Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Abstract

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.

Cocaine Is Self-Administered into the Shell but Not the Core of the Nucleus Accumbens of Wistar Rats

“…Direct microinjections of DA antagonists into the Acb resulted in compensatory increases in i.v. cocaine self-administration (Maldonado et al, 1993;McGregor and Roberts, 1993;Phillips et al, 1994b). Self-administration (i.v.…”

“…Subsequently, cocaine self-administration (i.v.) is altered by either systemic (Haile and Kosten, 2001) or intra-accumbens (McGregor and Roberts, 1993;Caine and Koob, 1994;Phillips et al, 1994b) administration of D 1 and D 2 receptor agents. Self-administration of the DA-reuptake inhibitor nomifensine into the AcbSh is reduced by coadministration of the D 2 receptor antagonist sulpiride (Carlezon et al, 1995).…”

“…self-administration paradigms, administration of D 1 and D 2 receptor antagonists typically increases the amount of responding, and number of infusions received for cocaine (McGregor and Roberts, 1993;Caine and Koob, 1994;Phillips et al, 1994b;Haile and Kosten, 2002). The increase in responding and number of infusions has been asserted as a compensatory reaction so that the organism maintains the previously established level of reinforcement (Caine and Koob, 1994;Phillips et al, 1994b). Under ICSA conditions, coadministration of D 2/3 receptor antagonists reduced cocaine self-administration in the mPFC and in the AcbSh.…”

“…For example, there is a marked contrast between the effects of systemic (Haile and Kosten, 2001) or intra-accumbens (McGregor and Roberts, 1993;Caine and Koob, 1994;Phillips et al, 1994b) administration of D 1 and D 2 receptor agents on i.v. self-administration of cocaine and cocaine ICSA.…”

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

“…This outcome contrasts with self-administration studies demonstrating that the reinforcing effect of cocaine using either FR or PR schedules is attenuated by D 2 antagonists administered either systemically (Ettenberg et al 1982;Roberts and Vickers 1984;Dalton et al 1986;Roberts et al 1989;Corrigall and Coen 1991;Caine and Koob 1994) or into the nucleus accumbens (Phillips et al 1994). Although D 2 antagonists administered prior to a self-administration session can produce non-specifi c effects on responding independent of reinforcing effects (e.g., Winger 1994), the increase in cocaine self-administration that occurs on an FR schedule following low doses of D 2 antagonists is generally thought to refl ect a decrease in the reinforcing effect of the self-administered cocaine.…”