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 (I _NaT) 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 I_NaT density and in the ability of D₁ receptor stimulation to inhibit I_NaT. Application of a protein kinase A (PKA) inhibitor blocked the ability of D ₁ receptor activation to inhibit I_NaT and increased the current density of both groups to similar values. These results suggest that repeated amphetamine exposure results in subsensitivity of the I_NaT 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.