Does Blockade of GABAA Receptors Affect Sociability in Rats?

Science Center, Bent Corridor

Background: Schizophrenia manifests itself in three symptom classes: positive, negative, and cognitive symptoms. Although the neurobiology mediating these symptoms is not understood, increasing evidence suggests that symptoms may be caused by decreased inhibitory GABA transmission. Indeed, post-mortem analyses find decreased expression of GAD67, upregulation of GAT1 and a variety of changes in the expression of GABAA receptor subunits. The goal of the current experiment was to determine if widespread blockade of GABAA receptors, using the GABAA receptor inverse agonist FG7142, could lead to schizophrenia-like changes in behaviors consistent with the negative symptoms of schizophrenia. A second goal was to compare the effects of GABAA receptor blockade to the effects of the NMDA receptor antagonism following systemic administration of MK801, given that blockade of NMDA receptors is a classic pharmacological model of schizophrenia. Methods: Male rats were administered IP MK801 (0.0 or 0.125 mg/kg) or FG7142 (0.0, 2.5 or 5.0 mg/kg) 30 minutes before behavioral tests. Rats were tested for drug-induced hyperlocomotion, sucrose preference, social interaction, and social preference during early adulthood (~PND 70). Results: Both FG7142 (5.0 mg/kg) and MK801 decreased social interactions but neither drug affected social preference. MK801, but not FG7142, increased ambulatory activity. Conversely, FG7142, but not MK801, decreased sucrose preference. Discussion: Interestingly, MK801 and FG7142 both decreased social interactions in rats, but neither drug affected social preference, suggesting that these drugs have complex effects on sociability. Reduced social interactions cannot be accounted for decreased locomotor ability. It is possible that rats find social interactions less rewarding following GABAA receptor blockade, because rats treated with FG7142 exhibited anhedonia (decreased sucrose preference). A change in the intrinsic reward of social interaction is not a likely explanation for the effects of NMDA receptor blockade on social interaction. GABAA receptors are widely expressed in the brain and future research using more selective drugs will be aimed at determining how GABAA receptors containing different α subunits uniquely contribute to the aforementioned behaviors.