Publications by authors named "Ewa Galaj"

31 Publications

The role of circTmeff-1 in incubation of context-induced morphine craving.

Pharmacol Res 2021 Jun 8;170:105722. Epub 2021 Jun 8.

College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang 050017, PR China. Electronic address:

A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541-5p and miR-6934-3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541-5p and miR-6934-3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541-5p and miR-6934-3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence.
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http://dx.doi.org/10.1016/j.phrs.2021.105722DOI Listing
June 2021

Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking.

Front Pharmacol 2021 25;12:686845. Epub 2021 May 25.

National Institute on Drug Abuse, Molecular Targets and Medications Discovery Branch, Baltimore, MD, United States.

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention.
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http://dx.doi.org/10.3389/fphar.2021.686845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185332PMC
May 2021

Cell-type specific expression and behavioral impact of galanin and GalR1 in the locus coeruleus during opioid withdrawal.

Addict Biol 2021 Mar 25:e13037. Epub 2021 Mar 25.

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

The neuropeptide galanin is reported to attenuate opioid withdrawal symptoms, potentially by reducing neuronal hyperactivity in the noradrenergic locus coeruleus (LC) via galanin receptor 1 (GalR1). We evaluated this mechanism by using RNAscope in situ hybridization to characterize GalR1 mRNA distribution in the dorsal pons and to compare galanin and GalR1 mRNA expression in tyrosine hydroxylase-positive (TH+) LC cells at baseline and following chronic morphine or precipitated withdrawal. We then used genetically altered mouse lines and pharmacology to test whether noradrenergic galanin (NE-Gal) modulates withdrawal symptoms. RNAscope revealed that, while GalR1 signal was evident in the dorsal pons, 80.7% of the signal was attributable to TH- neurons outside the LC. Galanin and TH mRNA were abundant in LC cells at baseline and were further increased by withdrawal, whereas low basal GalR1 mRNA expression was unaltered by chronic morphine or withdrawal. Naloxone-precipitated withdrawal symptoms in mice lacking NE-Gal (Gal ) were largely similar to WT littermates, indicating that loss of NE-Gal does not exacerbate withdrawal. Complementary experiments using NE-Gal overexpressor mice (NE-Gal OX) and systemic administration of the galanin receptor agonist galnon revealed that increasing galanin signaling also failed to alter behavioral withdrawal, while suppressing noradrenergic transmission with the alpha-2 adrenergic receptor agonist clonidine attenuated multiple symptoms. These results indicate that galanin does not acutely attenuate precipitated opioid withdrawal via an LC-specific mechanism, which has important implications for the general role of galanin in regulation of somatic and affective opioid responses and LC activity.
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http://dx.doi.org/10.1111/adb.13037DOI Listing
March 2021

Neurobiology of reward-related learning.

Neurosci Biobehav Rev 2021 05 10;124:224-234. Epub 2021 Feb 10.

Queens College, City University of New York, Department of Psychology, Flushing, NY, United States. Electronic address:

A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to elicit similar responses to those elicited by primary rewards. Our neurobiological model is predicated on the Hebbian idea that concurrent synaptic activity on the primary reward neural substrate-proposed to be ventral tegmental area (VTA) dopamine (DA) neurons-strengthens the synapses involved. We propose that VTA DA neurons receive both a strong unconditioned stimulus signal (acetylcholine stimulation of DA cells) from the primary reward capable of unconditionally activating DA cells and a weak stimulus signal (glutamate stimulation of DA cells) from the neutral stimulus. Through joint stimulation the weak signal is potentiated and capable of activating the VTA DA cells, eliciting a conditioned response. The learning occurs when this joint stimulation initiates intracellular second-messenger cascades resulting in enhanced glutamate-DA synapses. In this review we present evidence that led us to propose this model and the most recent evidence supporting it.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979510PMC
May 2021

Optogenetic brain-stimulation reward: A new procedure to re-evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter-Cre mice.

Addict Biol 2021 Jul 3;26(4):e13005. Epub 2021 Feb 3.

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

Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ -tetrahydrocannabinol (Δ -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB Rs are expressed mainly in VTA GABA and glutamate neurons, while CB Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB R and/or CB R in different populations of neurons in the brain may underlie the observed actions.
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http://dx.doi.org/10.1111/adb.13005DOI Listing
July 2021

Exogenous SO donor treatment impairs reconsolidation of drug reward memory in mice.

Eur J Pharmacol 2021 Apr 24;896:173911. Epub 2021 Jan 24.

Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medicinal University, 050017, China. Electronic address:

Substance-related and addictive disorders (SRADs) are characterized by compulsive drug use and recurrent relapse. The persistence of pathological drug-related memories indisputably contributes to a high propensity to relapse. Hence, strategies to disrupt reconsolidation of drug reward memory are currently being pursued as potential anti-relapse interventions. Sulfur dioxide (SO), acting as a potential gaseous molecule, endogenously derives from sulfur amino acid and can exert significant neural regulatory effects. However, the role of SO in reconsolidation of drug memory has not been determined. In the present study, we used morphine- or cocaine-induced conditioned place preference (CPP) mouse models with retrieval to investigate the effects of exogenous SO donor treatment on reconsolidation of drug reward memory. We found that administration of SO donor immediately after the retrieval impaired the expression of morphine or cocaine CPP. Furthermore, the exogenous SO donor treatment 6 h post-retrieval or in the absence of retrieval had no effect on drug reward memory and the expression of CPP. SO itself did not produce aversive effects nor did it acutely block morphine CPP. Our results indicate that exogenous SO impairs reconsolidation of drug reward memory rather than inhibits the expression of drug reward memory. As such, SO2 holds potential for the treatment and prevention of SRADs and should be studied further.
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http://dx.doi.org/10.1016/j.ejphar.2021.173911DOI Listing
April 2021

Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals.

Int J Mol Sci 2020 Dec 24;22(1). Epub 2020 Dec 24.

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

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.
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http://dx.doi.org/10.3390/ijms22010134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795330PMC
December 2020

Progress in opioid reward research: From a canonical two-neuron hypothesis to two neural circuits.

Pharmacol Biochem Behav 2021 01 20;200:173072. Epub 2020 Nov 20.

Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, United States of America. Electronic address:

Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying opioid abuse and addiction are still not fully understood. This review discusses recent progress in basic research dissecting receptor mechanisms and circuitries underlying opioid reward and addiction. We first review the canonical GABA-dopamine neuron hypothesis that was upheld for half a century, followed by major findings challenging this hypothesis. We then focus on recent progress in research evaluating the role of the mesolimbic and nigrostriatal dopamine circuitries in opioid reward and relapse. Based on recent findings that activation of dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is equally rewarding and that GABA neurons in the rostromedial tegmental nucleus (RMTg) and the substantia nigra pars reticula (SNr) are rich in mu opioid receptors and directly synapse onto midbrain DA neurons, we proposed that the RTMg→VTA → ventrostriatal and SNr → SNc → dorsostriatal pathways may act as the two major neural substrates underlying opioid reward and abuse. Lastly, we discuss possible integrations of these two pathways during initial opioid use, development of opioid abuse and maintenance of compulsive opioid seeking.
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http://dx.doi.org/10.1016/j.pbb.2020.173072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796909PMC
January 2021

Differential alterations of insular cortex excitability after adolescent or adult chronic intermittent ethanol administration in male rats.

J Neurosci Res 2021 02 22;99(2):649-661. Epub 2020 Oct 22.

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.

Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.
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http://dx.doi.org/10.1002/jnr.24737DOI Listing
February 2021

Beta-caryophyllene inhibits cocaine  addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder.

Neuropsychopharmacology 2021 03 17;46(4):860-870. Epub 2020 Oct 17.

Addiction Biology Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA.

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA-approved medication to treat cocaine use disorder (CUD). In this report, we explored the potential utility of beta-caryophyllene (BCP), an FDA-approved food additive for the treatment of CUD. We found that BCP, when administered intraperitoneally or intragastrically, dose-dependently attenuated cocaine self-administration, cocaine-conditioned place preference, and cocaine-primed reinstatement of drug seeking in rats. In contrast, BCP failed to alter food self-administration or cocaine-induced hyperactivity. It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential. BCP was previously reported to be a selective CB2 receptor agonist. Unexpectedly, pharmacological blockade or genetic deletion of CB1, CB2, or GPR55 receptors in gene-knockout mice failed to alter BCP's action against cocaine self-administration, suggesting the involvement of non-CB1, non-CB2, and non-GPR55 receptor mechanisms. Furthermore, pharmacological blockade of μ opioid receptor or Toll-like receptors complex failed to alter, while blockade of peroxisome proliferator-activated receptors (PPARα, PPARγ) reversed BCP-induced reduction in cocaine self-administration, suggesting the involvement of PPARα and PPARγ in BCP's action. Finally, we used electrical and optogenetic intracranial self-stimulation (eICSS, oICSS) paradigms to study the underlying neural substrate mechanisms. We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.
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http://dx.doi.org/10.1038/s41386-020-00885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026612PMC
March 2021

Dissecting the Role of GABA Neurons in the VTA SNr in Opioid Reward.

J Neurosci 2020 11 12;40(46):8853-8869. Epub 2020 Oct 12.

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

Opioid reward has traditionally been thought to be mediated by GABA-induced disinhibition of dopamine (DA) neurons in the VTA. However, direct behavioral evidence supporting this hypothesis is still lacking. In this study, we found that the μ opioid receptor (MOR) gene, , is highly expressed in GABA neurons, with ∼50% of GABA neurons in the substantia nigra pars reticulata (SNr), ∼30% in the VTA, and ∼70% in the tail of the VTA (also called the rostromedial tegmental nucleus) in male rats. No mRNA was detected in midbrain DA neurons. We then found that optogenetic inhibition of VTA DA neurons reduced intravenous heroin self-administration, whereas activation of these neurons produced robust optical intracranial self-stimulation in DAT-Cre mice, supporting an important role of DA neurons in opioid reward. Unexpectedly, pharmacological blockade of MORs in the SNr was more effective than in the VTA in reducing heroin reward. Optogenetic activation of VTA GABA neurons caused place aversion and inhibited cocaine, but not heroin, self-administration, whereas optogenetic activation of SNr GABA neurons caused a robust increase in heroin self-administration with an extinction pattern, suggesting a compensatory response in drug intake due to reduced heroin reward. In addition, activation of SNr GABA neurons attenuated heroin-primed, but not cue-induced, reinstatement of drug-seeking behavior, whereas inhibition of SNr GABA neurons produced optical intracranial self-stimulation and place preference. Together, these findings suggest that MORs on GABA neurons in the SNr play more important roles in opioid reward and relapse than MORs on VTA GABA neurons. Opioid reward has long been believed to be mediated by inhibition of GABA interneurons in the VTA that subsequently leads to disinhibition of DA neurons. In this study, we found that more μ opioid receptors (MORs) are expressed in GABA neurons in the neighboring SNr than in the VTA, and that pharmacological blockade of MORs in the SNr is more effective in reducing heroin reward than blockade of MORs in the VTA. Furthermore, optogenetic activation of VTA GABA neurons inhibited cocaine, but not heroin, self-administration, whereas activation of SNr GABA neurons inhibited heroin reward and relapse. These findings suggest that opioid reward is more likely mediated by stimulation of MORs in GABA afferents from other brain regions than in VTA GABA neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.0988-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659457PMC
November 2020

Contrasting effects of adolescent and early-adult ethanol exposure on prelimbic cortical pyramidal neurons.

Drug Alcohol Depend 2020 11 21;216:108309. Epub 2020 Sep 21.

Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, 13902, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address:

Background: Adolescence and early-adulthood are vulnerable developmental periods during which binge drinking can have long-lasting effects on brain function. However, little is known about the effects of binge drinking on the pyramidal cells of the prelimbic cortex (PrL) during early and protracted withdrawal periods.

Methods: In the present study, we performed whole-cell patch clamp recordings and dendritic spine staining to examine the intrinsic excitability, spontaneous excitatory post-synaptic currents (sEPSCs), and spine morphology of pyramidal cells in the PrL from rats exposed to chronic intermittent ethanol (CIE) during adolescence or early-adulthood.

Results: Compared to chronic intermittent water (CIW)-treated controls, the excitability of PrL-L5 pyramidal neurons was significantly increased 21 days after adolescent CIE but decreased 21 days after early-adult CIE. No changes of excitability in PrL Layer (L) 5 were detected 2 days after either adolescent or early-adulthood CIE. Interestingly, decreases in sEPSC amplitude and increases in thin spines ratio were detected 2 days after adolescent CIE. Furthermore, decreased frequency and amplitude of sEPSCs, accompanied by a decrease in the density of total spines and non-thin spines were observed 21 days after adolescent CIE. In contrast, increased frequency and amplitude of sEPSCs, accompanied by increased densities of total spines and non-thin spines were found 21 days after early adult CIE.

Conclusion: CIE produced prolonged neuronal and synaptic alterations in PrL-L5, and the developmental stage, i.e., adolescence vs. early-adulthood when subjects receive CIE, is a key factor in determining the direction of these changes.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814343PMC
November 2020

Xie2-64, a novel CB receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents.

Neuropharmacology 2020 10 24;176:108241. Epub 2020 Jul 24.

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

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB receptor (CBR) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CBR inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CBR in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529998PMC
October 2020

Berberine Facilitates Extinction of Drug-Associated Behavior and Inhibits Reinstatement of Drug Seeking.

Front Pharmacol 2020 24;11:476. Epub 2020 Apr 24.

College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, China.

A high rate of relapse is a major clinical problem among drug-addicted individuals. Persistent traces of drug-associated reward memories contribute to intense craving and often trigger relapse. A number of interventions on drug-associated memories have shown significant benefits in relapse prevention. Among them are pre- or post-extinction pharmacological manipulations that facilitate the extinction of drug-associated behavior. Berberine, a bioactive isoquinoline alkaloid, has been recently reported to provide therapeutic benefits for a number of central nervous system (CNS) disorders, including morphine addiction. The present study aimed to investigate whether berberine could serve as a post-extinction pharmacological intervention agent to reduce risks of reinstatement of drug seeking. We found that an intragastric administration of berberine at doses of 25 and 50 mg/kg during the critical time window significantly facilitated the extinction of morphine-reward related behavior in free access and confined conditioned place preference (CPP) extinction paradigms, and subsequently, it prevented reinstatement and spontaneous recovery of morphine-induced CPP in mice. Intriguingly, the berberine treatment with or without extinction training altered expression of plasticity-related proteins such as brain-derived neurotrophic factor (BDNF), AMPA receptors (GluA1 and GluA2) in the nucleus accumbens (NAc). Moreover, the post-extinction berberine treatment significantly reduced reinstatement of cocaine-induced CPP and operant intravenous self-administration (IVSA) memories in rats. Altogether, our findings suggest that extinction training combined with the post-extinction berberine treatment can facilitate extinction of drug-associated behavior making it an attractive therapeutic candidate in relapse prevention.
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http://dx.doi.org/10.3389/fphar.2020.00476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194034PMC
April 2020

Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges.

Neurosci Biobehav Rev 2020 07 3;114:38-52. Epub 2020 May 3.

Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, United States. Electronic address:

Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the current national opioid crisis. Although several opioid-based pharmacotherapies are available (e.g., methadone, buprenorphine, naloxone), they show limited effectiveness in long-term relapse prevention. In response to the opioid crisis, the National Institute on Drug Abuse proposed a list of pharmacological targets of highest priority for medication development for the treatment of opioid use disorders (OUD). Among these are antagonists of dopamine D3 receptors (D3R). In this review, we first review recent progress in research of the dopamine hypothesis of opioid reward and abuse and then describe the rationale and recent development of D3R ligands for the treatment of OUD. Herein, an emphasis is placed on the effectiveness of newly developed D3R antagonists in the animal models of OUD. These new drug candidates may also potentiate the analgesic effects of clinically used opioids, making them attractive as adjunctive medications for pain management and treatment of OUD.
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http://dx.doi.org/10.1016/j.neubiorev.2020.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252042PMC
July 2020

Aberrations in Incentive Learning and Responding to Heroin in Male Rats After Adolescent or Adult Chronic Binge-Like Alcohol Exposure.

Alcohol Clin Exp Res 2020 06 14;44(6):1214-1223. Epub 2020 May 14.

Department of Psychology, (EB, DM, RR), Queens College, City University of New York, Flushing, New York, USA.

Background And Purpose: Binge drinking is a serious problem among adolescents and young adults despite its adverse consequences on the brain and behavior. One area that remains poorly understood concerns the impact of chronic intermittent ethanol (CIE) exposure on incentive learning.

Methods: Here, we examined the effects of CIE exposure during different developmental stages on conditioned approach and conditioned reward learning in rats experiencing acute or protracted withdrawal from alcohol. Two or 21 days after adolescent or adult CIE exposure, male rats were exposed to pairings of a light stimulus (CS) and food pellets for 3 consecutive daily sessions (30 CS-food pellet pairings per session). This was followed by conditioned approach testing measuring responses (food trough head entries) to the CS-only presentations and by conditioned reward testing measuring responses on a lever producing the CS and on another producing a tone. We then measured behavioral sensitization to repeated injections of heroin (2 mg/kg/d for 9 days).

Results: Adolescent and adult alcohol-treated rats showed significantly impaired conditioned reward learning regardless of withdrawal period (acute or prolonged). We found no evidence of changes to conditioned approach learning after adolescent or adult exposure to CIE. Finally, in addition to producing long-term impairments in incentive learning, CIE exposure enhanced locomotor activity in response to heroin and had no effect on behavioral sensitization to heroin regardless of age and withdrawal period.

Conclusions: Our work sets a framework for identifying CIE-induced alterations in incentive learning and inducing susceptibility to subsequent opioid effects.
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http://dx.doi.org/10.1111/acer.14341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313436PMC
June 2020

β-Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents.

Br J Pharmacol 2020 05 15;177(9):2058-2072. Epub 2020 Feb 15.

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

Background And Purpose: β-Caryophyllene (BCP) is a plant-derived terpenoid used as a food additive for many decades. Recent studies indicate that BCP is a cannabinoid CB receptor agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.

Experiment Approach: We used pharmacological, transgenic, and optogenetic approaches to systematically evaluate the effects of BCP on nicotine-taking and nicotine-seeking behaviour in animal models of drug self-administration, electrical, and optical brain-stimulation reward.

Key Results: Systemic administration of BCP dose-dependently inhibited nicotine self-administration and motivation for nicotine seeking in rats and mice. The reduction in nicotine self-administration was blocked by AM630, a selective CB receptor antagonist, but not by AM251, a selective CB receptor antagonist, suggesting involvement of a CB receptor mechanism. Genetic deletion of CB receptors in mice blocked the reduction in nicotine self-administration produced only by low doses, but not by high doses, of BCP, suggesting involvement of both CB and non-CB receptor mechanisms. Furthermore, in the intracranial self-stimulation paradigm, BCP attenuated electrical brain-stimulation reward and nicotine-enhanced brain-stimulation reward in rats. Lastly, BCP also attenuated brain-stimulation reward maintained by optogenetic stimulation of dopaminergic neurons in the ventral tegmental area in DAT-cre mice, suggesting the involvement of a dopamine-dependent mechanism in BCP's action.

Conclusions And Implications: The present findings suggest that BCP has significant anti-nicotine effects via both CB and non-CB receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.
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http://dx.doi.org/10.1111/bph.14969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161544PMC
May 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

Therapeutic efficacy of environmental enrichment for substance use disorders.

Pharmacol Biochem Behav 2020 01 26;188:172829. Epub 2019 Nov 26.

Queens College, City University of New York, Flushing, NY, United States of America. Electronic address:

Addiction to drug and alcohol is regarded as a major health problem worldwide for which available treatments show limited effectiveness. The biggest challenge remains to enhance the capacities of interventions to reduce craving, prevent relapse and promote long-term recovery. New strategies to meet these challenges are being explored. Findings from preclinical work suggest that environmental enrichment (EE) holds therapeutic potential for the treatment of substance use disorders, as demonstrated in a number of animal models of drug abuse. The EE intervention introduced after drug exposure leads to attenuation of compulsive drug taking, attenuation of the rewarding (and reinforcing) effects of drugs, reductions in control of behavior by drug cues, and, very importantly, relapse prevention. Clinical work also suggests that multidimensional EE interventions (involving physical activity, social interaction, vocational training, recreational and community involvement) might produce similar therapeutic effects, if implemented continuously and rigorously. In this review we survey preclinical and clinical studies assessing the efficacy of EE as a behavioral intervention for substance use disorders and address related challenges. We also review work providing empirical evidence for EE-induced neuroplasticity within the mesocorticolimbic system that is believed to contribute to the seemingly therapeutic effects of EE on drug and alcohol-related behaviors.
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http://dx.doi.org/10.1016/j.pbb.2019.172829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944776PMC
January 2020

Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders.

CNS Drugs 2019 10;33(10):1001-1030

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

Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.
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http://dx.doi.org/10.1007/s40263-019-00664-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451396PMC
October 2019

Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT and TRPV1 receptor mechanisms.

Neuropharmacology 2020 05 19;167:107740. Epub 2019 Aug 19.

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

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research there is currently no FDA-approved medication to treat cocaine use disorder. The recent search has been focused on agents targeting primarily the dopamine system, while limited success has been achieved at the clinical level. Cannabidiol (CBD) is a U.S. FDA-approved cannabinoid for the treatment of epilepsy and recently was reported to have therapeutic potential for other disorders. Here we systemically evaluated its potential utility for the treatment of cocaine use disorder and explored the underlying receptor mechanisms in experimental animals. Systemic administration (10-40 mg/kg) of CBD dose-dependently inhibited cocaine self-administration, shifted a cocaine dose-response curve downward, and lowered break-points for cocaine self-administration under a progressive-ratio schedule of reinforcement. CBD inhibited cocaine self-administration maintained by low, but not high, doses of cocaine. In addition, CBD (3-20 mg/kg) dose-dependently attenuated cocaine-enhanced brain-stimulation reward (BSR) in rats. Strikingly, this reduction in both cocaine self-administration and BSR was blocked by AM630 (a cannabinoid CB2 receptor antagonist), WAY100135 (a 5-HT receptor antagonist), or capsazepine (a TRPV1 channel blocker), but not by AM251 (a CB1 receptor antagonist), CID16020046 (a GPR55 antagonist), or naloxone (an opioid receptor antagonist), suggesting the involvement of CB2, 5-HT, and TRPV1 receptors in CBD action. In vivo microdialysis indicated that pretreatment with CBD (10-20 mg/kg) attenuated cocaine-induced increases in extracellular dopamine (DA) in the nucleus accumbens, while CBD alone failed to alter extracellular DA. These findings suggest that CBD may have certain therapeutic utility by blunting the acute rewarding effects of cocaine via a DA-dependent mechanism.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493134PMC
May 2020

Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents.

Addict Biol 2020 07 19;25(4):e12783. Epub 2019 Jun 19.

Addiction Biology Unit, Molecular Targets and Medication Discoveries Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland.

A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)-approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self-administration in rodents and explored the receptor mechanisms underlying CBD-induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose-dependent reduction in sucrose self-administration in rats and in wild-type (WT) and CB1 mice but not in CB2 mice. CBD appeared to be more efficacious in CB1 mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD-induced reduction in sucrose self-administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose-dependent reduction in sucrose self-administration in WT and CB1 mice, but not in CB2 mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133-induced reduction in sucrose self-administration in WT mice, suggesting that CBD inhibits sucrose self-administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity.
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http://dx.doi.org/10.1111/adb.12783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920611PMC
July 2020

Nucleus accumbens shell small conductance potassium channels underlie adolescent ethanol exposure-induced anxiety.

Neuropsychopharmacology 2019 10 16;44(11):1886-1895. Epub 2019 May 16.

Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, 13902, USA.

Alcohol use typically begins in adolescence, increasing the likelihood of adult mental disorders such as anxiety. However, the cellular mechanisms underlying the consequences of adolescent alcohol exposure as well as the behavioral consequences remain poorly understood. We examined the effects of adolescent or adult chronic intermittent ethanol (CIE) exposure on intrinsic excitability of striatal medium-sized spiny neurons (MSNs) and anxiety levels. Rats underwent one of the following procedures: (1) light-dark transition (LDT) and open-field (OF) tests to evaluate anxiety levels and general locomotion; (2) whole-cell patch clamp recordings and biocytin labeling to assess excitability of striatal MSNs, as well as morphological properties; and (3) western blot immunostaining to determine small conductance (SK) calcium-activated potassium channel protein levels. Three weeks, but not 2 days, after CIE treatment, adolescent CIE-treated rats showed shorter crossover latency from the light to dark side in the LDT test and higher MSN excitability in the nucleus accumbens shell (NAcS). Furthermore, the amplitude of the medium afterhyperpolarization (mAHP), mediated by SK channels, and SK3 protein levels in the NAcS decreased concomitantly. Finally, increased anxiety levels, increased excitability, and decreased amplitude of mAHP of NAcS MSNs were reversed by SK channel activator 1-EBIO and mimicked by the SK channel blocker apamin. Thus, adolescent ethanol exposure increases adult anxiety-like behavior by downregulating SK channel function and protein expression, which leads to an increase of intrinsic excitability in NAcS MSNs. SK channels in the NAcS may serve as a target to treat adolescent alcohol binge exposure-induced mental disorders, such as anxiety in adulthood.
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http://dx.doi.org/10.1038/s41386-019-0415-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784903PMC
October 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

Dopamine D1 and D3 receptor polypharmacology as a potential treatment approach for substance use disorder.

Neurosci Biobehav Rev 2018 06 22;89:13-28. Epub 2018 Mar 22.

The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA; Department of Psychology, Queens College, City University of New York, 65-30 Kissena Blvd, Flushing NY 11367, USA. Electronic address:

In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor partial agonists and antagonists have been shown to reduce drug reward, reinstatement of drug seeking and conditioned place preference in rodents and non-human primates. However, translation of these encouraging results to clinical settings has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. This review highlights the role of D1 and D3 receptors in drug reward and seeking, the discovery of D1-D3 heteromers and their potential as targets in the treatment of addiction.
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http://dx.doi.org/10.1016/j.neubiorev.2018.03.020DOI Listing
June 2018

Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats.

Eur J Pharmacol 2018 Jan 20;818:480-485. Epub 2017 Nov 20.

Neuropsychology Doctoral Program, The Graduate Center of the City University of New York, New York, NY 10016, USA; Department of Psychology, Queens College, City University of New York, Flushing, NY 11367, USA. Electronic address:

Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK-801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS-only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS-only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs.
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http://dx.doi.org/10.1016/j.ejphar.2017.11.029DOI Listing
January 2018

The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats.

Drug Alcohol Depend 2015 Nov 25;156:228-233. Epub 2015 Sep 25.

CUNY Graduate Center, New York, NY, United States; Queens College of the City University of New York, Department of Psychology, Flushing, NY, United States. Electronic address:

Background: Because the role of dopamine (DA) D3 receptors has been investigated primarily in relation to cocaine-related behaviors little is known of the role of these receptors in heroin seeking.

Purposes: To investigate the effect of the selective DA D3 receptor antagonist, SR 21502, on cue-induced reinstatement of heroin seeking and heroin conditioned place preference (CPP).

Methods: In experiment 1, rats were trained to self-administer intravenous heroin for 15 days followed by extinction. Following extinction animals were treated with one of several SR 21502 doses (0, 7.5, 10 or 15mg/kg) and a cue-induced reinstatement test was conducted. In experiment 2, animals were conditioned to experience heroin in one compartment of a CPP apparatus and saline in the other. On the test day animals were treated with 0, 3.75, 7.5, 10 or 15mg/kg of SR 21502 and tested for their CPP.

Results: The results from experiment 1 showed a significant dose-related reduction in cue-induced reinstatement of active lever pressing in the 7.5 and 10mg groups and an absence of the reinstatement effect in the 15mg group. In experiment 2, animals treated with vehicle or 3.75mg of SR 21502 showed significant heroin place preferences but those treated with the higher doses showed no CPP.

Conclusions: Our findings suggest that DA D3 receptors play a significant role in heroin approach behaviors driven by conditioned stimuli. As such, we propose that SR 21502 holds potential as an effective pharmacotherapeutic agent for relapse prevention and should be studied further.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633332PMC
November 2015

Environmental enrichment induces early heroin abstinence in an animal conflict model.

Pharmacol Biochem Behav 2015 Nov 12;138:20-5. Epub 2015 Sep 12.

Graduate Center, City University of New York, New York, New York 10016, United States; Psychology Department, Queens College, 65-30 Kissena Blvd, Flushing, NY 11367, United States. Electronic address:

Rationale And Objectives: Heroin addiction is a significant health and societal problem for which there is no highly effective long-term behavioral or pharmacological treatment. Therefore, strategies that support heroin abstinence should be a primary focus of heroin treatment research. To this end, the current study used an animal conflict model that captures the aversive consequences of drug seeking (as are typical in humans, e.g., incarceration and job loss) to induce abstinence. Using this abstinence model, we examined the capacity of environmental enrichment (EE) to facilitate abstinence in heroin seeking rats.

Methods: The procedure consisted of two phases: drug self-administration (phase 1) and electric barrier application (phase 2) that resulted in abstinence. For phase 1, male rats were trained to self-administer intravenous heroin under a fixed-ratio schedule of reinforcement. After self-administration was acquired, animals were housed either in EE or standard cages (non-EE control). During abstinence in phase 2, the electric barrier was introduced in the operant conditioning chambers by electrifying the floor area near the levers.

Results: We found that EE rats achieved abstinence (zero active lever presses for 3 consecutive sessions) in significantly fewer sessions than NEE rats. Further, EE rats abstained at significantly lower electric currents than NEE rats.

Conclusions: EE facilitated abstinence in the conflict model. The current use of the abstinence-conflict model to investigate EE as a behavioral strategy to facilitate abstinence will help in the development of effective treatments for human addicts by bringing together the positive consequences of abstinent behavior in an enriched environment with the aversive consequences of drug seeking.
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http://dx.doi.org/10.1016/j.pbb.2015.09.009DOI Listing
November 2015

Differential effects on natural reward processing in rats after repeated heroin.

Psychopharmacology (Berl) 2013 Sep 23;229(1):125-32. Epub 2013 Apr 23.

The Graduate Center, City University of New York, New York, NY, USA.

Rationale: Heroin users report reward deficits as well as reward enhancements (to drug stimuli). To better understand the causal relation between chronic heroin and alterations in natural reward processing, we used experimental techniques in animal models.

Methods: Separate groups of rats were trained in several food reward paradigms: conditioned place preference (CPP), food-reinforced lever pressing under a progressive ratio schedule of reinforcement, free feeding, and lever pressing with conditioned reinforcement. After training, the rats were subjected to 10 daily heroin (2 mg/kg) or saline vehicle injections and tested at 3, 15, and 30 days post-treatment.

Results: Repeated heroin treatment abolished the CPP and significantly reduced break points for food reward at 3, 15, and 30 days post-treatment. Repeated heroin did not affect free feeding. Finally, repeated heroin significantly enhanced responding for a food-based conditioned reinforcer.

Conclusions: Repeated heroin decreases the attractiveness of food-associated cues and reduces motivation to work for natural reward. However, it appears to enhance natural conditioned reward processes that involve the acquisition of novel responding. Thus, repeated heroin appears to produce differential effects on natural reward processing depending on the nature of the reward-directed behavior.
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http://dx.doi.org/10.1007/s00213-013-3087-8DOI Listing
September 2013
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