Repeated amphetamine administration decreases D1 dopamine receptor-mediated inhibition of voltage-gated sodium currents in the prefrontal cortex.

Adaptations in dopamine (DA) transmission in the prefrontal cortex (PFC) are thought to be critical to the development and persistence of drug addiction. Our previous findings showed that medial PFC (mPFC) neurons in rats treated repeatedly with amphetamine exhibit a decreased inhibitory response to iontophoretically applied DA, demonstrating altered DA receptor transmission. To determine the role postsynaptic DA D1 receptors play in this effect, we used whole-cell patch-clamp recordings of acutely dissociated pyramidal mPFC neurons and inhibition of transient voltage-sensitive sodium current (INaT) as a measure of D1 receptor function. After 3 d of withdrawal, neurons recorded from amphetamine-treated rats (5 mg/kg for 5 d) demonstrated a significant decrease in whole-cell INaT density and in the ability of D1 receptor stimulation to inhibit INaT. Application of a protein kinase A (PKA) inhibitor blocked the ability of D1 receptor activation to inhibit INaT and increased the current density of both groups to similar values. These results suggest that repeated amphetamine exposure results in subsensitivity of the INaT to D1 receptor-mediated inhibition because of a possible increase in basal PKA activity. This adaptation may contribute to perseverative behaviors in animals that self-administer psychostimulants as well as compromised PFC-dependent behaviors in human addicts.