Loss of the trpc4 gene is associated with a reduction in cocaine self-administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards.

Among the canonical transient receptor potential (TRPC) channels, the TRPC4 non-selective cation channel is one of the most abundantly expressed subtypes within mammalian corticolimbic brain regions, but its functional and behavioral role is unknown. To identify a function for TRPC4 channels we compared the performance of rats with a genetic knockout of the trpc4 gene (trpc4 KO) to wild-type (WT) controls on the acquisition of simple and complex learning for natural rewards, and on cocaine self-administration (SA). Despite the abundant distribution of TRPC4 channels through the corticolimbic brain regions, we found trpc4 KO rats exhibited normal learning in Y-maze and complex reversal shift paradigms. However, a deficit was observed in cocaine SA in the trpc4 KO group, which infused significantly less cocaine than WT controls despite displaying normal sucrose SA. Given the important role of ventral tegmental area (VTA) dopamine neurons in cocaine SA, we hypothesized that TRPC4 channels may regulate basal dopamine neuron excitability. Double-immunolabeling showed a selective expression of TRPC4 channels in a subpopulation of putative dopamine neurons in the VTA. Ex vivo recordings of spontaneous VTA dopamine neuronal activity from acute brain slices revealed fewer cells with high-frequency firing rates in trpc4 KO rats compared to WT controls. Since deletion of the trpc4 gene does not impair learning involving natural rewards, but reduces cocaine SA, these data demonstrate a potentially novel role for TRPC4 channels in dopamine systems and may offer a new pharmacological target for more effective treatment of a variety of dopamine disorders.

A role for the subiculum in the brain motivation/reward circuitry.

The ventral subiculum (vSUB) is an interface between the hippocampal formation and structures in the brain reward circuitry, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). The vSUB powerfully activates the dopamine system, particularly in response to novelty. This activity is both necessary and sufficient to elevate nucleus accumbens dopamine levels triggered by a novel stimulus. Direct stimulation of the vSUB increases the population of active dopamine neurons in the ventral tegmental area and dopamine levels in the accumbens via a multisynaptic route relayed through the nucleus accumbens. Furthermore, activity in the vSUB is correlated with drug-seeking behaviour such that vSUB inhibition attenuates cocaine-primed reinstatement of drug-seeking, while brief vSUB activation triggers reinstatement cocaine-seeking. We report that acute cocaine alters vSUB pyramidal neuron activity by inducing a frequency-dependent output mode transition from bursting to single-spiking. We suggest that under normal conditions bursting and output mode switching (bursting to single-spiking) may be needed for proper routing of information in and out of the vSUB. We propose that psychostimulants disrupt bursting and output mode switching leading to inappropriate dopamine/novelty signaling that is necessary to set motivational states and direct attention and ultimately, behaviour.