Publications by authors named "Eliot L Gardner"

87 Publications

Cannabinoid CB receptors are expressed in glutamate neurons in the red nucleus and functionally modulate motor behavior in mice.

Neuropharmacology 2021 05 28;189:108538. Epub 2021 Mar 28.

Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA. Electronic address:

Cannabinoids produce a number of central nervous system effects via the CB receptor (CBR), including analgesia, antianxiety, anti-reward, hypoactivity and attenuation of opioid-induced respiratory depression. However, the cellular distributions of the CBRs in the brain remain unclear. We have reported that CBRs are expressed in midbrain dopamine (DA) neurons and functionally regulate DA-mediated behavior(s). Unexpectedly, high densities of CB-like signaling were also found in a neighboring motor structure - the red nucleus (RN) of the midbrain. In the present study, we systematically explored CBR expression and function in the RN. Immunohistochemistry and in situ hybridization assays showed high densities of CBR-immunostaining and mRNA signal in RN magnocellular glutamate neurons in wildtype and CB-knockout, but not CB-knockout, mice. Ex vivo electrophysiological recordings in midbrain slices demonstrated that CBR activation by JWH133 dose-dependently inhibited firing rates of RN magnocellular neurons in wildtype, but not CB-knockout, mice, while having no effect on RN GABA neurons in transgenic GAD67-GFP reporter mice, suggesting CB-mediated effects on glutamatergic neurons. In addition, microinjection of JWH133 into the RN produced robust ipsilateral rotations in wildtype, but not CB-knockout mice, which was blocked by pretreatment with either a CB or DA D1 or D2 receptor antagonist, suggesting a DA-dependent effect. Finally, fluorescent tract tracing revealed glutamatergic projections from the RN to multiple brain areas including the ventral tegmental area, thalamus, and cerebellum. These findings suggest that CBRs in RN glutamate neurons functionally modulate motor activity, and therefore, constitute a new target in cannabis-based medication development for motor disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122071PMC
May 2021

Dissecting the role of CB and CB receptors in cannabinoid reward versus aversion using transgenic CB- and CB-knockout mice.

Eur Neuropsychopharmacol 2021 Feb 15;43:38-51. Epub 2020 Dec 15.

Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 251 Bayview Blvd, NIDA IRP, BRC Suite 200, Baltimore, MD 21224, USA. Electronic address:

Cannabinoids produce both rewarding and aversive effects in humans and experimental animals. However, the mechanisms underlying these conflicting findings are unclear. Here we examined the potential involvement of CB and CB receptors in cannabinoid action using transgenic CB-knockout (CB-KO) and CB-knockout (CB-KO) mice. We found that Δ-tetrahydrocannabinol (Δ-THC) induced conditioned place preference at a low dose (1 mg/kg) in WT mice that was attenuated by deletion of the CB receptor. At 5 mg/kg, no subjective effects of Δ-THC were detected in WT mice, but CB-KO mice exhibited a trend towards place aversion and CB-KO mice developed significant place preferences. This data suggests that activation of the CB receptor is rewarding, while CBR activation is aversive. We then examined the nucleus accumbens (NAc) dopamine (DA) response to Δ-THC using in vivo microdialysis. Unexpectedly, Δ-THC produced a dose-dependent decrease in extracellular DA in WT mice, that was potentiated in CB-KO mice. However, in CB-KO mice Δ-THC produced a dose-dependent increase in extracellular DA, suggesting that activation of the CBR inhibits DA release in the NAc. In contrast, Δ-THC, when administered systemically or locally into the NAc, failed to alter extracellular DA in rats. Lastly, we examined the locomotor response to Δ-THC. Both CB and CB receptor mechanisms were shown to underlie Δ-THC-induced hypolocomotion. These findings indicate that Δ-THC's variable subjective effects reflect differential activation of cannabinoid receptors. Specifically, the opposing actions of CB and CB receptors regulate cannabis reward and aversion, with CB-mediated effects predominant in mice.
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http://dx.doi.org/10.1016/j.euroneuro.2020.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854511PMC
February 2021

Neurochemical and behavioral comparisons of contingent and non-contingent methamphetamine exposure following binge or yoked long-access self-administration paradigms.

Psychopharmacology (Berl) 2020 Jul 9;237(7):1989-2005. Epub 2020 May 9.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, 333 Cassell Drive, Baltimore, MD, 21224, USA.

Rationale: Abuse of the psychostimulant methamphetamine (METH) can cause long-lasting damage to brain monoaminergic systems and is associated with profound mental health problems for users, including lasting cognitive impairments. Animal models of METH exposure have been useful in dissecting the molecular effects of the drug on cognition, but many studies use acute, non-contingent "binge" administrations of METH which do not adequately approximate human METH use. Long-term METH exposure via long-access (LgA) self-administration paradigms has been proposed to more closely reflect human use and induce cognitive impairments.

Objective: To better understand the role of contingency and patterns of exposure in METH-induced cognitive impairments, we analyzed behavioral and neurochemical outcomes in adult male rats, comparing non-contingent "binge" METH administration with contingent (LgA) METH self-administration and non-contingent yoked partners.

Results: Binge METH (40 mg/kg, i.p., over 1 day) dramatically altered striatal and hippocampal dopamine, DOPAC, 5-HT, 5-HIAA, BDNF, and TrkB 75 days after drug exposure. In contrast, 6-h LgA METH self-administration (cumulative 24.8-48.9 mg METH, i.v., over 16 days) altered hippocampal BDNF in both contingent and yoked animals but reduced striatal 5-HIAA in only contingent animals. Neurochemical alterations following binge METH administration were not accompanied by cognitive deficits in Morris water maze, novel object recognition, or Y-maze tests. However, contingent LgA METH self-administration resulted in impaired spatial memory in the water maze.

Conclusions: Overall, substantial differences in neurochemical markers between METH exposure and self-administration paradigms did not consistently translate to deficits in cognitive tasks, highlighting the complexity of correlating METH-induced neurochemical changes with cognitive outcomes.
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http://dx.doi.org/10.1007/s00213-020-05513-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974824PMC
July 2020

Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: Opposite roles of CB /CB versus GPR55 receptors.

Br J Pharmacol 2020 04 11;177(8):1865-1880. Epub 2020 Feb 11.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland.

Background And Purpose: Cannabis or cannabinoids produce characteristic tetrad effects-analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB receptors. Given recent findings of CB and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action.

Experimental Approach: We compared Δ -tetrahydrocannabinol (Δ -THC)-, WIN55212-2-, or XLR11-induced tetrad effects between wild-type (WT) and each genotype of CB -, CB - or GPR55-knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice.

Key Results: Systemic administration of Δ -THC, WIN55212-2 or XLR11 produced dose-dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB receptor abolished analgesia and catalepsy produced by Δ -THC or WIN55212-2, but not by XLR11. Microinjections of Δ -THC into the lateral ventricles also produced tetrad effects in WT, but not in CB -KO mice. CB -KO mice displayed a reduction in intraventricular Δ -THC-induced analgesia and catalepsy. In contrast to CB and CB receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ -THC or WIN55212-2. Antagonisim of CB , CB or GPR55 receptors produced alterations similar to those observed in each genotype mouse line.

Conclusions And Implications: These findings suggest that in addition to CB , both CB and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB /CB , in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.
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http://dx.doi.org/10.1111/bph.14958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070166PMC
April 2020

Δ -Tetrahydrocannabivarin has potent anti-nicotine effects in several rodent models of nicotine dependence.

Br J Pharmacol 2019 12 28;176(24):4773-4784. Epub 2019 Oct 28.

Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.

Background And Purpose: Both types of cannabinoid receptors-CB and CB -regulate brain functions relating to addictive drug-induced reward and relapse. CB receptor antagonists and CB receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs. Δ -Tetrahydrocannabivarin (Δ -THCV)-a cannabis constituent-acts as a CB antagonist and a CB agonist. Δ -Tetrahydrocannabivarin (Δ -THCV) is a Δ -THCV analogue with similar combined CB antagonist/CB agonist properties.

Experimental Approach: We tested Δ -THCV in seven different rodent models relevant to nicotine dependence-nicotine self-administration, cue-triggered nicotine-seeking behaviour following forced abstinence, nicotine-triggered reinstatement of nicotine-seeking behaviour, acquisition of nicotine-induced conditioned place preference, anxiety-like behaviour induced by nicotine withdrawal, somatic withdrawal signs induced by nicotine withdrawal, and hyperalgesia induced by nicotine withdrawal.

Key Results: Δ -THCV significantly attenuated intravenous nicotine self-administration and both cue-induced and nicotine-induced relapse to nicotine-seeking behaviour in rats. Δ -THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice.

Conclusions And Implications: We conclude that Δ -THCV may have therapeutic potential for the treatment of nicotine dependence. We also suggest that tetrahydrocannabivarins should be tested for possible anti-addiction efficacy in a broader range of preclinical animal models, against other addictive drugs, and eventually in humans.
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http://dx.doi.org/10.1111/bph.14844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965695PMC
December 2019

Cannabinoid CB and CB receptor mechanisms underlie cannabis reward and aversion in rats.

Br J Pharmacol 2019 05 3;176(9):1268-1281. Epub 2019 Apr 3.

Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.

Background And Purpose: Endocannabinoids are critically involved in brain reward functions, mediated by activation of CB receptors, reflecting their high density in the brain. However, the recent discovery of CB receptors in the brain, particularly in the midbrain dopamine neurons, has challenged this view and inspired us to re-examine the roles of both CB and CB receptors in the effects of cannabis.

Experimental Approach: In the present study, we used the electrical intracranial self-stimulation paradigm to evaluate the effects of various cannabinoid drugs on brain reward in laboratory rats and the roles of CB and CB receptors activation in brain reward function(s).

Key Results: Two mixed CB / CB receptor agonists, Δ -tetrahydrocannabinol (Δ -THC) and WIN55,212-2, produced biphasic effects-mild enhancement of brain-stimulation reward (BSR) at low doses but inhibition at higher doses. Pretreatment with a CB receptor antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB receptor antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB and CB receptor agonists. These compounds produced significant BSR enhancement and inhibition, respectively.

Conclusions And Implications: CB receptor activation produced reinforcing effects, whereas CB receptor activation was aversive. The subjective effects of cannabis depend on the balance of these opposing effects. These findings not only explain previous conflicting results in animal models of addiction but also explain why cannabis can be either rewarding or aversive in humans, as expression of CB and CB receptors may differ in the brains of different subjects.
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http://dx.doi.org/10.1111/bph.14625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468271PMC
May 2019

Dopamine DR antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.

Neuropsychopharmacology 2019 07 27;44(8):1415-1424. Epub 2018 Nov 27.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.

Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.
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http://dx.doi.org/10.1038/s41386-018-0284-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785005PMC
July 2019

Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin.

Pharmacol Biochem Behav 2019 01 7;176:53-56. Epub 2018 Nov 7.

Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, United States of America. Electronic address:

The dopamine system-essential for mood and movement-can be activated in two ways: by excitatory inputs that cause burst firing and stamp-in learning or by slow excitatory or inhibitory inputs-like leptin, insulin, ghrelin, or corticosterone-that decrease or increase single-spike (pacemaker) firing rate and that modulate motivation. In the present study we monitored blood samples taken prior to and during intravenous cocaine or saline self-administration in rats. During cocaine-taking, growth hormone and acetylated ghrelin increased 10-fold; glucagon-like peptide-1 (GLP-1) doubled; non-acetylated ghrelin, insulin-like growth factor-1 (IGF-1), and corticosterone increased by 50% and adiponectin increased by 17%. In the same blood samples, leptin, insulin, gastric inhibitory polypeptide (GIP), and prolactin decreased by 40-70%. On the first day of testing under extinction conditions-where the animals earned unexpected saline instead of cocaine-5-fold increases were seen for growth hormone and acetylated ghrelin and equal changes-in amplitude and latency-were seen in each of the other cases except for IGF-1 (which increased at a slower rate). Single-spike firing affects the tonic activation level of the dopamine system, involving very different controls than those that drive burst firing; thus, the present data suggest interesting new targets for medications that might be used in the early stages of drug abstinence.
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http://dx.doi.org/10.1016/j.pbb.2018.11.001DOI Listing
January 2019

Deletion of the type 2 metabotropic glutamate receptor increases heroin abuse vulnerability in transgenic rats.

Neuropsychopharmacology 2018 12 3;43(13):2615-2626. Epub 2018 Oct 3.

Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.

Opioid abuse is a rapidly growing public health crisis in the USA. Despite extensive research in the past decades, little is known about the etiology of opioid addiction or the neurobiological risk factors that increase vulnerability to opioid use and abuse. Recent studies suggest that the type 2 metabotropic glutamate receptor (mGluR2) is critically involved in substance abuse and addiction. In the present study, we evaluated whether low-mGluR2 expression may represent a risk factor for the development of opioid abuse and addiction using transgenic mGluR2-knockout (mGluR2-KO) rats. Compared to wild-type controls, mGluR2-KO rats exhibited higher nucleus accumbens (NAc) dopamine (DA) and locomotor responses to heroin, higher heroin self-administration and heroin intake, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms. In contrast, mGluR2-KO rats displayed lower motivation for heroin self-administration under high price progressive-ratio (PR) reinforcement conditions. Taken together, these findings suggest that mGluR2 may play an inhibitory role in opioid action, such that deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Low-mGluR2 expression in the brain may therefore be a risk factor for the initial development of opioid abuse and addiction.
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http://dx.doi.org/10.1038/s41386-018-0231-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224385PMC
December 2018

PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models.

Biochem Pharmacol 2018 11 6;157:235-243. Epub 2018 Sep 6.

Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28224, Spain. Electronic address:

Recent studies have demonstrated the utility of drugs modulating the endogenous cannabinoid system to control excessive alcohol intake. Among them, drugs interacting with acylethanolamide receptors including cannabinoid CB1 receptor antagonists/inverse agonists, peroxisome proliferator-activated receptor alpha (PPARα) agonists or peroxisome proliferator-activated receptor gamma (PPARγ) agonists have demonstrated utility in the reduction of alcohol intake in animal models. However, few studies have addressed the potential utility of combining these classes of drugs, especially because of expected safety problems. In the present work we took the advantage of the availability of two novel dual ligands for these receptors, to test the hypothesis that these types of drugs might reproduce and even improve the pharmacological profile of those drugs interacting with single targets. To this end we tested (R)-3-[(4-Benzyl-2-oxooxazolidin-3-yl)methyl]-N-[4-(dodecylcarbamoyl)phenyl]benzamide (NF 10-360), a dual PPARα/γ agonist, and N-[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA), a dual CB1 receptor antagonist/PPARα agonist, in animal models of alcohol consumption. Both drugs were effective in reducing alcohol intake and alcohol self-administration, being OLHHA a very potent alcohol intake inhibitor (EC 0.2 mg/kg). OLHHA also reduced self-administration of the opioid oxycodone. OLHHA actions on alcohol self-administration were replicated in alcohol-preferring Marchigian-Sardinian msP rats. Repeated administration of OLHHA did result neither in tolerance nor in toxicological or deleterious metabolic changes in the liver of msP rats. These data support the feasibility of developing novel dual ligands interacting with cannabinoid targets to treat alcohol use disorder in humans.
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http://dx.doi.org/10.1016/j.bcp.2018.09.008DOI Listing
November 2018

Genetic deletion of the dopamine D3 receptor increases vulnerability to heroin in mice.

Neuropharmacology 2018 10 20;141:11-20. Epub 2018 Aug 20.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA. Electronic address:

Despite extensive research, the neurobiological risk factors that convey vulnerability to opioid abuse are still unknown. Recent studies suggest that the dopamine D3 receptor (D3R) is involved in opioid self-administration, but it remains unclear whether altered D3R availability is a risk factor for the development of opioid abuse and addiction. Here we used dopamine D3 receptor-knockout (D3-KO) mice to investigate the role of this receptor in the different phases of opioid addiction. D3-KO mice learned to self-administer heroin faster and took more heroin than wild-type mice during acquisition and maintenance of self-administration. D3R-KO mice also displayed higher motivation to work to obtain heroin reward during self-administration under progressive-ratio reinforcement, as well as elevated heroin-seeking during extinction and reinstatement testing. In addition, deletion of the D3R induced higher baseline levels of extracellular dopamine (DA) in the nucleus accumbens (NAc), higher basal levels of locomotion, and reduced NAc DA and locomotor responses to lower doses of heroin. These findings suggest that the D3R is critically involved in regulatory processes that normally limit opioid intake via DA-related mechanisms. Deletion of D3R augments opioid-taking and opioid-seeking behaviors. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561496PMC
October 2018

CB receptor antibody signal specificity: correlations with the use of partial CB-knockout mice and anti-rat CB receptor antibodies.

Acta Pharmacol Sin 2019 Mar 2;40(3):398-409. Epub 2018 Jul 2.

Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.

Cannabinoid CB receptors are highly expressed in the brain and functionally modulate presynaptic neurotransmitter release, while cannabinoid CB receptors (CBRs) were initially identified in the spleen and regarded as peripheral cannabinoid receptors. Recently, growing evidence indicates the presence of functional CBRs in the brain. However, this finding is disputed because of the specificity of CBR antibody signals. We used two strains of currently available partial CB-knockout (CB-KO) mice as controls, four anti-rat or anti-mouse CBR antibodies, and mRNA quantification to further address this issue. Western blot assays using the four antibodies detected a CBR-like band at ~40 kD in both the brain and spleen. Notably, more bands were detected in the brain than in the spleen, and specific immune peptides blocked band detection. Immunohistochemical assays also detected CB-like immunostaining in mouse midbrain dopamine neurons. CBR deletion in CB-KO mice may reduce or leave CBR-like immunoreactivity unaltered depending on antibody epitope. Antibodies with epitopes at the receptor-deleted region detected a significant reduction in CBR band density and immunostaining in N-terminal-deleted Deltagen and C-terminal-deleted Zimmer strain CB-KO mice. Other antibodies with epitopes at the predicted receptor-undeleted regions detected similar band densities and immunostaining in wild-type and CB-KO mice. Quantitative RT-PCR assays detected CB mRNA expression using probes that targeted upstream or downstream gene sequences but not the probe that targeted the gene-deleted sequence in Deltagen or Zimmer CB-KO mice. These findings suggest that none of the tested four polyclonal antibodies are highly mouse CBR-specific. Non-specific binding may be related to the expression of mutant or truncated CBR-like proteins in partial CB-KO mice and the use of anti-rat CB antibodies because the epitopes are different between rat and mouse CBRs.
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http://dx.doi.org/10.1038/s41401-018-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460367PMC
March 2019

CB receptor antibody signal specificity: correlations with the use of partial CB-knockout mice and anti-rat CB receptor antibodies.

Acta Pharmacol Sin 2019 Mar 2;40(3):398-409. Epub 2018 Jul 2.

Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.

Cannabinoid CB receptors are highly expressed in the brain and functionally modulate presynaptic neurotransmitter release, while cannabinoid CB receptors (CBRs) were initially identified in the spleen and regarded as peripheral cannabinoid receptors. Recently, growing evidence indicates the presence of functional CBRs in the brain. However, this finding is disputed because of the specificity of CBR antibody signals. We used two strains of currently available partial CB-knockout (CB-KO) mice as controls, four anti-rat or anti-mouse CBR antibodies, and mRNA quantification to further address this issue. Western blot assays using the four antibodies detected a CBR-like band at ~40 kD in both the brain and spleen. Notably, more bands were detected in the brain than in the spleen, and specific immune peptides blocked band detection. Immunohistochemical assays also detected CB-like immunostaining in mouse midbrain dopamine neurons. CBR deletion in CB-KO mice may reduce or leave CBR-like immunoreactivity unaltered depending on antibody epitope. Antibodies with epitopes at the receptor-deleted region detected a significant reduction in CBR band density and immunostaining in N-terminal-deleted Deltagen and C-terminal-deleted Zimmer strain CB-KO mice. Other antibodies with epitopes at the predicted receptor-undeleted regions detected similar band densities and immunostaining in wild-type and CB-KO mice. Quantitative RT-PCR assays detected CB mRNA expression using probes that targeted upstream or downstream gene sequences but not the probe that targeted the gene-deleted sequence in Deltagen or Zimmer CB-KO mice. These findings suggest that none of the tested four polyclonal antibodies are highly mouse CBR-specific. Non-specific binding may be related to the expression of mutant or truncated CBR-like proteins in partial CB-KO mice and the use of anti-rat CB antibodies because the epitopes are different between rat and mouse CBRs.
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http://dx.doi.org/10.1038/s41401-018-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460367PMC
March 2019

Selective dopamine D receptor antagonism significantly attenuates stress-induced immobility in a rat model of post-traumatic stress disorder.

Synapse 2018 08 7;72(8):e22035. Epub 2018 Jun 7.

Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric syndrome that occurs in individuals exposed to extremely threatening or traumatic events. In both animals and humans, dopamine (DA) function appears to be dysregulated in brain areas involved in the conditioned fear response(s) that underlie PTSD. In this study, we determined the effect of the selective DA D receptor antagonists YQA14A (6.25, 12.5 and 25 mg/kg i.p.) and SB-277011A (6 mg/kg i.p.) on tone-induced fear (assessed by measuring freeze time) in a modified version of the single-prolonged stress (SPS) model of PTSD in adult male Sprague-Dawley rats. Rats pretreated with vehicle and then subjected to restraint stress, forced swim and random foot shock (SPS) in the presence of a distinctive tone, displayed a significantly increased tone-induced contextual freeze time and fecal pellet mass following re-exposure to the tone. Rats pretreated with a single i.p. injection of 6.25 or 12.5 mg/kg of YQA14 or 6 mg/kg of SB-277011A showed significantly attenuated contextual freeze time in the presence of the tone when tested 14 days after exposure to SPS. Overall, our results indicate that selectively antagonizing DA D receptors significantly decreases freezing time caused by an environment previously associated with stress. If our findings can be extrapolated to humans with PTSD, they suggest that DA D receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD.
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http://dx.doi.org/10.1002/syn.22035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6574226PMC
August 2018

mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism.

Sci Rep 2018 02 27;8(1):3686. Epub 2018 Feb 27.

Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA.

Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism.
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http://dx.doi.org/10.1038/s41598-018-22087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829076PMC
February 2018

Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference.

Sci Rep 2017 12 12;7(1):17410. Epub 2017 Dec 12.

Department of Biology, William Paterson University, Wayne, New Jersey, 74070, USA.

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson's disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.
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http://dx.doi.org/10.1038/s41598-017-17796-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727179PMC
December 2017

CB1 Receptor Activation on VgluT2-Expressing Glutamatergic Neurons Underlies Δ-Tetrahydrocannabinol (Δ-THC)-Induced Aversive Effects in Mice.

Sci Rep 2017 09 26;7(1):12315. Epub 2017 Sep 26.

Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA.

Cannabis can be rewarding or aversive. Cannabis reward is believed to be mediated by activation of cannabinoid CB1 receptors (CB1Rs) on GABAergic neurons that disinhibit dopaminergic neurons in the ventral tegmental area (VTA). However, little is known about the mechanisms underlying cannabis aversion in rodents. In the present study, CB1Rs are found not only on VTA GABAergic neurons, but also on VTA glutamatergic neurons that express vesicular glutamate transporter 2 (VgluT2). We then used Cre-Loxp transgenic technology to selectively delete CB1Rs in VgluT2-expressing glutamatergic neurons (VgluT2-CB1 ) and Cre-dependent viral vector to express light-sensitive channelrhodopsin-2 into VTA glutamatergic neurons. We found that photoactivation of VTA glutamatergic neurons produced robust intracranial self-stimulation (ICSS) behavior, which was dose-dependently blocked by DA receptor antagonists, but enhanced by cocaine. In contrast, Δ-tetrahydrocannabinol (Δ-THC), the major psychoactive component of cannabis, produced dose-dependent conditioned place aversion and a reduction in the above optical ICSS in VgluT2-cre control mice, but not in VgluT2-CB1 mice. These findings suggest that activation of CB1Rs in VgluT2-expressing glutamate neurons produces aversive effects that might explain why cannabinoid is not rewarding in rodents and might also account for individual differences in the hedonic effects of cannabis in humans.
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http://dx.doi.org/10.1038/s41598-017-12399-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614984PMC
September 2017

The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats.

Neuropharmacology 2017 Nov 6;126:190-199. Epub 2017 Sep 6.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA. Electronic address:

The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4-10 mg/kg, i.p.) dose-dependently decreased oxycodone self-administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4-4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4-10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2-015 or BAK4-54) provide new lead molecules for development.
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http://dx.doi.org/10.1016/j.neuropharm.2017.09.007DOI Listing
November 2017

The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic.

Neuropsychopharmacology 2017 Aug 7;42(9):1871-1883. Epub 2017 Mar 7.

Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.

(±)Modafinil ((±)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (±)MOD analogs, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters, and enzymes. Although at a concentration of 10 μM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D-like, and sigma receptors. R-MOD was more selective, but had much lower affinity at the DAT (K=3 μM) than JJC8-016 (K=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.
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http://dx.doi.org/10.1038/npp.2017.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564383PMC
August 2017

Cannabidiol: a potential treatment for post Ebola syndrome?

Int J Infect Dis 2016 Nov 26;52:74-76. Epub 2016 Sep 26.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA. Electronic address:

Patients recovered from Ebola virus infection may experience short- and long-term physical, neuropsychological and social sequelae, including arthralgia, musculoskeletal pain, ophthalmic inflammation, auditory problems, fatigue, confusion, insomnia, short-term memory impairment, anxiety, depression and anorexia, all lasting from two weeks to more than two years. Currently there are no treatments for post Ebola sequelae. We hypothesize that cannabidiol (CBD) may attenuate some of these post Ebola sequelae, several of which have been postulated to result from inflammation and/or an autoimmune response. CBD has anti-inflammatory actions in various animal models. Clinical studies have shown that oral administration of CBD, compared to placebo, significantly reduces anxiety, has antinociceptive and anticonvulsant actions, and may be therapeutic for insomnia. Overall, CBD has a number of pharmacological effects that may significantly improve the mental and somatic health of patients suffering from post Ebola sequelae. In humans, CBD, at therapeutic doses, does not: 1) elicit dependence or tolerance; 2) significantly alter heart rate or blood pressure; 3) affect gastrointestinal transit; 4) produce significant cognitive or psychomotor impairments. Mild sedation and nausea are the most commonly reported adverse effects associated with CBD.CBD, based on its pharmacological effects and favorable safety profile, should be considered as a treatment for individuals with post Ebola sequelae.
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http://dx.doi.org/10.1016/j.ijid.2016.09.020DOI Listing
November 2016

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction.

Neuropsychopharmacology 2017 02 18;42(3):682-694. Epub 2016 Aug 18.

Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine-associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.
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http://dx.doi.org/10.1038/npp.2016.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240176PMC
February 2017

Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors.

Behav Brain Res 2016 May 22;305:87-99. Epub 2016 Feb 22.

Undergraduate Program in Neuroscience, University of Michigan, Ann Arbor, MI, United States; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States. Electronic address:

Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01-0.32mg/kg) or pramipexole (0.032-0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities.
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http://dx.doi.org/10.1016/j.bbr.2016.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821629PMC
May 2016

Expression of functional cannabinoid CB receptor in VTA dopamine neurons in rats.

Addict Biol 2017 May 1;22(3):752-765. Epub 2016 Feb 1.

Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.

We have recently reported the expression of functional cannabinoid CB receptors (CB Rs) in midbrain dopamine (DA) neurons in mice. However, little is known whether CB Rs are similarly expressed in rat brain because significant species differences in CB R structures and expression are found. In situ hybridization and immunohistochemical assays detected CB gene and receptors in DA neurons of the ventral tegmental area (VTA), which was up-regulated in cocaine self-administration rats. Electrophysiological studies demonstrated that activation of CB Rs by JWH133 inhibited VTA DA neuronal firing in single dissociated neurons. Systemic administration of JWH133 failed to alter, while local administration of JWH133 into the nucleus accumbens inhibited cocaine-enhanced extracellular DA and i.v. cocaine self-administration. This effect was blocked by AM630, a selective CB R antagonist. These data suggest that CB Rs are expressed in VTA DA neurons and functionally modulate DA neuronal activities and cocaine self-administration behavior in rats.
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http://dx.doi.org/10.1111/adb.12367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969232PMC
May 2017

The selective dopamine D3 receptor antagonist SB-277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in male Sprague-Dawley rats.

Synapse 2015 Oct 14;69(10):512-4. Epub 2015 Jul 14.

Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, 21224.

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http://dx.doi.org/10.1002/syn.21839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526079PMC
October 2015

The selective dopamine D₃ receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

Synapse 2015 Jun;69(6):336-44

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, 11439.

We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors.
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http://dx.doi.org/10.1002/syn.21820DOI Listing
June 2015

The selective dopamine D₃ receptor antagonist SB-277011-A significantly decreases binge-like consumption of ethanol in C57BL/J6 mice.

Synapse 2015 Jun;69(6):295-8

Psychology Department, Furman University, Greenville, South Carolina, 29613.

The authors show that the dopamine D3 antagonist SB-277011-A consistently and persistently decrease binge-like EtOH consumption at 30 mg/kg and it decreases binge-like consumption on days 3, 7, 9, and 11-13 at 15 mg/kg. These findings suggest that the brain's D3 receptor may also be involved in not only ethanol reward but binge drinking as well.
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http://dx.doi.org/10.1002/syn.21816DOI Listing
June 2015

R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats.

Neuropsychopharmacology 2015 Jun 23;40(7):1762-71. Epub 2015 Jan 23.

Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.
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http://dx.doi.org/10.1038/npp.2015.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915260PMC
June 2015

Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats.

Neuropsychopharmacology 2015 Mar 6;40(4):1037-51. Epub 2014 Nov 6.

Neurobiology of Relapse Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.

The discovery of functional cannabinoid receptors 2 (CB2Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats.
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http://dx.doi.org/10.1038/npp.2014.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330519PMC
March 2015

Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice.

Proc Natl Acad Sci U S A 2014 Nov 3;111(46):E5007-15. Epub 2014 Nov 3.

Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224;

Cannabinoid CB2 receptors (CB2Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB2Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB2 mRNA and CB2R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 or other CB2R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB1(-/-) mice are blocked by CB2R antagonist and absent in CB2(-/-) mice. These data suggest that CB2R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.
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http://dx.doi.org/10.1073/pnas.1413210111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246322PMC
November 2014

Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats.

Neuropharmacology 2014 Feb 28;77:398-405. Epub 2013 Oct 28.

Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. Electronic address:

Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone did not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.
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http://dx.doi.org/10.1016/j.neuropharm.2013.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867233PMC
February 2014