Hippocampal a5-GABAA Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area

BACKGROUND: Aberrant dopamine neuron activity is attributable to hyperactivity in hippocampal subfields driving a pathological increase in dopamine neuron activity, which is positively correlated with psychosis in humans. Evidence indicates that hippocampal hyperactivity is due to loss of intrinsic GABAergic (gamma-aminobutyric acidergic) in-hibition. We have previously demonstrated that hippocampal GABAergic neurotransmission can be modulated by targeting a5-GABAA receptors, which are preferentially expressed in hippocampal regions. Positive and negative allosteric modulators of a5-GABAA receptors (a5-PAMs and a5-NAMs) elicit effects on hippocampal-dependent behaviors. We posited that the selective manipulation of hippocampal inhibition, using a5-PAMs or a5-NAMs, would modulate dopamine activity in control rats. Further, a5-PAMs would reverse aberrant dopamine neuron activity in a rodent model with schizophrenia-related pathophysiologies (methylazoxymethanol acetate [MAM] model). METHODS: We performed in vivo extracellular recordings of ventral tegmental area dopamine neurons in anes-thetized rats to compare the effects of two novel, selective a5-PAMs (GL-II-73, MP-III-022), a nonselective a-PAM (midazolam), and two selective a5-NAMs (L-655,708, TB 21007) in control and MAM-treated male Sprague Dawley rats (n = 5-9). RESULTS: Systemic or intracranial administration of selective a5-GABAA receptor modulators regulated dopamine activity. Specifically, both a5-NAMs increased dopamine neuron activity in control rats, whereas GL-II-73, MP-III-022, and L-655,708 attenuated aberrant dopamine neuron activity in MAM-treated rats, an effect mediated by the ventral hippocampus. CONCLUSIONS: This study demonstrated that a5-GABAA receptor modulation can regulate dopamine neuron activity under control or abnormal activity, providing additional evidence that a5-PAMs and a5-NAMs may have therapeutic applications in psychosis and other psychiatric diseases where aberrant hippocampal activity is present.