Effects of dopamine D 1-like and D 2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions

Caine, S. Barak; Negus, S. Stevens; Mello, Nancy K.

doi:10.1007/s002130050023

Cited by 65 publications

(67 citation statements)

References 37 publications

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“…Studies focusing specifically on the dopamine D 2 receptor have typically reported an increase in D 2 receptor density following chronic exercise (Gilliam et al, 1984;MacRae et al, 1987). The D 2 receptor plays an important modulatory role in cocaine's reinforcing effects (Nader et al, 1999;Caine et al, 2000;Khroyan et al, 2000), and there is an increasing body of evidence that the reinforcing effects of psychomotor stimulants are inversely related to D 2 receptor density. For instance, in humans, the psychomotor stimulant methylphenidate is rated as less pleasurable and more aversive in people with high D 2 receptor density than in people with low D 2 receptor density (Volkow et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Smith

Schmidt

Iordanou

et al. 2008

Drug and Alcohol Dependence

138

146

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Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixedratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3 mg/kg/infusion) and high (1.0 mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.

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Section: Discussionmentioning

confidence: 99%

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Smith

Schmidt

Iordanou

et al. 2008

Drug and Alcohol Dependence

138

146

View full text Add to dashboard Cite

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“…The acute effects of mixed mu/kappa agonists on cocaine's reinforcing and discriminative stimulus effects have been less consistent. In a drug self-administration procedure where treatment drug effects on multiple unit doses of cocaine could be evaluated in two or three sessions (Caine et al, 2000), the mixed mu/ kappa agonists (À)cyclorphan, Mr2034, and MCL-101 dose dependently decreased cocaine self-administration with minimal side effects (Bowen et al, 2003). However, acute administration of the same mixed mu/kappa agonists that reduced cocaine self-administration did not significantly attenuate cocaine discrimination, and did not produce rightward shifts in the cocaine discrimination dose-effect curve in rhesus monkeys (Negus and Mello, 1999;Bowen et al, 2003).…”

Section: Kappa Opioid-cocaine Interactionsmentioning

confidence: 99%

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

Mello

Mendelson

Sholar

et al. 2004

Neuropsychopharmacol

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Kappa opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and reduce cocaine selfadministration by rhesus monkeys. We compared the cardiovascular and subjective effects of acute doses of the mu/kappa opioid nalbuphine alone (5 mg/70 kg, intravenous (i.v.)), with cocaine alone (0.2 mg/kg, i.v.), and with nalbuphine þ cocaine in combination, under placebo-controlled, double-blind conditions. Subjects met American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV) criteria for current cocaine abuse. Nalbuphine serum levels exceeded 50 ng/ml within 10 min after injection, and cocaine plasma levels exceeded 130 ng/ml within 4 min. Cocaine's pharmacokinetic profile did not change after concurrent nalbuphine administration. The nalbuphine þ cocaine combination was safe and without synergistic effects on heart rate and systolic or diastolic blood pressure. Moreover, the addition of cocaine did not increase the subjective effects of nalbuphine. Visual Analog Scale (VAS) ratings of High, Euphoria, Stimulated, and Good Effect were equivalent after nalbuphine þ cocaine and nalbuphine alone, and both were significantly higher than after cocaine alone (area under the curve analysis) (po0.05-0.01). Peak VAS ratings of High, Stimulated, Good Effect, and Drug Effect were also significantly higher after nalbuphine þ cocaine than after cocaine alone (po0.01). Addiction Research Center Inventory (ARCI) scores were equivalent for nalbuphine þ cocaine and nalbuphine alone, but the PCAG, MBG, and amphetamine scores were significantly higher after both nalbuphine þ cocaine and nalbuphine alone than after cocaine alone (po0.01-0.003). Thus, there were no additive interactions between nalbuphine and cocaine on cardiovascular, subjective, or drug level measures after acute administration.

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“…The D1 receptor plays a critical role in mediating the behavioral and cellular effects of cocaine. For example, D1 receptor agonists and antagonists can affect cocaine-induced locomotor responses, discriminative stimulus, reinforcing effects, and reinstatement in a variety of experimental animal systems (Cabib et al, 1991;Caine and Koob, 1994;Tella, 1994;Cervo and Samanin, 1995;Pruitt et al, 1995;Self et al, 1996;Grech et al, 1996;Baker et al, 1998;Tzschentke, 1998;Caine et al, 1999Caine et al, , 2000Katz et al, 1999;Khroyan et al, 2000;Anderson et al, 2003;Nazarian et al, 2004). Repeated cocaine injections also lead to persistent increases in D1 receptor sensitivity within the NAc (Henry and White, 1995).…”

Section: Introductionmentioning

confidence: 99%

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor 1, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca 2 þ /calmodulin-dependent protein kinase II a subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.

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Effects of dopamine D 1-like and D 2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions

Abstract: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.

Cited by 65 publications

References 37 publications

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

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