Dual Effect of 5-HT_1B/1D Receptors on Dopamine Neurons in Ventral Tegmental Area: Implication for the Functional Switch After Chronic Cocaine Exposure

Background: Serotonin (5-HT) 1B/1D receptor (5-HT_1B/1DR) agonists undergo an abstinence-induced switch in their effects on cocaine-related behaviors, which may involve changes in modulation of dopamine (DA) neurons in the ventral tegmental area (VTA). However, it is unclear how 5-HT_1B/1DRs affect VTA DA neuronal function and whether modulation of these neurons mediates the abstinence-induced switch after chronic cocaine exposure. Methods: We examined the ability of 5-HT_1B/1DRs to modulate D₂ autoreceptors (D₂ARs) and synaptic transmission in the VTA by slice recording and single unit recording in vivo in naïve mice and in mice with chronic cocaine treatment. Results: We report a bidirectional modulation of VTA DA neuronal firing through the interaction of VTA 5-HT_1B/1DRs and D₂ARs. In both VTA slices and the VTA of anesthetized mice, the 5-HT_1B/1DR agonist CP94253 decreased DA neuronal firing rate and evoked excitatory postsynaptic currents to DA neurons in slice. Paradoxically, CP94253 decreased quinpirole-induced inhibition of DA neurons by reducing D₂AR-mediated G protein–gated inwardly rectifying potassium current. This manifested decreased GABA_A (gamma-aminobutyric acid A) receptor–mediated evoked inhibitory postsynaptic currents in slice, resulting in disinhibition of DA neurons, in opposition to the 5-HT_1B/1DR-induced inhibition. This dual effect was verified in chronic cocaine-treated and mild stress-treated, male mice on days 1 and 20 posttreatment. Conclusions: This study revealed dual effects of CP94253 on VTA DA neurons that are dependent on D₂AR sensitivity, with anti-inhibition under normal D₂AR sensitivity and inhibition under low D₂AR sensitivity. These dual effects may underlie the ability of CP94253 to both enhance and inhibit cocaine-induced behaviors.