet.2021.135777DOI Listing
April 2021

Methamphetamine and social rewards interact to produce enhanced conditioned place preference in male adolescent rats.

Pharmacol Biochem Behav 2021 02 14;201:173091. Epub 2020 Dec 14.

University of New Mexico, Department of Psychology, 1-University of New Mexico, MSC03-2220, Albuquerque, NM 87131, USA. Electronic address:

Elucidating the influence of social context on drug reward is critical for understanding substance use disorders. Adolescents demonstrate enhanced sensitivity to drug and social rewards. However, the extent to which methamphetamine interacts with social reward in adolescents has not been thoroughly examined. Therefore, the present study used the conditioned place preference (CPP) model to examine the relationship between methamphetamine and social rewards in adolescent male rats. Sprague-Dawley rats (PND 30) were randomly assigned to one of the following four conditioning groups: saline alone (SA), methamphetamine alone (MA), saline with a social partner (SS) or methamphetamine with a social partner (MS). Testing occurred in a two-chamber biased apparatus across seven consecutive days using parameters presumed to be sub-threshold for establishing social- and methamphetamine-induced CPP. Similar to previous reports for nicotine and cocaine, the present results indicate that rats receiving methamphetamine with a social partner (i.e., MS) during conditioning demonstrated a significantly greater preference shift compared to all other groups. These findings further highlight the importance of social context in influencing the magnitude of drug reward during adolescence.
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http://dx.doi.org/10.1016/j.pbb.2020.173091DOI Listing
February 2021

Coyote urine, but not 2-phenylethylamine, induces a complete profile of unconditioned anti-predator defensive behaviors.

Physiol Behav 2021 02 14;229:113210. Epub 2020 Oct 14.

Department of Psychology, University of New Mexico, Albuquerque, New Mexico, USA. Electronic address:

Predator odors from various sources (e.g. fur/skin, urine, feces) provide prey animals valuable information that allows them to gage potential environmental threat via the detection of semiochemicals called kairomones. However, studies in rodents have revealed inconsistent and often conflicting results, which may occur from any combination of factors, including source and freshness of the odorant, sex, and genetic strain of the prey animal and/or predator. Regardless of cause, few odorants tested, if any, have lived up to the potent unconditioned predator odor stimuli - cat fur/skin odor - that induces a complete profile of innate unconditioned defensive behaviors (e.g., avoidance, risk assessment and freezing) and produces rapid aversive conditioned responses, both of which are sensitive to standard anxiolytic/anxiogenic drugs. Therefore, the present study investigated the effectiveness of coyote urine and 2-phenylethylamine (PEA), two commercially available predator odor cues, in satisfying the first of these criteria in predator odor naïve, adult male Long-Evans hooded rats. The data revealed that coyote urine, but not PEA, was effective in inducing a complete profile of anti-predator defensive behaviors characterized by avoidance, risk assessment, freezing and a reduction in exploratory behavior. We conclude that commercially available coyote urine satisfies the first criterion of a defense inducing unconditioned predator odor stimulus. In order to fully validate the use of coyote urine as an anxiety- and/or fear-like threat stimulus, future research needs to examine whether it produces aversive conditioning and whether the defensive profile induced by the odorant responds to standard anxiolytic drugs.
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http://dx.doi.org/10.1016/j.physbeh.2020.113210DOI Listing
February 2021

Preclinical support for the therapeutic potential of zolmitriptan as a treatment for cocaine use disorders.

Transl Psychiatry 2020 08 3;10(1):266. Epub 2020 Aug 3.

School of Life Sciences, Arizona State University, Tempe, AZ, USA.

Serotonin 1B receptor (5-HTR) agonists enhance cocaine intake in rats during daily self-administration but attenuate cocaine intake after prolonged abstinence. Here we investigated whether the less selective but clinically available 5-HTR agonist, zolmitriptan, produces similar effects. Male and free-cycling female Sprague-Dawley rats were trained to lever press for cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg pellet) reinforcement until performance rates stabilized. Rats then received zolmitriptan (3.0, 5.6, and 10 mg/kg, s.c.) prior to testing for its effects on response and reinforcement rates. Under cocaine testing conditions, rats had access to the training dose for the first hour followed by a lower cocaine dose (0.075 mg/kg, i.v.) for the second hour. Zolmitriptan decreased cocaine intake at both cocaine doses and in both sexes even without a period of abstinence and without altering sucrose intake. A separate group of rats underwent identical training procedures and were tested for effects of the selective 5-HT and 5-HT receptor antagonists, SB224289 (3.2, 5.6, and 10 mg/kg, s.c.) and BRL15572 (0.3, 1.0, and 3.0 mg/kg, i.p.), respectively, alone or in combination with zolmitriptan (5.6 mg/kg, s.c.) under identical cocaine testing procedures as above. The zolmitriptan-induced decrease in cocaine intake was reversed by SB224289 and to a lesser extent by BRL15572, suggesting that the effects of zolmitriptan involve both 5-HT and 5-HT receptors. Neither zolmitriptan, SB224289, or BRL15572 altered locomotor activity at the doses effective for modulating cocaine intake. These findings suggest that zolmitriptan has potential for repurposing as a treatment for cocaine use disorders.
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http://dx.doi.org/10.1038/s41398-020-00956-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398918PMC
August 2020

Antagonizing serotonin 2A (5-HT) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats.

Drug Alcohol Depend 2020 10 10;215:108178. Epub 2020 Jul 10.

Department of Psychology, University of New Mexico, Albuquerque, New Mexico, USA. Electronic address:

Background: Methamphetamine is a highly addictive and abused psychostimulant. Symptoms of methamphetamine withdrawal including drug craving and anxiety that can drive relapse. Currently, there is no FDA approved treatment for methamphetamine use disorder, highlighting the need for research examining the neural mechanisms underlying psychostimulant-induced behaviors. Research indicates that the 5-HT receptor antagonist M100907 attenuates several psychostimulant-induced behaviors, including conditioned place preference (CPP). However, these findings have not been extended to methamphetamine. The present study investigated the effects of M100907 on acquisition of methamphetamine-CPP and methamphetamine-induced anxiety-like behavior.

Methods: Adult male rats were tested across eight consecutive days. Prior to methamphetamine administration (0 or 1 mg/kg, i.p.), rats were pretreated with their assigned dose of M100907 (0, 0.0025 .025 or 0.25 mg/kg, i.p.) and were placed into their initially non-preferred chamber. After four methamphetamine conditioning sessions, the effects of M100907 on methamphetamine-induced CPP were assessed. Following CPP testing, rats were screened for anxiety-like behaviors in the elevated plus-maze.

Results: Pretreatment with M100907 attenuated methamphetamine-induced CPP without producing any observable rewarding or aversive effects in methamphetamine naïve rats. Additionally, M100907 blocked methamphetamine-induced increases in anxiety-like behavior and attenuated some indices of anxiety in methamphetamine naïve rats.

Conclusions: Results suggest that blocking 5-HT receptors with the selective antagonist M100907 attenuates the rewarding effects of methamphetamine and does not produce any rewarding or aversive effects alone. Further, M100907 pretreatment blocked the anxiety-inducing effects of methamphetamine. Collectively, these data suggest that the 5-HT receptor subtype represents a novel target for treating methamphetamine use disorder.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108178DOI Listing
October 2020

The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model.

Life (Basel) 2020 May 18;10(5). Epub 2020 May 18.

Department of Anesthesiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.

Background: Few models exist that can control for placebo and expectancy effects commonly observed in clinical trials measuring '' pharmacodynamics. We used the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model to measure the effect of "full-spectrum" whole plant extracted hemp oil on chronic neuropathic pain sensitivity in mice.

Methods: Male BALBc mice were submitted to the FRICT-ION chronic neuropathic pain model with oral insertion through an incision in the buccal/cheek crease of 3 mm of chromic gut suture (4-0). The suture, wedged along the V2 trigeminal nerve branch, creates a continuous irritation that develops into secondary mechanical hypersensitivity on the snout. Von Frey filament stimuli on the mouse whisker pad was used to assess the mechanical pain threshold from 0-6 h following dosing among animals (n = 6) exposed to 5 μL of whole plant extracted hemp oil combined with a peanut butter vehicle (0.138 mg/kg), the vehicle alone (n = 3) 7 weeks post-surgery, or a naïve control condition (n = 3).

Results: Mechanical allodynia was alleviated within 1 h (d = 2.50, < 0.001) with a peak reversal effect at 4 h (d = 7.21, < 0.001) and remained significant throughout the 6 h observation window. There was no threshold change on contralateral whisker pad after hemp oil administration, demonstrating the localization of anesthetic response to affected areas.

Conclusion: Future research should focus on how whole plant extracted hemp oil affects multi-sensory and cognitive-attentional systems that process pain.
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http://dx.doi.org/10.3390/life10050069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281216PMC
May 2020

Moderate prenatal alcohol exposure reduces parvalbumin expressing GABAergic interneurons in the dorsal hippocampus of adult male and female rat offspring.

Neurosci Lett 2020 01 23;718:134700. Epub 2019 Dec 23.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States. Electronic address:

Prenatal alcohol exposure (PAE) negatively impacts hippocampal development and impairs hippocampal-sensitive learning and memory. However, hippocampal neural adaptations in response to moderate PAE are not completely understood. To explore the effects of moderate PAE on GABAergic interneuron expression, this study used a rat model of moderate PAE to examine the effects of PAE on parvalbumin (PARV)-positive cells in fields CA1, CA3 and the dentate gyrus (DG) of the dorsal hippocampus (dHC). Long-Evans dams were given daily access to 5 % (vol/vol) ethanol or saccharine (SAC) control solutions throughout the course of gestation. Offspring were divided into four separate groups: PAE (n = 7) or SAC (n = 7) males, or PAE (n = 8) or SAC (n = 8) females. All rats were aged to adulthood and, following testing in the Morris water task, their brains were analyzed for the expression of the GABAergic neuronal marker PARV. We report a main effect of PAE on GABAergic expression, with significant reductions in PARV-positive cells in area CA3 for males and the DG for females. There was also a trend for a reduction in PARV expressing neurons in fields CA1 and CA3 in females. The results are discussed in relation to hippocampal GABAergic interneuron function, PAE and behavior.
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http://dx.doi.org/10.1016/j.neulet.2019.134700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179818PMC
January 2020

Effects of estrus cycle stage on defensive behavior in female Long-Evans hooded rats.

Physiol Behav 2018 10 22;194:41-47. Epub 2018 Apr 22.

Department of Psychology, University of Hawaii at Manoa, 2530 Dole Street, Sakamaki C 400, Honolulu, HI 96822, USA; Pacific Biosciences Research Center, University of Hawaii at Manoa, 1993 East-West Road, Honolulu, HI 96822, USA.

This study investigated the influence of the estrus cycle in mediating cat odor-induced unconditioned and conditioned defensive behaviors in female Long-Evans hooded rats. Unconditioned defensive behaviors were assessed during predatory cue exposure; conditioned defensive behaviors were examined 24 h after threat exposure. Estrus phases were determined by microscopic examination of vaginal smears within 10 min of completing the behavioral tests. Compared to no-odor controls, female rats exposed to cat odor exhibited both unconditioned and conditioned defensive behaviors, including elevated levels of freezing, risk assessment and avoidance. Rats in proestrus and estrus exhibited reduced levels of defensive behavior during the unconditioned test trial compared to subjects in diestrus and metestrus. Specifically, estrus stages characterized by high levels of circulating estrogens and progesterone were associated with reduced immobility (i.e. freezing) and enhanced active defense (i.e. risk assessment), profiles that may enable mate seeking and subsequent reproduction in potentially dangerous or novel environments. These results suggest a specific role for ovarian hormone fluctuations in mediating unconditioned fear- and anxiety-like defensive behaviors during exposure to predatory odors.
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http://dx.doi.org/10.1016/j.physbeh.2018.04.028DOI Listing
October 2018

Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease.

Neurobiol Aging 2018 01 5;61:169-176. Epub 2017 Oct 5.

Department of Psychology, University of New Mexico, Albuquerque, NM, USA. Electronic address:

Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944488PMC
January 2018

Effects of a 5-HT Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice.

Front Syst Neurosci 2017 10;11:73. Epub 2017 Oct 10.

School of Life Sciences, Arizona State University, Tempe, AZ, United States.

5-HT receptors (5-HTRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HTR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12-13 of the chronic regimen), conditioning (days 14-19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22-34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement.The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HTR agonists may be useful anti-cocaine medications.
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http://dx.doi.org/10.3389/fnsys.2017.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641409PMC
October 2017

Effects of sex and housing on social, spatial, and motor behavior in adult rats exposed to moderate levels of alcohol during prenatal development.

Behav Brain Res 2016 10 15;313:233-243. Epub 2016 Jul 15.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States; Department of Neurosciences, University of New Mexico, Albuquerque, NM, United States. Electronic address:

Persistent deficits in social behavior, motor behavior, and behavioral flexibility are among the major negative consequences associated with exposure to ethanol during prenatal development. Prior work from our laboratory has linked moderate prenatal alcohol exposure (PAE) in the rat to deficits in these behavioral domains, which depend upon the ventrolateral frontal cortex (Hamilton et al., 2014) [20]. Manipulations of the social environment cause modifications of dendritic morphology and experience-dependent immediate early gene expression in ventrolateral frontal cortex (Hamilton et al., 2010) [19], and may yield positive behavioral outcomes following PAE. In the present study we evaluated the effects of housing PAE rats with non-exposed control rats on adult behavior. Rats of both sexes were either paired with a partner from the same prenatal treatment condition (ethanol or saccharin) or from the opposite condition (mixed housing condition). At four months of age (∼3 months after the housing manipulation commenced), social behavior, tongue protrusion, and behavioral flexibility in the Morris water task were measured as in (Hamilton et al., 2014) [20]. The behavioral effects of moderate PAE were primarily limited to males and were not ameliorated by housing with a non-ethanol exposed partner. Unexpectedly, social behavior, motor behavior, and spatial flexibility were adversely affected in control rats housed with a PAE rat (i.e., in mixed housing), indicating that housing with a PAE rat has broad behavioral consequences beyond the social domain. These observations provide further evidence that moderate PAE negatively affects social behavior, and underscore the importance of considering potential negative effects of housing with PAE animals on the behavior of critical comparison groups.
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http://dx.doi.org/10.1016/j.bbr.2016.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987176PMC
October 2016

Curiosity as an approach to ethoexperimental analysis: Behavioral neuroscience as seen by students and colleagues of Bob Blanchard.

Neurosci Biobehav Rev 2017 05 24;76(Pt B):415-422. Epub 2016 Mar 24.

Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Neuroscience Group, BBS, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA. Electronic address:

This review is a synopsis of an International Behavioral Neuroscience Society (IBNS) symposium which focused on the elements of Behavioral Neuroscience for which Robert J. Blanchard was a Pioneer, Leading Expert, Advocate, Mentor, and Sage. Bob Blanchard's work demonstrably changed our broad understanding of animal behavior, and led the way to experimental design and analysis for studies of animal behavior that helped to clarify the deep complexity and subtleties of behavior. Bob's impact on the field of Behavioral Neuroscience includes the behavior, neurocircuitry, neurochemistry, and pharmacology related to social interactions, aggressive behavior, defensive behaviors, flight, freezing, threat, attack, risk assessment, anxiety disorders, animal models, models of social behavior, and autism. The methods and designs developed by Bob Blanchard over a lifetime have been adopted by scientists around the world, and form a standard of excellence in the field. The article addresses these topics in a way that presents developments in the field, describes the newest research data, and pays tribute to a great scientist and founder of this field of work, Bob Blanchard.
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http://dx.doi.org/10.1016/j.neubiorev.2016.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035557PMC
May 2017

Effects of the 5-HT2C receptor agonist CP809101 in the amygdala on reinstatement of cocaine-seeking behavior and anxiety-like behavior.

Int J Neuropsychopharmacol 2014 Nov 1;17(11):1751-62. Epub 2014 Jul 1.

Department of Psychology,Arizona State University,950 S. McAllister, Tempe, AZ 85287,USA.

Serotonin 2C receptor (5-HT2CR) agonists attenuate reinstatement of cocaine-seeking behavior. These receptors are found throughout the limbic system, including the basolateral amygdala (BlA), which is involved in forming associations between emotional stimuli and environmental cues, and the central amygdala (CeA), which is implicated in the expression of conditioned responding to emotional stimuli. This study investigated whether 5-HT2CRs in the amygdala are involved in cue and cocaine-primed reinstatement of cocaine-seeking behavior. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) which that was paired with light and tone cues, and then subsequently they underwent daily extinction training. Rats then received bilateral microinfusions of the 5-HT2CR agonist CP809101 (0.01-1.0 μg/0.2 μl/side) into either the BlA or CeA prior to tests for cue or cocaine-primed (10 mg/kg, i.p.) reinstatement. Rats were also tested for CP809101 effects on anxiety-like behavior on the elevated plus-maze (EPM). Surprisingly, intra-BlA CP809101 had no effect on cue reinstatement, though it did increase anxiety-like behavior on the EPM. Intra-CeA infusions of CP809101 attenuated cocaine-primed reinstatement, an effect that was prevented with concurrent administration of the 5-HT2CR antagonist SB242084 (0.1 μg/0.2 μl/side). CP809101 had no effect on cue reinstatement or anxiety-like behavior on the EPM. These findings suggest that 5-HT2CRs in the BlA modulate anxiety, whereas those in the CeA modulate incentive motivational effects induced by cocaine priming injections.
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http://dx.doi.org/10.1017/S1461145714000856DOI Listing
November 2014

Pharmacological evidence for an abstinence-induced switch in 5-HT1B receptor modulation of cocaine self-administration and cocaine-seeking behavior.

ACS Chem Neurosci 2014 Mar 15;5(3):168-76. Epub 2014 Jan 15.

School of Life Sciences, Arizona State University , Box 874501, Tempe, Arizona 85287, United States.

Studies examining serotonin-1B (5-HT1B) receptor manipulations on cocaine self-administration and cocaine-seeking behavior initially seemed discrepant. However, we recently suggested based on viral-mediated 5-HT1B-receptor gene transfer that the discrepancies are likely due to differences in the length of abstinence from cocaine prior to testing. To further validate our findings pharmacologically, we examined the effects of the selective 5-HT1B receptor agonist CP 94,253 (5.6 mg/kg, s.c.) on cocaine self-administration during maintenance and after a period of protracted abstinence with or without daily extinction training. We also examined agonist effects on cocaine-seeking behavior at different time points during abstinence. During maintenance, CP 94,253 shifted the cocaine self-administration dose-effect function on an FR5 schedule of reinforcement to the left, whereas following 21 days of abstinence CP 94,253 downshifted the function and also decreased responding on a progressive ratio schedule of reinforcement regardless of extinction history. CP 94,253 also attenuated cue-elicited and cocaine-primed drug-seeking behavior following 5 days, but not 1 day, of forced abstinence. The attenuating effects of CP 94,253 on the descending limb of the cocaine dose-effect function were blocked by the selective 5-HT1B receptor antagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating 5-HT1B receptor mediation. The results support a switch in 5-HT1B receptor modulation of cocaine reinforcement from facilitatory during self-administration maintenance to inhibitory during protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medication for treating cocaine dependence.
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http://dx.doi.org/10.1021/cn400155tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986226PMC
March 2014

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development.

Neuropharmacology 2014 Jan 23;76 Pt B:301-19. Epub 2013 Aug 23.

School of Life Sciences, P.O. Box 874501, Arizona State University, Tempe, AZ 85287-4501, USA. Electronic address:

Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during self-administration versus abstinence, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine's reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
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http://dx.doi.org/10.1016/j.neuropharm.2013.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041184PMC
January 2014

Cortagine infused into the medial prefrontal cortex attenuates predator-induced defensive behaviors and Fos protein production in selective nuclei of the amygdala in male CD1 mice.

Horm Behav 2013 Aug 9;64(3):519-26. Epub 2013 Jul 9.

Department of Psychology, University of Hawaii, Honolulu, HI, USA; Pacific Biomedical Research Center, University of Hawaii, Honolulu, HI, USA; Specialized Neuroscience Research Program, University of Hawaii, Honolulu, HI, USA. Electronic address:

Corticotropin-releasing factor (CRF) plays an essential role in coordinating the autonomic, endocrine and behavioral responses to stressors. In this study, we investigated the role of CRF within the medial prefrontal cortex (mPFC) in modulating unconditioned defensive behaviors, by examining the effects of microinfusing cortagine a selective type-1 CRF receptor (CRF1) agonist, or acidic-astressin a preferential CRF1 antagonist, into the mPFC in male CD-1 mice exposed to a live predator (rat exposure test--RET). Cortagine microinfusions significantly reduced several indices of defense, including avoidance and freezing, suggesting a specific role for CRF1 within the infralimbic and prelimbic regions of the mPFC in modulating unconditioned behavioral responsivity to a predator. In contrast, microinfusions of acidic-astressin failed to alter defensive behaviors during predator exposure in the RET. Cortagine microinfusions also reduced Fos protein production in the medial, central and basomedial, but not basolateral subnuclei of the amygdala in mice exposed to the rat predatory threat stimulus. These results suggest that CRF1 activation within the mPFC attenuates predator-induced unconditioned anxiety-like defensive behaviors, likely via inhibition of specific amygdalar nuclei. Furthermore, the present findings suggest that the mPFC represents a unique neural region whereby activation of CRF1 produces behavioral effects that contrast with those elicited following systemic administration of CRF1 agonists.
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http://dx.doi.org/10.1016/j.yhbeh.2013.06.008DOI Listing
August 2013

5-HT(2A) receptor blockade and 5-HT(2C) receptor activation interact to reduce cocaine hyperlocomotion and Fos protein expression in the caudate-putamen.

Synapse 2012 Dec 11;66(12):989-1001. Epub 2012 Sep 11.

Department of Psychology, Arizona State University, 950 S. McAllister, Tempe, Arizona 85287-1104, USA.

Both the 5-HT(2A) receptor (R) antagonist M100907 and the 5-HT(2C) R agonist MK212 attenuate cocaine-induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose-effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5-HT(2A)/5-HT(2C) R interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1-h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine-induced Fos expression in the dorsolateral caudate-putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5-HT(2A) Rs and 5-HT(2C) Rs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5-HT(2) R subtypes on behavior. Further research investigating combined 5-HT(2A) R antagonism and 5-HT(2C) R agonism as a treatment for cocaine dependence is warranted.
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http://dx.doi.org/10.1002/syn.21592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476845PMC
December 2012

Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors.

Biol Psychiatry 2012 Sep 27;72(5):396-404. Epub 2012 Apr 27.

School of Life Sciences, Arizona State University, Tempe, Arizona 85287-4501, USA.

Background: The role of serotonin-1B receptors (5-HT(1B)Rs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT(1B)Rs in the mesolimbic pathway may vary depending on the stage of the addiction cycle.

Methods: To test this hypothesis, we examined the effects of increasing 5-HT(1B)R production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT(1B)R or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal.

Results: 5-HT(1B)R receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT(1B)R gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior.

Conclusions: This unique pattern of effects suggests that mesolimbic 5-HT(1B)Rs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT(1B)Rs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle.
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http://dx.doi.org/10.1016/j.biopsych.2012.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071622PMC
September 2012

Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues.

Neuropsychopharmacology 2012 Aug 25;37(9):2109-20. Epub 2012 Apr 25.

Department of Psychology, Arizona State University, Tempe, AZ 85287-4501, USA.

Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.
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http://dx.doi.org/10.1038/npp.2012.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398726PMC
August 2012

Limited physical contact through a mesh barrier is sufficient for social reward-conditioned place preference in adolescent male rats.

Physiol Behav 2012 Feb 8;105(3):749-56. Epub 2011 Oct 8.

Department of Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ 85287-1104, USA.

Adolescence is a period of enhanced sensitivity to social influences and vulnerability to drug abuse. Social reward in adolescent rats has been demonstrated with the conditioned place preference (CPP) model, but it is not clear whether limited contact with another rat without play is sufficient to produce reward. We investigated this issue using an apparatus containing two main compartment, each with a wire mesh barrier that allowed rats placed on either side of the barrier to have limited physical contact. Adolescent male rats were given two conditioning sessions/day for 2 or 8 days following baseline preference tests. Rats were placed into their preferred side alone for one daily 10-min session and into their initially non-preferred side (i.e., CS) for the other session during which they either had restricted or unrestricted physical access to another rat (Rat/Mesh or Rat/Phys, respectively) or to a tennis ball (Ball/Mesh or Ball/Phys, respectively) unconditioned stimulus (US). Only the Rat/Phys group exhibited CPP after 2 CS-US pairings; however, after 8 CS-US pairings, the Rat/Mesh and Ball/Phys groups also exhibited CPP. During conditioning, the rat US elicited more robust approach and contact behavior compared to the ball, regardless of physical or restricted access. The incidence of contact and/or approach increased as the number of exposures increased. The results suggest that the rank order of US reward efficacy was physical contact with a rat>limited contact with a rat>physical contact with a ball, and that rough-and-tumble play is not necessary to establish social reward-CPP. The findings have important implications for emerging drug self-administration models in which two rats self-administering drug intravenously have limited physical contact via a mesh barrier shared between their respective operant conditioning chambers.
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http://dx.doi.org/10.1016/j.physbeh.2011.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975131PMC
February 2012

Environmental enrichment counters cocaine abstinence-induced stress and brain reactivity to cocaine cues but fails to prevent the incubation effect.

Addict Biol 2012 Mar 4;17(2):365-77. Epub 2011 Aug 4.

Department of Psychology, Arizona State University, Tempe, AZ 85287, USA.

Environmental enrichment (EE) during a period of forced abstinence attenuates incentive motivational effects of cocaine-paired stimuli. Here we examined whether EE during forced abstinence from cocaine self-administration would prevent time-dependent increases in cue-elicited cocaine-seeking behavior (i.e. the incubation effect). Rats were trained to self-administer cocaine, which was paired with light/tone cues, for 15 days while living in isolated conditions (IC). Controls received yoked saline infusions. Subsequently, rats were assigned to live in either continued IC or EE for either 1 or 21 days of forced abstinence prior to a test for cocaine-seeking behavior. During testing, responding resulted only in presentation of the light/tone cues. Contrary to our prediction, cocaine-seeking behavior increased over time regardless of living condition during abstinence; however, EE attenuated cocaine-seeking behavior relative to IC regardless of length of abstinence. Brains were harvested and trunk blood was collected immediately after the 60-minute test and later assayed. Results indicated that short-term EE elevated hippocampal brain-derived neurotrophic factor and reduced plasma corticosterone compared with IC. Furthermore, 21 days of EE during forced abstinence prevented increases in the cue-elicited amygdala phosphorylated extracellular signal-regulated kinase expression that was observed in IC rats. These findings suggest that EE attenuates incentive motivational effects of cocaine cues through a mechanism other than preventing the incubation effect, perhaps involving reduction of stress and neural activity in response to cocaine-paired cues during acute withdrawal.
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http://dx.doi.org/10.1111/j.1369-1600.2011.00358.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220742PMC
March 2012

Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats.

Psychopharmacology (Berl) 2011 Feb 16;213(2-3):307-20. Epub 2010 Nov 16.

Department of Psychology, Arizona State University, Tempe, AZ 85287, USA.

Rationale: The action of serotonin (5-HT) at the 5-HT(2A) receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT(2A) receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior.

Objectives: This study examined the hypothesis that M100907, a 5-HT(2A) receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior.

Methods: Rats trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10 mg/kg, i.p.) within 1 min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5 μg/0.2 μl/side) into the vmPFC.

Results: Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5 μg) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement.

Conclusions: The results suggest that the blockade of 5-HT(2A) receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.
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http://dx.doi.org/10.1007/s00213-010-2071-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072217PMC
February 2011

Stimulation of dopamine D2/D3 but not D1 receptors in the central amygdala decreases cocaine-seeking behavior.

Behav Brain Res 2010 Dec 19;214(2):386-94. Epub 2010 Jun 19.

Department of Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ 85287-1104, United States.

Alterations in dopamine output within the various subnuclei of the amygdala have previously been implicated in cocaine reinforcement, as well as cocaine-seeking behavior. To elucidate the potential for increased stimulation of D1- and D2-like receptors (D1Rs and D2Rs, respectively) specifically in the central nucleus of the amygdala (CeA) to modulate cue- and cocaine-elicited reinstatement of cocaine-seeking behavior, we infused either the D1R agonist, SKF-38393 (0-4.0 microg/side) or the D2R agonist, 7-OH-DPAT (0-4.0 microg/side) into the CeA immediately prior to tests for cue and cocaine-primed reinstatement. We also examined the effects of 7-OH-DPAT on cocaine self-administration as a positive behavioral control. 7-OH-DPAT decreased cue-and cocaine-primed reinstatement, and reduced the number of cocaine infusions obtained during self-administration; SKF-38393 produced no discernable effects. The results suggest that enhanced stimulation of D2Rs, but not D1Rs, in the CeA is sufficient to inhibit expression of the incentive motivational effects of cocaine priming and cocaine-paired cues. Together with previous findings that D1R blockade attenuates reinstatement of cocaine-seeking behavior, the results suggest that D1R stimulation may be necessary, but not sufficient, to modulate the incentive motivational effects of cues and cocaine priming.
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http://dx.doi.org/10.1016/j.bbr.2010.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071986PMC
December 2010

Stimulation of medial prefrontal cortex serotonin 2C (5-HT(2C)) receptors attenuates cocaine-seeking behavior.

Neuropsychopharmacology 2010 Sep 2;35(10):2037-48. Epub 2010 Jun 2.

Department of Psychology, Arizona State University, Tempe, 85287-1104, USA.

Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.
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http://dx.doi.org/10.1038/npp.2010.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055305PMC
September 2010

Maternal separation modulates short-term behavioral and physiological indices of the stress response.

Horm Behav 2010 Jul 15;58(2):241-9. Epub 2010 Mar 15.

Department of Psychology, University of Hawaii, 2430 Campus Rd., Honolulu, HI 96822, USA.

Early-life stress produces an anxiogenic profile in adulthood, presumably by activating the otherwise quiescent hypothalamic-pituitary-adrenal (HPA) axis during the vulnerable 'stress hyporesponsive period'. While the long-term effects of such early-life manipulations have been extensively characterized, little is known of the short-term effects. Here, we compared the short-term effects of two durations of maternal separation stress and one unseparated group (US) on behavioral and physiological indices of the stress response in rat pups. Separations included 3h on each of 12days, from postnatal day (PND) 2 to 13 (MS2-13) and 3days of daily, 6-h separation from PND11-13 (MS11-13). On PND14 (Experiment 1), both MS2-13 and MS11-13 produced marked reductions in freezing toward an adult male conspecific along with reduced levels of glucocorticoid type 2 (GR) and CRF type-1 (CRF(1)) receptor mRNA in the hippocampus. Group MS2-13 but not MS11-13 produced deficits in stressor-induced corticosterone secretion, accompanied by reductions in body weight. Our results suggest that GR and/or CRF(1) levels, not solely the magnitude of corticosterone secretion, may be involved in the modulation of freezing. In a second experiment, we aimed to extend these findings by testing male and female separated and unseparated pups' unconditioned defensive behaviors to cat odor on PND26, and subsequent cue+context conditioning and extinction throughout postnatal days 27-32. Our results show that maternal separation produced reductions in unconditioned freezing on PND26, with MS2-13 showing stronger deficits than MS11-13. However, separation did not affect any other defensive behaviors. Furthermore, separated rats failed to show conditioned freezing, although they did avoid the no-odor block conditioned cue. There were no sex differences other than weight. We suggest that maternal separation may have produced these changes by disrupting normal development of hippocampal regions involved in olfactory-mediated freezing, not in mechanisms of learning and memory per se. These findings may have direct relevance for understanding the mechanisms by which early-life adverse experiences produce short-term and lasting psychopathologies.
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http://dx.doi.org/10.1016/j.yhbeh.2010.03.010DOI Listing
July 2010

Anti-craving effects of environmental enrichment.

Int J Neuropsychopharmacol 2009 Oct 20;12(9):1151-6. Epub 2009 Aug 20.

Arizona State University, Tempe, AZ, USA.

We hypothesized that environmental enrichment in rats may reduce cocaine-seeking behaviour elicited by cocaine-priming injections and by cocaine-associated cues. Rats trained to self-administer cocaine while housed in isolated conditions were then assigned to live in isolation or an enriched environment for 21 d of forced abstinence. Subsequently, extinction and reinstatement of cocaine-seeking behaviour (operant responses without cocaine available) were assessed. Expt 1 showed that enrichment resulted in less cocaine-seeking behaviour during extinction and cue-elicited reinstatement compared to continued isolation housing, but had no effect on cocaine-primed reinstatement. A subsequent experiment, which included a pair-housed group to control for potential isolation stress, again demonstrated that enrichment attenuated cocaine seeking during extinction, but not cocaine-primed reinstatement, relative to both isolation and pair-housed conditions. The findings suggest that enrichment reduces the impact of cocaine-associated environmental stimuli, and hence it may be a useful intervention for attenuating cue-elicited craving in humans.
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http://dx.doi.org/10.1017/S1461145709990472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832121PMC
October 2009

Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior.

Addict Biol 2009 Sep 24;14(4):419-30. Epub 2009 Jul 24.

Department of Psychology, Arizona State University, USA.

Paradoxically, stimulation of 5-HT(1B) receptors (5-HT(1B)Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5-HT(1B)R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253 would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT(1B)Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT(1B)Rs may be a novel target for developing medications for cocaine dependence.
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http://dx.doi.org/10.1111/j.1369-1600.2009.00162.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846432PMC
September 2009

Cocaine-induced Fos expression is detectable in the frontal cortex and striatum of rats under isoflurane but not alpha-chloralose anesthesia: implications for FMRI.

J Neurosci Methods 2009 Jul 23;181(2):241-8. Epub 2009 May 23.

Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, USA.

The ability of intravenous cocaine to induce Fos protein expression in anesthetized rats was tested. Two anesthetic regimens commonly used for in vivo FMRI of animals, i.v. alpha-chloralose and gaseous isoflurane, were studied in separate cohorts. The first experiment included three groups that received the following treatments: saline i.v. and no anesthetic; 2 mg/kg cocaine i.v. and no anesthetic; and 2mg/kg cocaine i.v. under 36 mg/kg/h alpha-chloralose anesthesia. The second experiment had a factorial design of four groups that were either nonanesthetized or isoflurane-treated and were either given saline or cocaine (2 mg/kg, i.v.). Anesthetized rats were maintained for 2 h under 2.5-3.5% isoflurane anesthesia, while nonanesthetized rats were kept in an alternative environment for the same time period. Rats were given 2 mg/kg cocaine or saline i.v., 30 min into the test session. Rats were perfused and their brains were processed for Fos immunohistochemistry 90 min after the i.v. treatment. In both experiments, the frontal cortex and striatum of the cocaine-treated nonanesthetized rats expressed Fos in greater amounts than the saline-treated nonanesthetized rats, as expected. The alpha-chloralose treatment prevented cocaine-induced Fos expression across all eight subregions of the striatum and frontal cortex that were examined. In contrast, isoflurane only partially attenuated Fos expression in the orbital and Cg2 subregions of frontal cortex. These results suggest a strong advantage for using isoflurane, as opposed to alpha-chloralose, when studying anesthetized rats for in vivo effects of psychostimulants.
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http://dx.doi.org/10.1016/j.jneumeth.2009.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748745PMC
July 2009