Role of the Transient Receptor Potential Channels in Modulating Prefrontal Cortical Excitability and the Behavioral Responses to Cocaine

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Drug addiction is a disease that is influenced by both genetic and environmental factors that result in altered excitability in the key brain regions associated with reward and decision-making. The prefrontal cortex (PFC) processes reward-related information; and pathologies in PFC excitability resulting from prolonged drug use may lead to the loss of control over drug intake associated with drug addiction. We show that layer 5 pyramidal neurons in the PFC exhibit a prolonged depolarizing response to Gq-coupled receptor activation, which produces a period of heightened excitability of the cell following brief bursts of action potential activity. This burst triggered delayed depolarization enables the cell to convert subthreshold inputs into persistent firing output and may be a way for the cell to hold information in a short term memory buffer. The delayed after-depolarization (dADP) is reduced by dopamine and chronic cocaine, which may serve to bias the cell towards very strong inputs, such as those associated with drug cues, while preventing the cell from responding to smaller, subthreshold inputs. The dADP is induced by activation of Gq-coupled receptors, such as metabotropic glutamate receptors or muscarinic acetylcholine receptors and is mediated by subsequent activation of a non-selective cation channel, which pharmacological data suggested to be a canonical transient receptor potential (TRPC) channel. We used in situ hybridization, immunoblots, and real-time PCR to examine the expression of the TRPC channels and found dense expression of TRPC5 in the pyramidal cell layers of the PFC. Using adeno-associated viral mediated knock-down of TRPC5 in the prefrontal cortex of TRPC5flx mice, we show that TRPC5 channels are necessary for induction of the dADP in the PFC. We show that loss of TRPC5 in the PFC increases the locomotor activating and rewarding effects of cocaine. Knock-out of TRPC1 channels, on the other hand, has no effect on the dADP and does not alter behavioral responses to cocaine, suggesting that TRPC5 homomultimeric complexes rather than TRPC1/5 heteromultimeric complexes underlie the dADP in the PFC. These studies identify the TRPC5 channels as important for modulating neuronal excitability in the PFC and the behavioral responses to cocaine.

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