Ethanol Consumption and Behavioral Impulsivity Are Increased in Protein Kinase Cγ Null Mutant Mice

Abstract

Etiological factors influencing the development of alcoholism are complex and, at a minimum, include an interaction between polygenic factors and personality and biological traits. Human and animal studies suggest that some genes may regulate both the traits associated with alcohol abuse, such as decreased sensitivity or anxiety, and vulnerability to alcoholism. The identification of these genes could elucidate neurochemical pathways that are important in the development of alcohol abuse. Results from the present study indicate that the gene encoding the neuronal-specific gamma subtype of protein kinase C (PKCgamma) influences both ethanol consumption and behavioral impulsivity, a personality characteristic associated with Type II alcoholics, in a pleiotropic manner. Mice lacking PKCgamma consume more ethanol in a two-bottle choice paradigm and also demonstrate increased behavioral impulsivity in an appetitive-signaled nosepoke task when compared with wild-type littermate control mice. Therefore, PKCgamma may be an important mechanism within the cell that mediates one or more neurochemical pathways relevant to an increased predisposition to alcoholism.

Genetic Analysis of the Hypothalamic Neurotensin System

“…The NTta and NTR3ta QTL on proximal chromosome 7 are of particular interest as this is one of the loci that coincide between the present study and the previous investigation of NT-IR. The protein kinase C gamma (Prkcc) subunit resides at 2 cM of chromosome 7 and this gene product has been implicated in various neurobehavioral processes including anxiety behaviors, spatial and contextual learning, ethanol consumption and impulsive behaviors (Abeliovich et al, 1993a, b;Bowers et al, 2000;Bowers and Wehner, 2001). There are a number of intriguing genes within the NTta LRS peak on chromosome 9, between 25 and 35 cM including the dopamine 2 receptor structural gene (Drd2) at 28 cM (O'Dowd et al, 1990), hypothermia sensitivity (Hts) which is in response to D2-selective agent quinpirole (Buck et al, 2000), cocaine-related behavior 8 (Cocrb8) at 28 cM, ethanol consumption 3 (Etohc3) at 29 cM (Phillips et al, 1998;Jones et al, 1999), and haloperidol-induced catalepsy 1 (Hpic1) at 35 cM (Patel and Hitzemann, 1999).…”

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

“…If 5-HT 2A receptor function is enhanced in PKCγ mutant mice, the impulsive responding that we observed in these mice may be regulated by increased sensitivity to endogenous serotonin. This idea is more compelling in relationship to the findings of Dalley et al (2002) because the appetitive signaled-nosepoke task that was used to evaluate impulsivity in the PKC mice is based on impulse control to an auditory stimulus (Bowers and Wehner, 2001). Thus, we speculate that alterations in 5HT 2A/C receptor function observed here may underlie the increased impulsivity phenotype in PKCγ mutants.…”

“…The PKCγ mutation is maintained in a heterozygous condition on C57BL/6 and 129/S6 inbred strains because homozygous null mutant mice do not survive on the C57BL/6 background (Bowers et al, 1999). All mice were genotyped prior to testing using DNA analysis of tail DNA as described previously (Bowers and Wehner, 2001). Groups of null mutant and wild-type littermate control mice used in the following experiments were derived from multiple litters.…”

“…PKCγ mutants show increased impulsivity in a signaled-nosepoke task (Bowers and Wehner, 2001). Impulsivity in humans and rodents has been associated with decreased serotonin levels in brain (Harrison et al, 1997;Leyton et al, 2001).…”

“…Null mutant mice lacking the neuronal-specific gamma isotype of protein kinase C (PKCγ) are more impulsive in an appetitive signaled-nosepoke task and consume more ethanol in a freechoice paradigm when compared to wild-type control mice (Bowers and Wehner, 2001). The neural mechanism by which PKCγ impacts these behaviors is most likely complex.…”