Dual Effect Of 5-Ht1b/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-HT1B/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/1D)Rs 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-HT1B/1D DRS to modulate D-2 autoreceptors (D-2 ARs) and synaptic transmission in the VTA by slice recording and single unit recording in vivo in naive 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-HT1B/1DRS and D-2 ARs. In both VTA slices and the VTA of anesthetized mice, the 5-HT1B/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 D(2)AR-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 HT1B/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 D(2)AR sensitivity, with anti-inhibition under normal D(2)AR sensitivity and inhibition under low D(2)AR sensitivity. These dual effects may underlie the ability of CP94253 to both enhance and inhibit cocaine-induced behaviors.