Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior

Spealman, Roger D.; Barrett-Larimore, Rita L.; Rowlett, James K.; Platt, Donna M.; Khroyan, Taline V.

doi:10.1016/s0091-3057(99)00049-0

Cited by 157 publications

(173 citation statements)

References 65 publications

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Section: Discussionsupporting

confidence: 87%

“…Nonetheless, the attenuation of cueinduced cocaine-seeking behavior by SCH 23390 and nafadotride is consistent with the finding that cocaineassociated environmental stimuli increase extracellular dopamine levels in limbic brain regions . Moreover, these data complement and extend prior evidence that has implicated D 1 (Ciccocioppo et al 1999;Spealman et al 1999;Weissenborn et al 1996) and D 2/3 (Pilla et al 1999) receptors in the mediation of the conditioned effects of cocaine-related environmental stimuli.In conclusion, the results show that cocaine-seeking behavior elicited by drug-related discriminative stimuli in rats is highly resistant to extinction. The enduring responsiveness to these stimuli may involve learned or drug-induced changes in dopaminergic function, necessary for the expression of cocaine-seeking behavior induced by cocaine-predictive environmental stimuli.…”

supporting

confidence: 87%

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Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

Weiss

2001

Neuropsychopharmacology

183

131

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The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocainerelated stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S D ) with the availability of intravenous cocaine (S ϩ ) vs. the availability of non-rewarding (S Ϫ)Cocaine addiction is a chronic relapsing disorder (Leshner 1997;O'Brien et al. 1998;O'Brien and McLellan 1996). Relapse prevention has therefore emerged as a central issue in treatment and medications development efforts (Carroll et al. 1991;DeLong 1994; O'Brien 362 F. Weiss et al. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 3 and McLellan 1996). A wealth of clinical studies point towards drug-related stimuli or events as a critical factor in the long-lasting compulsion to abuse drugs. This literature suggests that environmental stimuli repeatedly paired with the subjective actions of cocaine throughout an individual's history of drug abuse can produce intense drug craving (Childress et al. 1988;Ehrman et al. 1992;Kilgus and Pumariega 1994;Robbins et al. 1997;Satel et al. 1995;Wallace 1989) or elicit automatic behavioral responses (Miller and Gold 1994;Tiffany and Carter 1998) that may lead to relapse.Consistent with a role of conditioning factors in the resumption of drug abuse habits, several studies in animals have demonstrated that drug-associated stimuli can elicit a transient recovery of extinguished responding at a lever previously associated with cocaine selfadministration (e.g., deWit and Stewart 1981;Fuchs et al. 1998). However, little information is available, to date, about the persistence of cue-induced drug-seeking behavior. In recent work that has begun to address this issue, appreciable cued recovery of cocaine-seeking behavior was observed when rats were presented with cocaine cues on two separate occasions spaced 20 days apart. Similarly, the efficacy of a cocaine cue to reinstate extinguished cocaine-seeking behavior was found to persist for up to eight days of intermittent testing . The latter study revealed also that cocaine cues increase extracellular dopamine levels in the nucleus accumbens and amygdala. These findings indicate that the behavioral effects of cocaine-related environmental stimuli can show resistance to extinction, and that their motivating effects may involve activation of forebrain DA neurotransmission.Considering the mounting evidence that learned responses to cocaine-related stimuli represents a significant factor in long-lasting relapse risk (see O'Brien et al. 1998 for review), better understanding of the environmental, behavioral, and neuropharmacological bases of this phenomenon will be of substantial clinical benefit. The purpose of the present study was to characterize the resistance to extinction of cocaine-seeking behav...

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Section: Discussionsupporting

confidence: 87%

supporting

confidence: 87%

Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

Weiss

2001

Neuropsychopharmacology

183

131

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“…A number of studies have shown that D 1 -or D 2 -preferring antagonists inhibit cocaine self-administration, cocaineenhanced BSR, and cocaine-triggered reinstatement of drug-seeking behavior (Wilson and Schuster, 1972;de Wit and Wise, 1977;Koob et al, 1987;Bergman et al, 1990;Corrigall and Coen, 1991;McGregor and Roberts, 1993;Caine and Koob, 1994;Caine et al, 1995Caine et al, , 2002Self et al, 1996;Awasaki et al, 1997;Ikemoto et al, 1997;Kita et al, 1999;Spealman et al, 1999;Khroyan et al, 2000Khroyan et al, , 2003Hummel and Unterwald, 2002;Norman et al, 2002;Anderson et al, 2003;Sanchez et al, 2003; for reviews see Platt et al, 2002;Kapur and Mamo, 2003;Gorelick et al, 2004). Consequently, this raises the issue of whether the presently observed attenuating effects of NGB 2904 in these three behavioral paradigms might be attributable to D 1 or D 2 receptor-selective antagonism rather than to D 3 receptor-selective antagonism.…”

Section: Ngb 2904's Selective Blockade Of Da D 3 Receptorsmentioning

confidence: 99%

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

Newman

Gilbert

et al. 2005

Neuropsychopharmacol

145

177

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Accumulating evidence indicates that dopamine (DA) D 3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D 3 -selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D 3 -selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

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“…Reinstatement test sessions used procedures identical to those during cocaine self-administration except that only saline was available for self-administration. Except when noted below, responsecontingent presentations of the cocaine-paired stimulus were restored during reinstatement test sessions because earlier studies showed that reinstatement of drug seeking induced by cocaine priming was greatest when priming injections were accompanied by restoration of the cocainepaired stimulus (Spealman et al, 1999(Spealman et al, , 2004. Between reinstatement test sessions with different doses of a particular drug, extinction sessions were conducted for 3 or more days to ensure that monkeys maintained low rates of responding in the absence of cocaine self-administration.…”

Section: Reinstatement Of Drug Seekingmentioning

confidence: 99%

Pharmacological Blockade of α2-Adrenoceptors Induces Reinstatement of Cocaine-Seeking Behavior in Squirrel Monkeys

Lee

Tiefenbacher

Platt

et al. 2004

Neuropsychopharmacol

148

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Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an a 2 -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 a 2 -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 cocaineseeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocainepaired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and selfgrooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the a 2 -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 a 2 -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.

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Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior

Cited by 157 publications

References 65 publications

Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

Pharmacological Blockade of α2-Adrenoceptors Induces Reinstatement of Cocaine-Seeking Behavior in Squirrel Monkeys

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