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.
Highlights
A common symptom among alcohol-dependent individuals is the presence of an executive dysfunction (Kril et al, 1997; DaoCastellana et al, 1998)
Pretreatment for 5 days with 2.58 mg/kg PCP did not affect the response to ethanol or PCP and a further study of the gene expression of markers normally affected by PCP treatment (e.g. GABAergic markers, immediate early genes, etc.) did not provide any evidence of prefrontal cortex hypofunction in these animals after exposure to this low and nontoxic PCP dose
An interaction between ethanol and PCP was expected from previous studies (Brunet et al, 1985) but this is the first time an interaction has been demonstrated at the level of dopamine release in the nucleus accumbens
Summary
A common symptom among alcohol-dependent individuals is the presence of an executive dysfunction (Kril et al, 1997; DaoCastellana et al, 1998). Some have observed signs of dependence (e.g. impulsive responding) after self-administration methods (McGregor and Gallate, 2004; Belin et al, 2008) while others have employed chronic exposure (Wolffgramm and Heyne, 1995; Turyabahika-Thyen and Wolffgramm, 2006), repeated deprivation periods (Spanagel and Holter, 1999), ethanol vapor chamber approaches (Rimondini et al, 2003) or severe withdrawal effects (Diana et al, 1993) to produce rats which are ‘dependent’ on ethanol The disadvantage of these procedures is the considerable investment in time and the need for substantial animal facilities to house such large populations of rats for up to a year, something which is beyond the scope of most laboratories. Rather than using chronic ethanol exposure to induce a prefrontal cortex dysfunction, our goal was to induce dysfunction first in order to determine whether this would affect the response to ethanol
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