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International audienceAddiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, and leading to lifelong changes. A common substrate of these changes lies in alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT2B receptor has been involved in various behaviors including impulsivity, response to antidepressants and to psychostimulants pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single cell mRNA amplification indicated that 5-HT2B receptors are expressed by mesolimbic dopamine neurons. In-vivo and ex-vivo electrophysiological recordings showed that 5-HT2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA- over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.SIGNIFICANCE STATEMENTHere we report that mice lacking 5-HT2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. In spite of the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity, and lower cocaine operant self-administration. We described the selective expression of 5-HT2B receptors in subpopulation of dopamine neurons sending axons to ventral striatum. An increased bursting in-vivo properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to ex-vivo dopamine neurons was found in mice lacking 5-HT2B receptors. These data support that the chronic 5-HT2B-receptor inhibition makes mice behaving as animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in DA neuron reactivity

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses