The Supramammillary Nucleus Mediates Primary Reinforcement via GABAA Receptors

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Abstract
The supramammillary nucleus (SUM), a dorsal layer of the mammillary body, has recently been implicated in positive reinforcement. The present study examined whether GABAA 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 GABAA 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 GABAA agonist muscimol disrupted picrotoxin self-administration, and another GABAA antagonist, bicuculline, was also self-administered into the SUM; thus, the reinforcing effect of picrotoxin is mediated by GABAA receptors. Since rats did not self-administer the GABAB antagonist 2-hydroxysaclofen into the SUM, the role of GABAB receptors may be distinct from that of GABAA 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 GABAA receptor blockade depend on normal dopamine transmission. In conclusion, the blockade of GABAA receptors in the SUM is reinforcing, and the brain ‘reward’ circuitry appears to be tonically inhibited via supramammillary GABAA receptors and more extensive than the meso-limbic dopamine system.