Dual Effect of 5-HT 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-HTR) 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-HTRs 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-HTRs to modulate D autoreceptors (DARs) 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-HTRs and DARs. In both VTA slices and the VTA of anesthetized mice, the 5-HTR 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 DAR-mediated G protein-gated inwardly rectifying potassium current. This manifested decreased GABA (gamma-aminobutyric acid A) receptor-mediated evoked inhibitory postsynaptic currents in slice, resulting in disinhibition of DA neurons, in opposition to the 5-HTR-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 DAR sensitivity, with anti-inhibition under normal DAR sensitivity and inhibition under low DAR sensitivity. These dual effects may underlie the ability of CP94253 to both enhance and inhibit cocaine-induced behaviors.