Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents

Abstract

Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC. This long-lasting, cocaine-induced plasticity of membrane excitability in PFC pyramidal neurons may contribute to the impaired decision making and drug craving that characterize cocaine withdrawal.

Figure 1.

Repeated cocaine treatment reduces the VGKC and increases membrane excitability in PFC pyramidal neurons. A1, Examples of IRKC and VGKC in PFC pyramidal neurons from animals receiving cocaine (COC) and saline (SAL) pretreatments. Voltage protocol used to sequentially elicit IRKC and VGKC is shown above the traces. The arrows indicate the time points at which IRKC (downward arrows) and VGKC (upward arrows) were measured. A2, Summary of current densities indicates that VGKC, but not IRKC, is significantly reduced in PFC neurons from animals receiving cocaine when compared with saline pretreatments (^*p < 0.05 in this and all of the subsequent figures). B1, Examples of IRKC and VGKC in motor cortex (Motor Ctx) pyramidal neurons from animals receiving cocaine and saline pretreatments. B2, Summary of current densities indicates that both VGKC and IRKC in motor cortex neurons are not significantly affected by chronic cocaine administration. C, Examples of action potentials elicited by a constant current injection (200 pA, 500 ms) in PFC neurons from animals receiving saline or cocaine pretreatment. D, Summary of the number of action potentials elicited by constant current injection in cocaine-pretreated and saline-pretreated PFC neurons.

Figure 2.

A central role of DA D₁ receptor signaling in cocaine-induced neuroadaptations in PFC neurons. A1, A2, Examples of D₁R-mediated suppression of VGKC in PFC neurons from animals receiving saline (SAL; A1) and cocaine (COC; A2) pretreatments. A3, Summary shows that the D₁R-mediated suppression of VGKC in PFC neurons is diminished by cocaine pretreatment. B1, B2, Examples of effects of cBIMP on VGKC in PFC neurons from animals receiving saline (B1) and cocaine (B2) pretreatments. B3, Summary shows that the cBIMP-induced suppression of VGKC in PFC neurons is diminished by cocaine pretreatment. C1, C2, Examples of effects of OA on VGKC in PFC neurons from animals receiving saline (C1) and cocaine (C2) pretreatments. C3, Summary shows that OA-induced suppression of VGKC in PFC neurons is diminished by cocaine pretreatment. D1, D2, Examples of effects of Rp-cAMP on VGKC in PFC neurons from animals receiving saline (D1) and cocaine (D2) pretreatments. D3, Summary shows that the Rp-cAMP-induced enhancment of VGKC in PFC neurons is increased by cocaine pretreatment. E, Summary of current density of basal VGKC and modulated VGKC (by Rp-cAMP and OA) suggests that basal cAMP/PKA activity is upregulated by chronic cocaine pretreatment. Cntl, Control; SKF, SKF81297.

Figure 3.

Chronic cocaine enhances basal PKA activity in PFC neurons. A, Examples of gels showing phosphorylation of peptide substrate resulting from PKA activity in tissue from PFC and MC obtained from saline (SAL)- and cocaine (COC)-pretreated animals. B, Summary shows that PKA activity within PFC, but not in MC, is significantly increased by cocaine pretreatment.