Ethanol and phencyclidine interact with respect to nucleus accumbens dopamine release: differential effects of administration order and pretreatment protocol

Abstract

Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used 'PFC hypofunction protocols'. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration.

Keywords: alcoholism; executive dysfunction; microdialysis; prefrontal cortex hypofunction; schizophrenia.

Figure 1

In vivo microdialysis measuring dopamine release in the nucleus accumbens of awake, freely-moving animals. (A) Systemic injection of 5 mg/kg PCP-induced dopamine release but blocked the dopamine-elevating effects of a local 300 mM ethanol infusion. No differences were observed when animals were pretreated for 5 days with 2.58 mg/kg PCP. (B) 300 mM ethanol infusion produced the expected dopamine increase and 5 mg/kg PCP injection led to a potentiated dopamine response compared to the first experiment. Again, no effect of PCP pretreatment was observed. (C) PCP injection (5 mg/kg) alone produced a sustained dopamine release from 40 to 120 min. Three hundred millimolar ethanol infusion into the nucleus accumbens produced a peak dopamine release after 40 min which then fell to levels close to baseline by 60 min. Based on these results, drugs in the combination experiments were administered 60 min after the each other. (D) Comparison of the relative dopamine release stimulated by PCP injection. When ethanol was administered first, the PCP-induced dopamine elevation was greater than PCP alone (t-test, *p < 0.05). (E) Comparison of the relative dopamine release stimulated by ethanol infusion. Ethanol induced significantly less dopamine release when the infusion was proceeded by PCP injection (t-test, *p < 0.05).

Figure 2

Boxplot of differential gene expression generated by the REST2008 software. The considerable variability in Arc and parvalbumin compared to other genes suggests PCP-induced dysfunction in some but not all individuals.