Donna M. Platt

Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior

Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli: however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaines indirect dopamine agonist properties or that act as direct agonists at D2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D1- and D2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/ or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.

Pharmacological blockade of α2-Adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys

Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an α2-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct α2-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1–0.56 mg/kg, i.m.) or RS-79948 (0.01–0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the α2-adrenoceptor agonist clonidine (0.1–0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of α2-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.

Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development

Abstract Rationale. The illicit use of cocaine is a persistent health problem worldwide. Currently, there are no broadly effective pharmacotherapies to treat cocaine addiction. A prerequisite for development of useful anti-cocaine medications is an understanding of the pharmacological basis of cocaines effects. The functional analysis of behavior in laboratory animals has allowed for the development of strategies identifying candidate medications to treat cocaine addiction. Objectives. This review summarizes the current status of dopaminergic compounds as cocaine pharmacotherapies in animal models of cocaine addiction. Results. Maintenance medications should share key subjective effects with cocaine, yet have limited abuse liability and side effects. However, maintenance medications often have reinforcing effects that could contribute to abuse potential and side effects that could deter patient compliance. Combined with cocaine, these drugs enhance cocaines effects. Cocaine antagonists should block the effects of cocaine and have no cocaine-like effects or side effects on their own. However, the cocaine-modulating effects of candidate cocaine antagonists are often surmountable, and, on their own, these drugs produce severe motoric side effects. In contrast, dopamine (DA) partial agonists should exhibit reduced abuse potential relative to agonists, as well as less severe motoric effects relative to antagonists. Combined with cocaine, these drugs should antagonize cocaines effects. Conclusions. DA partial agonists, in particular the D3-selective and the D1-like partial agonists, offer a more encouraging profile for novel anti-cocaine medications. Neither class of drug is self-administered, and side effects are often less severe and only observed at doses above those that antagonize the effects of cocaine.

κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms

κ Opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that κ agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the κ agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the α2-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of κ opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by κ agonists.

D-cycloserine Deters Reacquisition of Cocaine Self-Administration by Augmenting Extinction Learning

Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse.

Pharmacological Stimulation of Group II Metabotropic Glutamate Receptors Reduces Cocaine Self-Administration and Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

Group II metabotropic glutamate receptors (mGluRs) have been implicated in regulating the psychopharmacologic effects of cocaine and other drugs of abuse. The present study investigated the interactions between the group II mGluR agonist LY379268 [(-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate] and cocaine in squirrel monkeys whose operant behavior was maintained under a second order schedule of i.v. cocaine self-administration with or without presentations of a cocaine-paired visual stimulus, extinguished and subsequently reinstated by priming injections of cocaine with or without presentations of a cocaine-paired stimulus, and controlled by cocaine trained as a discriminative stimulus. Antagonism studies with the group II mGluR antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl) propanoic acid] investigated the extent to which the cocaine-modulating effects of LY379268 could be reversed by blocking group II mGluRs. Quantitative observational studies investigated the effects of LY379268 and LY341495 on species-typical behaviors, balance, and muscle resistance. Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner. Significant effects of LY379268 were observed both in the presence and absence of the cocaine-paired stimulus. LY379268 did not alter the discriminative stimulus effects of cocaine, nor did it markedly affect observed behavior, with the exception of an increase in visual scanning. Emesis frequently was observed after the highest dose of LY379268 (1.0 mg/kg). The results suggest that LY379268, by stimulating group II mGluRs, can attenuate the reinforcing and priming effects of cocaine at doses that do not alter its perceptibility or markedly suppress other behaviors.

Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine

RationaleThe mGluR5 antagonist MPEP has effects that suggest potential as a pharmacotherapy for cocaine addiction. MPEP can attenuate self-administration of cocaine in animals; however, studies usually involved only acute treatment with MPEP and a single dose of self-administered cocaine. Cocaine addicts use varied amounts of cocaine over long periods of time, and an effective pharmacotherapy would almost certainly require more chronic treatment.ObjectivesThe present study (1) compared the effects of repeated treatment with MPEP or the NMDA receptor antagonist dizocilpine on the reinforcing effects of a range of doses of cocaine and (2) determined the pharmacological specificity of the effects of the drugs in attenuating cocaine self-administration compared to food-reinforced behavior. An effective pharmacotherapy should selectively reduce cocaine self-administration.Materials and methodsGroups of monkeys responded under a fixed-ratio schedule of i.v. cocaine self-administration or food-pellet delivery. The effects of daily treatment with MPEP and dizocilpine were determined under both the schedule of i.v. cocaine injection and food delivery.ResultsTreatment with MPEP and dizocilpine significantly reduced cocaine self-administration, producing rightward and downward shifts in the ascending limb of the cocaine dose–response function. MPEP and dizocilpine selectively and significantly attenuated self-administration of a low reinforcing dose of cocaine compared to food without evidence of tolerance.ConclusionsBoth MPEP and dizocilpine functioned as partially surmountable antagonists of the reinforcing effects of cocaine. The similar effects of the two drugs raises the possibility that MPEP attenuated the reinforcing effects of cocaine, at least in part, via mGluR5-mediated inhibition of NMDA receptor activity.

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaines abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin- 1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl]methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaines discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaines DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine- and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaines DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.

Noradrenergic Mechanisms in Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

Norepinephrine (NE) uptake and NE receptor mechanisms play important modulating roles in the discriminative stimulus and stimulant effects of cocaine. The present study investigated the role of NE mechanisms in cocaine priming-induced reinstatement of extinguished drug seeking. Squirrel monkeys (Saimiri sciureus) were trained to stability under a second-order fixed interval, fixed ratio schedule of drug self-administration in which operant responding was maintained jointly by i.v. cocaine injections and presentations of a cocaine-paired stimulus. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In test sessions during which the cocaine-paired stimulus was reintroduced but only vehicle was available for self-administration, priming with cocaine, the dopamine transport inhibitor 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), and the NE transport inhibitors nisoxetine and talsupram induced dose-dependent reinstatement of drug seeking. The maximum effect of the NE transport inhibitors was less than half that of cocaine. Both nisoxetine and talsupram augmented the priming effects of a low but not a high dose of cocaine. The priming effects of nisoxetine were blocked by the α1-adrenoceptor antagonist prazosin, the α2-adrenoceptor agonist clonidine, and the β-adrenoceptor antagonist propranolol, but not by the dopamine receptor antagonist flupenthixol. The priming effects of cocaine were antagonized by clonidine and flupenthixol. Neither nisoxetine nor cocaine increased physiological (salivary cortisol) or behavioral (self-directed behaviors) markers of stress. These findings suggest that NE transporter inhibition and α2-adrenoceptor mechanisms play a significant role in cocaine-induced reinstatement of drug seeking that is not secondary to activation of brain stress pathways.

A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys

BACKGROUND Variation at the human mu-opioid receptor has been associated with alcohol abuse. The A118G (N40D) polymorphism in humans is functionally mimicked by the C77G (P26R) polymorphism in rhesus monkeys; both show similar in vitro influences on ligand binding and in vivo correlations with physiological measures as well as behavioral measures including predilection towards alcohol consumption. Naltrexone, an antagonist at the receptor, has been used to treat alcoholism in humans and has been reported to show differences in effectiveness depending on genotype. METHODS Here we describe a study in which we a priori selected rhesus monkeys based on genotype at the OPRM1 C77G single nucleotide polymorphism, trained them to self-administer alcohol, and assessed naltrexone responsiveness. RESULTS Alcohol intake in rhesus monkeys varied with genotype across a range of alcohol concentrations (0.5-4%, w/v) such that animals with the G/G genotype drank consistently more alcohol than those animals with the C/C genotype. Additionally, naltrexone attenuated alcohol drinking in a dose- and genotype-dependent manner. Animals harboring the G/G genotype were more sensitive to the effects of naltrexone and showed greater reductions in alcohol consumption at lower naltrexone doses compared to animals with a C/G or C/C genotype. CONCLUSIONS This preliminary study demonstrates a pharmacogenomic response to naltrexone in rhesus monkeys that parallels that seen in humans. This finding provides a basis for developing a pharmacogenetic animal model for naltrexone effect that can expand further our understanding of the causes and treatments of alcohol use disorders.