Hippocampal α5-GABAA Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area
Stephanie M. Perez, Alexandra M. McCoy, Thomas D. Prévot, Md Yeunus Mian, Flavia Carreño, Alan Frazer, James M. Cook, Etienne Sibille, Daniel J. Lodge
Abstract
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) inhibition. We have previously demonstrated that hippocampal GABAergic neurotransmission can be modulated by targeting α5-GABAA receptors, which are preferentially expressed in hippocampal regions. Positive and negative allosteric modulators of α5-GABAA receptors (α5-PAMs and α5-NAMs) elicit effects on hippocampal-dependent behaviors. We posited that the selective manipulation of hippocampal inhibition, using α5-PAMs or α5-NAMs, would modulate dopamine activity in control rats. Further, α5-PAMs would reverse aberrant dopamine neuron activity in a rodent model with schizophrenia-related pathophysiologies (methylazoxymethanol acetate [MAM] model). We performed in vivo extracellular recordings of ventral tegmental area dopamine neurons in anesthetized rats to compare the effects of two novel, selective α5-PAMs (GL-II-73, MP-III-022), a nonselective α-PAM (midazolam), and two selective α5-NAMs (L-655,708, TB 21007) in control and MAM-treated male Sprague Dawley rats (n = 5–9). Systemic or intracranial administration of selective α5-GABAA receptor modulators regulated dopamine activity. Specifically, both α5-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. This study demonstrated that α5-GABAA receptor modulation can regulate dopamine neuron activity under control or abnormal activity, providing additional evidence that α5-PAMs and α5-NAMs may have therapeutic applications in psychosis and other psychiatric diseases where aberrant hippocampal activity is present.