¹Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA

Correspondence: Dr S Ikemoto, Behavioral Neuroscience Branch, NIDA, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: +410 550 1447; Fax: +410 550 1612; E-mail: sikemoto@intra.nida.nih.gov

Received 20 August 2004; Revised 23 November 2004; Accepted 29 November 2004; Published online 2 February 2005.

Abstract

The supramammillary nucleus (SUM), a dorsal layer of the mammillary body, has recently been implicated in positive reinforcement. The present study examined whether GABA_A receptors in the SUM or adjacent regions are involved in primary reinforcement using intracranial self-administration procedures. Rats learned quickly to lever-press for infusions of the GABA_A antagonist picrotoxin into the SUM. Although picrotoxin was also self-administered into the posterior hypothalamic nuclei and anterior ventral tegmental area, these regions were less responsive to lower doses of picrotoxin than the SUM. The finding that rats learned to respond selectively on the lever triggering drug infusions is consistent with picrotoxin's reinforcing effect. Coadministration of the GABA_A agonist muscimol disrupted picrotoxin self-administration, and another GABA_A antagonist, bicuculline, was also self-administered into the SUM; thus, the reinforcing effect of picrotoxin is mediated by GABA_A receptors. Since rats did not self-administer the GABA_B antagonist 2-hydroxysaclofen into the SUM, the role of GABA_B receptors may be distinct from that of GABA_A receptors. Pretreatment with the dopamine receptor antagonist SCH 23390 (0.05 mg/kg, i.p.) extinguished picrotoxin self-administration into the SUM, suggesting that the reinforcing effects of GABA_A receptor blockade depend on normal dopamine transmission. In conclusion, the blockade of GABA_A receptors in the SUM is reinforcing, and the brain 'reward' circuitry appears to be tonically inhibited via supramammillary GABA_A receptors and more extensive than the meso-limbic dopamine system.