Attenuation of the Euphoric Effects of Cocaine by the Dopamine D1/D5 Antagonist Ecopipam (SCH 39166)

Romach, Myroslava K.; Glue, Paul; Kampman, Kyle M.; Kaplan, Howard L.; Somer, Gail; Poole, Sabrina; Clarke, Laura; Coffin, Vicki L.; Cornish, James; O’Brien, Charles P.; Sellers, Edward M.

doi:10.1001/archpsyc.56.12.1101

Cited by 106 publications

(81 citation statements)

References 22 publications

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“…Lowdose D 1 antagonist treatments alter the direct reinforcing actions of cocaine without interfering with motor performance (Amalric et al 1993) or food-maintained behavior (Caine and Koob 1994). Consistent with these observations, a selective D 1 antagonist (SCH 39166) was recently shown to attenuate the euphoric effects of cocaine in humans without inducing sedation or nonspecific anhedonic effects (Romach et al 1999). More importantly, SCH 23390 selectively and dose-dependently reduced conditioned responding maintained by a cocaine-related conditioned stimulus, while leaving fully intact behavior maintained by a stimulus associated with a food reinforcer (Weissenborn et al 1996).…”

Section: Discussionmentioning

confidence: 66%

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: Discussionmentioning

confidence: 66%

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

Weiss

2001

Neuropsychopharmacology

183

131

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“…If weight loss typically results in improvements in mood across methods of weight loss (37,38), a treatment that results in sustained weight loss would be expected to improve instead of worsen the mood of the participants. Previous human studies of ecopipam in cocaine-abusing patients did not report any psychiatric adverse effects including depression or suicidality (22,23,39); however, these studies were all of short duration and do not offer sufficient assurance that depression may not occur with the more extended treatment that would be required to treat obesity.…”

Section: Discussionmentioning

confidence: 97%

“…Subjects could continue dyslipidemic medications in all studies and oral hypoglycemic and anti-hypertensive medications in Study 3.3. Outpatient visits were scheduled on Day 1 and at Weeks 2,4,8,12,16,22,28,34,40,46,and 52. Study medication was counted at each visit to confirm compliance.…”

Section: Methodsmentioning

confidence: 99%

Randomized Controlled Trials of the D1/D5 Antagonist Ecopipam for Weight Loss in Obese Subjects

Astrup

Greenway

Ling

et al. 2007

Obesity

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“…No effect (Haney 1999) No data No data Increase with low dose of cocaine; no effect with high dose of cocaine (Haney 2001) Subjective effects of cocaine in a laboratory setting Decrease (Haney 1999) No data Decrease (Romach 1999) Increase (Haney 2001) Craving for cocaine in a laboratory setting Decrease (trend) (Haney 1999) No data Decrease (Romach 1999) Decrease (with placebo cocaine) (Haney 2001) …”

Section: Alcoholmentioning

confidence: 99%

The reinstatement model and relapse prevention: a clinical perspective

2003

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Objectives-This commentary assesses the degree to which the reinstatement model is homologous to the human experience of relapse.Results-A review of the literature suggests that the relationship is less clear than is often assumed, largely due to a lack of prospective data on the precipitants and process of relapse (especially relapse to heroin or cocaine abuse). However, reinstatement does not need to resemble relapse to have immediate clinical value; predictive validity as a medication screen would be sufficient. Whether the model has predictive validity is unknown, because, to date, very few clinical trials have tested medications that are effective in the reinstatement model, and even fewer have used designs comparable to those of reinstatement experiments. A clinical trial comparable to a reinstatement experiment would enroll participants who are already abstinent, and its main outcome measure would be propensity to undergo a specific type of relapse (e.g., relapse induced by stress or cues).Conclusions-Until clinical and preclinical work are more comparable, criticisms of the reinstatement model's presumed shortcomings are premature.The reinstatement model has generated a body of preclinical data that grows increasingly substantial and impressive (Shaham et al. 2003). Yet opinions remain divided about its relation to clinical realities (Marlatt 1996;Bergman and Katz 1998). In this commentary, we address the issues of whether reinstatement resembles relapse, whether it can be useful without resembling relapse, and why neither of those questions can yet be answered satisfactorily. We have drawn on clinical literature and on our own experiences working with substance abusers. Does reinstatement resemble relapse? MaybeIn most published discussions of the reinstatement model, attention is drawn to the fact that the most widely studied precipitants of reinstatement in rats (drug priming, drug-associated cues, and stress) are provocatively similar to the precipitants of relapse in humans. This is typically taken as a point of commonality between the reinstatement model and the real-life experiences of recovered addicts. It is tempting to agree without further consideration; the assertion that priming, cues, and stress precipitate relapse is intuitively appealing and seems to accord with clinical experience. But how strong is the evidence that most relapses are precipitated by any of those three factors?No definitive answer can be found in the clinical literature. Relapse is usually described retrospectively, with weeks or months intervening between the event and its recollection. This leaves ample time for the introduction of recall bias and the formation of post hoc explanations for the reporter's behavior. As an only slightly tangential illustration of the problem, consider the intuitively plausible prediction that abused children are at increased risk for later addiction. The prediction is confirmed when adult addicts are asked retrospectively about their childhoods -but not when abused and nonabused c...

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Attenuation of the Euphoric Effects of Cocaine by the Dopamine D1/D5 Antagonist Ecopipam (SCH 39166)

Abstract: These data indicate a potentially important role for D1-like receptors in the acute mood-altering and rewarding effects of cocaine in humans.

Cited by 106 publications

References 22 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

Randomized Controlled Trials of the D1/D5 Antagonist Ecopipam for Weight Loss in Obese Subjects

The reinstatement model and relapse prevention: a clinical perspective

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