Heroin and cocaine intravenous self-administration in rats: Mediation by separate neural systems

Ettenberg, Aaron; Pettit, Hugh O.; Bloom, Floyd E.; Koob, George F.

doi:10.1007/bf00428151

Cited by 537 publications

(284 citation statements)

References 32 publications

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“…SA. This observation, consistent with previous studies on the effect of DA receptor antagonists on the acquisition of heroin SA (Ettenberg et al, 1982), excludes the possibility that impairment of cocaine SA induced by silencing of NAc shell DA D1aR is due to a general impairment of instrumental learning or motivation. Collectively therefore, the impairment of cocaine self-administration, elicited by silencing of D1aR expression in the NAc shell, can be interpreted as due to a devaluation of the reinforcing properties of cocaine.…”

Section: Discussionsupporting

confidence: 91%

“…At low doses it selectively increases responding for cocaine without affecting responding for heroin, while at higher doses, it reduces responding for both drugs (Ettenberg et al, 1982). These observations have been interpreted to mean that low doses of flupentixol selectively impair cocaine reinforcement, while higher doses exert a general effect on motivation and on its expression into action (Ettenberg et al, 1982). Given these premises, manipulation of DA D1aR expression by RNAi in the NAc shell versus core was utilized to investigate the role of DA in these two NAc subdivisions in cocaine reinforcement.…”

Section: Introductionmentioning

confidence: 95%

“…Early experimental studies by Ettenberg et al (1982) showed that systemic administration of DA receptor antagonists elicits a compensatory increase of intravenous (i.v.) cocaine selfadministration (SA) in fully trained rats, thus mimicking the effect of non-reinforcement.…”

Section: Introductionmentioning

confidence: 99%

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Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

et al. 2015

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Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of cFos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 95%

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Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

et al. 2015

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“…In the present study, the monoamine releaser damphetamine was tested as a candidate 'agonist' medication, because it produces many cocaine-like effects (Colpaert et al, 1979;Hoffman, 2001), and because several recent clinical studies reported promising results with d-amphetamine maintenance in the treatment of stimulant abuse (Fleming and Roberts, 1994;Charnaud and Griffiths, 1998;White, 2000;Grabowski et al, 2001). Flupenthixol was tested as a representative 'antagonist' medication, because it is a nonselective antagonist at D1 and D2 dopamine receptors that was reported to block some abuse-related effects of cocaine (Ettenberg et al, 1982;Baker et al, 1993) and that has also been evaluated as a treatment for cocaine dependence (Soyka and DeVry, 2000;Evans et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Rapid Assessment of Choice between Cocaine and Food in Rhesus Monkeys: Effects of Environmental Manipulations and Treatment with d-Amphetamine and Flupenthixol

Negus

2002

Neuropsychopharmacol

183

118

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The present study describes a procedure that permits rapid assessment of environmental and pharmacological factors that may influence the choice between cocaine and food in rhesus monkeys. Daily 2 h sessions were divided into five components. During each component, monkeys (N ¼ 4) chose between i.v. cocaine (0-0.1 mg/kg/injection) and food (0, 1, or 3 food pellets). Up to 10 reinforcers were available during each component, and different discriminative stimuli were associated with each magnitude of each reinforcer. Cocaine choice was directly related to cocaine dose, and a cocaine choice dose-effect curve could be determined in a single experimental session. The choice between cocaine and food was influenced by the schedules of cocaine and food reinforcement, the magnitude of the food reinforcer, and the amount of noncontingent food provided outside the experimental session. These results confirm and extend previous findings with other choice procedures and validate the sensitivity of the present procedure to environmental manipulations. The choice between cocaine and food could also be influenced by treatment with candidate pharmacotherapies for cocaine abuse and dependence. The 'agonist' medication d-amphetamine produced rightward shifts in the cocaine choice dose-effect curve and decreased cocaine choice, whereas the 'antagonist' medication flupenthixol had little effect on cocaine choice. Overall, these results suggest that this choice procedure may be useful for the evaluation of both environmental determinants of cocaine use and candidate pharmacotherapies for the treatment of cocaine abuse.

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“…Cocaine is a psychostimulant that is addictive and readily self-administered by humans and various animal species (Ettenberg et al 1982;Koob 1992;Ritz et al 1988). Cocaine decreases dopamine reuptake by inhibiting the dopamine transporter in the mesolimbic system, an effect thought to be critical for self-administration and other behaviors associated with cocaine reinforcement (Goeders and Smith 1983;Karler et al 1989;Ritz et al 1987;RoddHenricks et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

et al. 2008

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Rationale-Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.Objective-This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling in order to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.Methods-Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n=48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine treated animals from this initial experiment (n=24) also received an acute cocaine challenge on day 18 of testing.Results-Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 mins after cocaine injection and attenuated the sustained locomotor response 15 to 40 mins after cocaine. Further, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 mins after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.Conclusion-Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.

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Heroin and cocaine intravenous self-administration in rats: Mediation by separate neural systems

Cited by 537 publications

References 32 publications

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Rapid Assessment of Choice between Cocaine and Food in Rhesus Monkeys: Effects of Environmental Manipulations and Treatment with d-Amphetamine and Flupenthixol

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

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