Taline Khroyan - Academia.edu (original) (raw)

Papers by Taline Khroyan

Research paper thumbnail of Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/ Opioid Receptor Ligands: Implications for Therapeutic Applications

Journal of Pharmacology and Experimental Therapeutics, 2009

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treat... more The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the -opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphineinduced CPP.

Research paper thumbnail of High Affinity α3β4 Nicotinic Acetylcholine Receptor Ligands AT-1001 and AT-1012 Attenuate Cocaine-Induced Conditioned Place Preference and Behavioral Sensitization in Mice

Biochemical Pharmacology, 2015

Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circui... more Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1-10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.

Research paper thumbnail of Universal opioid receptor ligands - buprenorphine and related orvinols

Pharmacological reports: PR

Research paper thumbnail of Varenicline enhances dopamine release facilitation more than nicotine after long-term nicotine treatment and withdrawal

Pharmacology Research & Perspectives, 2014

An important factor contributing to the high relapse rates among smokers is nicotine withdrawal s... more An important factor contributing to the high relapse rates among smokers is nicotine withdrawal symptoms. Multiple studies suggest that decreased dopamine release in nucleus accumbens plays a key role in withdrawal. However, recent reports showed that long-term nicotine exposure itself also decreases accumbal dopamine release, suggesting that additional mechanisms are involved in withdrawal. Here, we used real-time cyclic voltammetry in brain slices containing the nucleus accumbens to further elucidate the changes in dopamine release linked to nicotine withdrawal. Rats received vehicle or nicotine via the drinking water for 2-3 months. Studies assessing the expression of somatic signs in vehicle-treated, nicotine-treated, and 24-h nicotine withdrawn rats showed that nicotine withdrawal led to a significant increase in somatic signs. Subsequent voltammetry studies showed that long-term nicotine decreased single-pulse-stimulated dopamine release via an interaction at a6b2* receptors. Nicotine withdrawal led to a partial recovery in a6b2* receptor-mediated release. In addition, long-term nicotine treatment alone increased dopamine release paired-pulse ratios and this was partially reversed with nicotine removal. We then evaluated the effect of bath-applied nicotine and varenicline on dopamine release. Nicotine and varenicline both decreased single-pulse-stimulated release in vehicle-treated, nicotine-treated, and nicotine withdrawn rats. However, bath-applied varenicline increased paired-pulse ratios to a greater extent than nicotine during long-term nicotine treatment and after its withdrawal. Altogether these data suggest that nicotine withdrawal is associated with a partial restoration of dopamine release measures to control levels and that varenicline's differential modulation of dopamine release may contribute to its mechanism of action.

Research paper thumbnail of Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide

Attachment of a glucose moiety to 6-b-aminomorphine afforded compound 3, where the glucose moiety... more Attachment of a glucose moiety to 6-b-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-b-aminomorphine and 2,3,4,6-tetra-O-benzyl-D D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the l opioid receptor with a K i value of 3.5 nM. The C-glycoside 3 exhibited d/l and j/l selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the l opioid receptor with a K i value of 0.5 nM, was less selective for the l opioid receptor. The [ 35 S]GTPcS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the l opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.

Research paper thumbnail of Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2003

This article describes the ongoing collaborative effort of six research teams to operationalize a... more This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the...

Research paper thumbnail of The role of alpha3beta4 nicotinic receptors in cocaine-induced reward acquisition and behavioral sensitization

Drug and Alcohol Dependence, 2014

Research paper thumbnail of Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception

The FASEB Journal, 2012

Computational methods have led two groups to predict the endogenous presence of a highly conserve... more Computational methods have led two groups to predict the endogenous presence of a highly conserved, amidated, 14-amino acid neuropeptide called either spexin or NPQ. NPQ/spexin is part of a larger prohormone that contains three sets of RR residues, suggesting that it could yield more than one bioactive peptide; yet no in vivo activity has been demonstrated for any peptide processed from this precursor. Here we demonstrate biological activity for two peptides present within proNPQ/spexin. NPQ/spexin (NWTPQAMLYLKGAQ-NH2) and NPQ53-70 (FISDQSRRKDLSDRPLPE) have differing renal and cardiovascular effects when administered intracerebroventricularly or intravenously into rats. Intracerebroventricular injection of NPQ/spexin produced a 13±2 mm Hg increase in mean arterial pressure, a 38±8 bpm decrease in heart rate, and a profound decrease in urine flow rate. Intracerebroventricular administration of NPQ53-70 produced a 26±9 bpm decrease in heart rate with no change in mean arterial pressure, and a marked increase in urine flow rate. Intraventricular NPQ/spexin and NPQ53-70 also produced antinociceptive activity in the warm water tail-withdrawal assay in mice (ED 50 < 30 nmol and 10 nmol for NPQ/spexin and NPQ53-70 respectively). We conclude that newly identified peptides derived from the NPQ/spexin precursor contribute to CNS-mediated control of arterial blood pressure and salt and water balance, and modulate nociceptive responses.

Research paper thumbnail of Effects of intraaccumbens administration of SCH‐23390 on cocaine‐induced locomotion and conditioned place preference

Synapse, 1998

The effects of systemic (0-1.0 mg/kg) or intraaccumbens (0-1.0 microg/side) administration of SCH... more The effects of systemic (0-1.0 mg/kg) or intraaccumbens (0-1.0 microg/side) administration of SCH-23390 on cocaine-induced (0 or 4.2 mg/kg, i.v.) locomotion, sniffing, and conditioned place preference (CPP) were investigated in rats. After behavioral testing was completed, animals were injected with their respective dose of SCH-23390 into the nucleus accumbens (NAc), followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by intraaccumbens SCH-23390, and therefore protected from EEDQ-induced inactivation, were then quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of 0.5 and 1.0 mg/kg SCH-23390 reversed cocaine-induced locomotion, sniffing, and CPP, suggesting that stimulation of D1-like receptors is necessary for these behavioral changes. Intraaccumbens administration of 1.0 microg/side SCH-23390 reversed cocaine-CPP, and this dose occupied D1-like receptors primarily in the rostral pole of the NAc. Intraaccumbens administration of 0.5 microg/side SCH-23390 reversed cocaine-induced locomotion. However, this dose occupied a similar number of D1-like receptors in the NAc as a lower and behaviorally ineffective dose of 0.1 microg/side, but occupied more receptors in the caudate-putamen relative to both the 0.1 and 1.0 microg/side doses. These findings suggest that stimulation of D1-like receptors in the NAc is necessary for cocaine-CPP, but not for cocaine-induced locomotion.

Research paper thumbnail of Effects of SCH-23390 on dopamine D1 receptor occupancy and locomotion produced by intraaccumbens cocaine infusion

Synapse, 1998

This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 i... more This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 in rats on dopamine D1 receptor occupancy and on locomotor activity produced by intraaccumbens infusion of cocaine. In experiment 1, rats received SCH-23390 (0-1 mg/kg, i.p.) 15 minutes prior to intraaccumbens infusion of cocaine (0 or 100 microg/side). In experiment 2, rats received coinfusion of SCH-23390 (0-1 microg/side) and cocaine (0 or 100 microg/side) into the nucleus accumbens (NAc). After behavioral testing, receptors occupied by SCH-23390 were quantified by injecting animals with their respective dose of SCH-23390, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by SCH-23390, and therefore protected from EEDQ-induced inactivation, were quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of SCH-23390 dose-dependently (0.1-1.0 mg/kg) reversed cocaine-induced locomotion and occupied 72-100% of D1-like receptors in the anterior NAc. D1 receptor occupancy following systemic administration of SCH-23390 was evident as an inverted U-shaped, dose-dependent change, with the greatest occupancy observed at the intermediate dose of 0.3 mg/kg. Intraaccumbens infusion of SCH-23390 did not alter cocaine-induced locomotor activity despite occupying 40-60% of D1-like receptors in the anterior NAc core and shell. The findings that systemic, but not intraaccumbens, administration of SCH-23390 potently reversed locomotion produced by intraaccumbens cocaine infusion suggest that stimulation of D1 receptors in regions other than the NAc is involved in locomotion produced by intraaccumbens infusion of cocaine, and that stimulation of D1 receptors in the NAc is not necessary for this behavior.

Research paper thumbnail of Genetics and Drug Use as a Complex Phenotype

Substance Use & Misuse, 2004

Drug use is a complex behavior influenced by multiple biological, family, and sociocultural facto... more Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.

Research paper thumbnail of Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning

Psychopharmacology, 1995

Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assess... more Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assessed. Three 2-day conditioning trials were conducted. On 1 day, animals received an injection of one of eight doses of 7-OH-DPAT (0-5 mg/kg) and were placed into a distinct compartment for 40 min. On the other day, animals received an injection of saline and were placed into a different compartment for 40 min. Locomotion, sniffing, and yawning were measured following the first and last injection of 7-OH-DPAT. Place conditioning was assessed on the day following the last trial. 7-OH-DPAT produced a U-shaped dose-dependent change in locomotion and sniffing, and an inverted U-shaped dose-dependent change in yawning. Additionally, repeated administration of 0.1 mg/kg sensitized yawning, whereas 5 mg/kg sensitized locomotion. None of the doses of 7-OH-DPAT produced conditioned place preference, however, there was a trend for conditioned place aversion at 0.03 mg/kg. By contrast, LiCl (127 mg/kg) produced conditioned place aversion and amphetamine (1 mg/kg) produced conditioned place preference using the same conditioning parameters. A subsequent experiment in which the number of animals and conditioning trials were increased demonstrated that the 0.03 mg/kg dose of 7-OH-DPAT produced conditioned place aversion. 7-OH-DPAT has a higher affinity for D3 receptors relative to D2 receptors. Therefore, it is suggested that intermediate doses (0.01-0.1 mg/kg) that increase yawning, and decrease locomotion and sniffing, may preferentially occupy D3 receptors. Furthermore, the results suggest that these putative D3-preferring doses have weak aversive effects.

Research paper thumbnail of Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference

Psychopharmacology, 1998

Low doses of the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-D... more Low doses of the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) produce a behavioral profile that is opposite to that produced by the psychomotor stimulants cocaine and amphetamine. For example, low doses of 7-OH-DPAT produce conditioned place aversion and hypolocomotion, whereas psychomotor stimulants produce conditioned place preference (CPP) and hyperlocomotion. In experiment 1, the effects of low doses of 7-OH-DPAT (0.01-0.1 mg/kg) on d-amphetamine-induced (1 mg/kg) motor behaviors and CPP were assessed. In experiment 2, the effects of 0.1 mg/kg 7-OH-DPAT on d-amphetamine (0-10 mg/kg) dose-response curves for the same behaviors were examined. During conditioning, drug injections were paired with a distinct compartment, whereas saline injections were paired with another compartment. Locomotion and headbobbing were measured following acute and repeated drug administration during conditioning and place conditioning was assessed 24 h following the last conditioning day. In experiment 1, d-amphetamine-induced locomotion was dose-dependently decreased by 7-OH-DPAT following repeated administration, which was probably due to the emergence of headbobbing, a behavior not observed with d-amphetamine alone. d-Amphetamine-CPP was not altered by co-administration of 0-0.03 mg/kg 7-OH-DPAT, but was attenuated by co-administration of 0.1 mg/kg 7-OH-DPAT. In experiment 2, 7-OH-DPAT co-administered with low doses of d-amphetamine (0-0.5 mg/kg) produced a decrease in locomotion following acute administration. However, 7-OH-DPAT produced sensitization of locomotion at the 0.5 mg/kg dose of d-amphetamine and an increase in headbobbing at the 0.5-10 mg/kg doses of d-amphetamine following repeated administration. In contrast, d-amphetamine-CPP was attenuated by co-administration of 7-OH-DPAT. These findings suggest that 0.1 mg/kg 7-OH-DPAT attenuates the reinforcing effects of d-amphetamine despite enhancing stereotypic behaviors.

Research paper thumbnail of Dose-dependent characterization of the rewarding and stimulant properties of cocaine following intraperitoneal and intravenous administration in rats

Psychopharmacology, 1996

Dose-dependent differences in the rewarding and stimulant properties of cocaine administered intr... more Dose-dependent differences in the rewarding and stimulant properties of cocaine administered intravenously (IV) and intraperitoneally (IP) were compared. Six 2-day conditioning trials were conducted over consecutive days. Rats received cocaine and were placed into a compartment on one day of the trial, and were directly placed into a different compartment without drug on the other day. Rats were exposed to the compartments for either 20 or 40 min. The effects of cocaine on stimulant behaviors, including locomotion and stereotypies, were compared following the first and last injection. After conditioning, three tests were given with 1 rest day intervening each: (1) conditioned place preference (CPP) was measured as an increase in the amount of time animals spent in the injection compartment relative to the noninjection compartment when given access to both, (2) conditioned activity (CA) was measured as an increase in stimulant behaviors in cocaine-treated animals relative to saline controls following an injection of saline in the injection compartment and (3) context-independent sensitization was measured as an increase in stimulant behaviors following an injection of cocaine in the noninjection compartment relative to the animals&amp;amp;#39; behavior following the first injection. Cocaine did not reliably produce sensitization of locomotion under any of the conditions examined. Cocaine produced sensitization of headbobbing that was more robust following IP administration than it was following IV administration. In both cases, sensitization of headbobbing involved a context-independent component. Cocaine produced CPP and CA with both routes of administration. CPP was established more readily with 40-min relative to 20-min exposures following IV administration, whereas CA was more prevalent with 20-min relative to 40-min exposures. This study provides a thorough characterization of the behavioral effects of cocaine administered IV and a new efficient method for assessing the effects of cocaine on conditioned and unconditioned behaviors following repeated administration.

Research paper thumbnail of Attenuation of relapse to cocaine seeking by dopamine D 1 receptor agonists and antagonists in non-human primates

Psychopharmacology, 2003

Abstracts Rationale: Dopamine D 1 receptor agonists and antagonists attenuate reinstatement of co... more Abstracts Rationale: Dopamine D 1 receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D 1 receptor drugs produce these similar effects on cocaine seeking are unknown. Objectives: This study investigated how D 1 receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus. Methods: Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixedinterval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D 1 receptor highand low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking. Results: Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D 1 receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually. Conclusions: These findings suggest that D 1 receptor high-and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D 1 receptors.

Research paper thumbnail of Rodent models of nicotine reward: What do they tell us about tobacco abuse in humans?

Pharmacology Biochemistry and Behavior, 2009

Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrat... more Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditioning (PC), and the intracranial self-stimulation (ICSS) paradigms in rodents. The strengths, limitations and procedural variables of these models are reviewed, followed by a discussion of how the animal models have been used to study factors such as age, sex, stress, and the effects of tobacco products other than nicotine. These factors are discussed in light of their influences on human tobacco abuse. The rodent models are evaluated in the context of face, predictive, and construct validity, and we propose that inclusion of factors such as age, sex, stress and other constituents of tobacco aside from nicotine can increase the utility of these animal models by more closely mimicking human tobacco abuse.

Research paper thumbnail of Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration

Pharmacology Biochemistry and Behavior, 2002

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), o... more Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Research paper thumbnail of Novel ligands interacting with opioid receptors

Pharmacological Reports, 2011

Research paper thumbnail of Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR

The Pharmacogenomics Journal, 2005

The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopa... more The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior. In a study of smokers enrolled in an open-label, randomized effectiveness trial, we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling. Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women who carry both A2 alleles, women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects (odds ratio (OR)=1.91, 95% confidence interval (CI)=1.01-3.60; P&amp;amp;amp;amp;lt;0.04) and at 12 months were somewhat more likely to report smoking (OR=0.76, 95% CI=0.56-1.03; P&amp;amp;amp;amp;lt;0.076). Significant associations or trends were not observed in men. In women, individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function.

Research paper thumbnail of Intergenerational transmission of tobacco use and dependence: A transdisciplinary perspective

Nicotine & Tobacco Research, 2003

Numerous questions remain regarding the intergenerational transmission of tobacco use and depende... more Numerous questions remain regarding the intergenerational transmission of tobacco use and dependence, and some of these questions are best approached from a transdisciplinary perspective. For example, considering both genetic and environmental influences on cigarette smoking promises to be a fruitful venue for future investigations. In this paper, we consider the evidence regarding intergenerational influences on the transmission of tobacco use and nicotine dependence in both humans and animal models; our focus will be on genetic influences, in utero exposure to nicotine, and some postnatal influences. Research gaps that exist between scientific disciplines are highlighted, and some directions for future research are suggested.

Research paper thumbnail of Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/ Opioid Receptor Ligands: Implications for Therapeutic Applications

Journal of Pharmacology and Experimental Therapeutics, 2009

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treat... more The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the -opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphineinduced CPP.

Research paper thumbnail of High Affinity α3β4 Nicotinic Acetylcholine Receptor Ligands AT-1001 and AT-1012 Attenuate Cocaine-Induced Conditioned Place Preference and Behavioral Sensitization in Mice

Biochemical Pharmacology, 2015

Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circui... more Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1-10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.

Research paper thumbnail of Universal opioid receptor ligands - buprenorphine and related orvinols

Pharmacological reports: PR

Research paper thumbnail of Varenicline enhances dopamine release facilitation more than nicotine after long-term nicotine treatment and withdrawal

Pharmacology Research & Perspectives, 2014

An important factor contributing to the high relapse rates among smokers is nicotine withdrawal s... more An important factor contributing to the high relapse rates among smokers is nicotine withdrawal symptoms. Multiple studies suggest that decreased dopamine release in nucleus accumbens plays a key role in withdrawal. However, recent reports showed that long-term nicotine exposure itself also decreases accumbal dopamine release, suggesting that additional mechanisms are involved in withdrawal. Here, we used real-time cyclic voltammetry in brain slices containing the nucleus accumbens to further elucidate the changes in dopamine release linked to nicotine withdrawal. Rats received vehicle or nicotine via the drinking water for 2-3 months. Studies assessing the expression of somatic signs in vehicle-treated, nicotine-treated, and 24-h nicotine withdrawn rats showed that nicotine withdrawal led to a significant increase in somatic signs. Subsequent voltammetry studies showed that long-term nicotine decreased single-pulse-stimulated dopamine release via an interaction at a6b2* receptors. Nicotine withdrawal led to a partial recovery in a6b2* receptor-mediated release. In addition, long-term nicotine treatment alone increased dopamine release paired-pulse ratios and this was partially reversed with nicotine removal. We then evaluated the effect of bath-applied nicotine and varenicline on dopamine release. Nicotine and varenicline both decreased single-pulse-stimulated release in vehicle-treated, nicotine-treated, and nicotine withdrawn rats. However, bath-applied varenicline increased paired-pulse ratios to a greater extent than nicotine during long-term nicotine treatment and after its withdrawal. Altogether these data suggest that nicotine withdrawal is associated with a partial restoration of dopamine release measures to control levels and that varenicline's differential modulation of dopamine release may contribute to its mechanism of action.

Research paper thumbnail of Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide

Attachment of a glucose moiety to 6-b-aminomorphine afforded compound 3, where the glucose moiety... more Attachment of a glucose moiety to 6-b-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-b-aminomorphine and 2,3,4,6-tetra-O-benzyl-D D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the l opioid receptor with a K i value of 3.5 nM. The C-glycoside 3 exhibited d/l and j/l selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the l opioid receptor with a K i value of 0.5 nM, was less selective for the l opioid receptor. The [ 35 S]GTPcS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the l opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.

Research paper thumbnail of Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2003

This article describes the ongoing collaborative effort of six research teams to operationalize a... more This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the...

Research paper thumbnail of The role of alpha3beta4 nicotinic receptors in cocaine-induced reward acquisition and behavioral sensitization

Drug and Alcohol Dependence, 2014

Research paper thumbnail of Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception

The FASEB Journal, 2012

Computational methods have led two groups to predict the endogenous presence of a highly conserve... more Computational methods have led two groups to predict the endogenous presence of a highly conserved, amidated, 14-amino acid neuropeptide called either spexin or NPQ. NPQ/spexin is part of a larger prohormone that contains three sets of RR residues, suggesting that it could yield more than one bioactive peptide; yet no in vivo activity has been demonstrated for any peptide processed from this precursor. Here we demonstrate biological activity for two peptides present within proNPQ/spexin. NPQ/spexin (NWTPQAMLYLKGAQ-NH2) and NPQ53-70 (FISDQSRRKDLSDRPLPE) have differing renal and cardiovascular effects when administered intracerebroventricularly or intravenously into rats. Intracerebroventricular injection of NPQ/spexin produced a 13±2 mm Hg increase in mean arterial pressure, a 38±8 bpm decrease in heart rate, and a profound decrease in urine flow rate. Intracerebroventricular administration of NPQ53-70 produced a 26±9 bpm decrease in heart rate with no change in mean arterial pressure, and a marked increase in urine flow rate. Intraventricular NPQ/spexin and NPQ53-70 also produced antinociceptive activity in the warm water tail-withdrawal assay in mice (ED 50 < 30 nmol and 10 nmol for NPQ/spexin and NPQ53-70 respectively). We conclude that newly identified peptides derived from the NPQ/spexin precursor contribute to CNS-mediated control of arterial blood pressure and salt and water balance, and modulate nociceptive responses.

Research paper thumbnail of Effects of intraaccumbens administration of SCH‐23390 on cocaine‐induced locomotion and conditioned place preference

Synapse, 1998

The effects of systemic (0-1.0 mg/kg) or intraaccumbens (0-1.0 microg/side) administration of SCH... more The effects of systemic (0-1.0 mg/kg) or intraaccumbens (0-1.0 microg/side) administration of SCH-23390 on cocaine-induced (0 or 4.2 mg/kg, i.v.) locomotion, sniffing, and conditioned place preference (CPP) were investigated in rats. After behavioral testing was completed, animals were injected with their respective dose of SCH-23390 into the nucleus accumbens (NAc), followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by intraaccumbens SCH-23390, and therefore protected from EEDQ-induced inactivation, were then quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of 0.5 and 1.0 mg/kg SCH-23390 reversed cocaine-induced locomotion, sniffing, and CPP, suggesting that stimulation of D1-like receptors is necessary for these behavioral changes. Intraaccumbens administration of 1.0 microg/side SCH-23390 reversed cocaine-CPP, and this dose occupied D1-like receptors primarily in the rostral pole of the NAc. Intraaccumbens administration of 0.5 microg/side SCH-23390 reversed cocaine-induced locomotion. However, this dose occupied a similar number of D1-like receptors in the NAc as a lower and behaviorally ineffective dose of 0.1 microg/side, but occupied more receptors in the caudate-putamen relative to both the 0.1 and 1.0 microg/side doses. These findings suggest that stimulation of D1-like receptors in the NAc is necessary for cocaine-CPP, but not for cocaine-induced locomotion.

Research paper thumbnail of Effects of SCH-23390 on dopamine D1 receptor occupancy and locomotion produced by intraaccumbens cocaine infusion

Synapse, 1998

This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 i... more This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 in rats on dopamine D1 receptor occupancy and on locomotor activity produced by intraaccumbens infusion of cocaine. In experiment 1, rats received SCH-23390 (0-1 mg/kg, i.p.) 15 minutes prior to intraaccumbens infusion of cocaine (0 or 100 microg/side). In experiment 2, rats received coinfusion of SCH-23390 (0-1 microg/side) and cocaine (0 or 100 microg/side) into the nucleus accumbens (NAc). After behavioral testing, receptors occupied by SCH-23390 were quantified by injecting animals with their respective dose of SCH-23390, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by SCH-23390, and therefore protected from EEDQ-induced inactivation, were quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of SCH-23390 dose-dependently (0.1-1.0 mg/kg) reversed cocaine-induced locomotion and occupied 72-100% of D1-like receptors in the anterior NAc. D1 receptor occupancy following systemic administration of SCH-23390 was evident as an inverted U-shaped, dose-dependent change, with the greatest occupancy observed at the intermediate dose of 0.3 mg/kg. Intraaccumbens infusion of SCH-23390 did not alter cocaine-induced locomotor activity despite occupying 40-60% of D1-like receptors in the anterior NAc core and shell. The findings that systemic, but not intraaccumbens, administration of SCH-23390 potently reversed locomotion produced by intraaccumbens cocaine infusion suggest that stimulation of D1 receptors in regions other than the NAc is involved in locomotion produced by intraaccumbens infusion of cocaine, and that stimulation of D1 receptors in the NAc is not necessary for this behavior.

Research paper thumbnail of Genetics and Drug Use as a Complex Phenotype

Substance Use & Misuse, 2004

Drug use is a complex behavior influenced by multiple biological, family, and sociocultural facto... more Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.

Research paper thumbnail of Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning

Psychopharmacology, 1995

Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assess... more Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assessed. Three 2-day conditioning trials were conducted. On 1 day, animals received an injection of one of eight doses of 7-OH-DPAT (0-5 mg/kg) and were placed into a distinct compartment for 40 min. On the other day, animals received an injection of saline and were placed into a different compartment for 40 min. Locomotion, sniffing, and yawning were measured following the first and last injection of 7-OH-DPAT. Place conditioning was assessed on the day following the last trial. 7-OH-DPAT produced a U-shaped dose-dependent change in locomotion and sniffing, and an inverted U-shaped dose-dependent change in yawning. Additionally, repeated administration of 0.1 mg/kg sensitized yawning, whereas 5 mg/kg sensitized locomotion. None of the doses of 7-OH-DPAT produced conditioned place preference, however, there was a trend for conditioned place aversion at 0.03 mg/kg. By contrast, LiCl (127 mg/kg) produced conditioned place aversion and amphetamine (1 mg/kg) produced conditioned place preference using the same conditioning parameters. A subsequent experiment in which the number of animals and conditioning trials were increased demonstrated that the 0.03 mg/kg dose of 7-OH-DPAT produced conditioned place aversion. 7-OH-DPAT has a higher affinity for D3 receptors relative to D2 receptors. Therefore, it is suggested that intermediate doses (0.01-0.1 mg/kg) that increase yawning, and decrease locomotion and sniffing, may preferentially occupy D3 receptors. Furthermore, the results suggest that these putative D3-preferring doses have weak aversive effects.

Research paper thumbnail of Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference

Psychopharmacology, 1998

Low doses of the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-D... more Low doses of the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) produce a behavioral profile that is opposite to that produced by the psychomotor stimulants cocaine and amphetamine. For example, low doses of 7-OH-DPAT produce conditioned place aversion and hypolocomotion, whereas psychomotor stimulants produce conditioned place preference (CPP) and hyperlocomotion. In experiment 1, the effects of low doses of 7-OH-DPAT (0.01-0.1 mg/kg) on d-amphetamine-induced (1 mg/kg) motor behaviors and CPP were assessed. In experiment 2, the effects of 0.1 mg/kg 7-OH-DPAT on d-amphetamine (0-10 mg/kg) dose-response curves for the same behaviors were examined. During conditioning, drug injections were paired with a distinct compartment, whereas saline injections were paired with another compartment. Locomotion and headbobbing were measured following acute and repeated drug administration during conditioning and place conditioning was assessed 24 h following the last conditioning day. In experiment 1, d-amphetamine-induced locomotion was dose-dependently decreased by 7-OH-DPAT following repeated administration, which was probably due to the emergence of headbobbing, a behavior not observed with d-amphetamine alone. d-Amphetamine-CPP was not altered by co-administration of 0-0.03 mg/kg 7-OH-DPAT, but was attenuated by co-administration of 0.1 mg/kg 7-OH-DPAT. In experiment 2, 7-OH-DPAT co-administered with low doses of d-amphetamine (0-0.5 mg/kg) produced a decrease in locomotion following acute administration. However, 7-OH-DPAT produced sensitization of locomotion at the 0.5 mg/kg dose of d-amphetamine and an increase in headbobbing at the 0.5-10 mg/kg doses of d-amphetamine following repeated administration. In contrast, d-amphetamine-CPP was attenuated by co-administration of 7-OH-DPAT. These findings suggest that 0.1 mg/kg 7-OH-DPAT attenuates the reinforcing effects of d-amphetamine despite enhancing stereotypic behaviors.

Research paper thumbnail of Dose-dependent characterization of the rewarding and stimulant properties of cocaine following intraperitoneal and intravenous administration in rats

Psychopharmacology, 1996

Dose-dependent differences in the rewarding and stimulant properties of cocaine administered intr... more Dose-dependent differences in the rewarding and stimulant properties of cocaine administered intravenously (IV) and intraperitoneally (IP) were compared. Six 2-day conditioning trials were conducted over consecutive days. Rats received cocaine and were placed into a compartment on one day of the trial, and were directly placed into a different compartment without drug on the other day. Rats were exposed to the compartments for either 20 or 40 min. The effects of cocaine on stimulant behaviors, including locomotion and stereotypies, were compared following the first and last injection. After conditioning, three tests were given with 1 rest day intervening each: (1) conditioned place preference (CPP) was measured as an increase in the amount of time animals spent in the injection compartment relative to the noninjection compartment when given access to both, (2) conditioned activity (CA) was measured as an increase in stimulant behaviors in cocaine-treated animals relative to saline controls following an injection of saline in the injection compartment and (3) context-independent sensitization was measured as an increase in stimulant behaviors following an injection of cocaine in the noninjection compartment relative to the animals&amp;amp;#39; behavior following the first injection. Cocaine did not reliably produce sensitization of locomotion under any of the conditions examined. Cocaine produced sensitization of headbobbing that was more robust following IP administration than it was following IV administration. In both cases, sensitization of headbobbing involved a context-independent component. Cocaine produced CPP and CA with both routes of administration. CPP was established more readily with 40-min relative to 20-min exposures following IV administration, whereas CA was more prevalent with 20-min relative to 40-min exposures. This study provides a thorough characterization of the behavioral effects of cocaine administered IV and a new efficient method for assessing the effects of cocaine on conditioned and unconditioned behaviors following repeated administration.

Research paper thumbnail of Attenuation of relapse to cocaine seeking by dopamine D 1 receptor agonists and antagonists in non-human primates

Psychopharmacology, 2003

Abstracts Rationale: Dopamine D 1 receptor agonists and antagonists attenuate reinstatement of co... more Abstracts Rationale: Dopamine D 1 receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D 1 receptor drugs produce these similar effects on cocaine seeking are unknown. Objectives: This study investigated how D 1 receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus. Methods: Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixedinterval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D 1 receptor highand low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking. Results: Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D 1 receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually. Conclusions: These findings suggest that D 1 receptor high-and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D 1 receptors.

Research paper thumbnail of Rodent models of nicotine reward: What do they tell us about tobacco abuse in humans?

Pharmacology Biochemistry and Behavior, 2009

Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrat... more Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditioning (PC), and the intracranial self-stimulation (ICSS) paradigms in rodents. The strengths, limitations and procedural variables of these models are reviewed, followed by a discussion of how the animal models have been used to study factors such as age, sex, stress, and the effects of tobacco products other than nicotine. These factors are discussed in light of their influences on human tobacco abuse. The rodent models are evaluated in the context of face, predictive, and construct validity, and we propose that inclusion of factors such as age, sex, stress and other constituents of tobacco aside from nicotine can increase the utility of these animal models by more closely mimicking human tobacco abuse.

Research paper thumbnail of Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration

Pharmacology Biochemistry and Behavior, 2002

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), o... more Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Research paper thumbnail of Novel ligands interacting with opioid receptors

Pharmacological Reports, 2011

Research paper thumbnail of Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR

The Pharmacogenomics Journal, 2005

The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopa... more The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior. In a study of smokers enrolled in an open-label, randomized effectiveness trial, we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling. Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women who carry both A2 alleles, women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects (odds ratio (OR)=1.91, 95% confidence interval (CI)=1.01-3.60; P&amp;amp;amp;amp;lt;0.04) and at 12 months were somewhat more likely to report smoking (OR=0.76, 95% CI=0.56-1.03; P&amp;amp;amp;amp;lt;0.076). Significant associations or trends were not observed in men. In women, individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function.

Research paper thumbnail of Intergenerational transmission of tobacco use and dependence: A transdisciplinary perspective

Nicotine & Tobacco Research, 2003

Numerous questions remain regarding the intergenerational transmission of tobacco use and depende... more Numerous questions remain regarding the intergenerational transmission of tobacco use and dependence, and some of these questions are best approached from a transdisciplinary perspective. For example, considering both genetic and environmental influences on cigarette smoking promises to be a fruitful venue for future investigations. In this paper, we consider the evidence regarding intergenerational influences on the transmission of tobacco use and nicotine dependence in both humans and animal models; our focus will be on genetic influences, in utero exposure to nicotine, and some postnatal influences. Research gaps that exist between scientific disciplines are highlighted, and some directions for future research are suggested.