Chronic Cocaine Treatment Decreases Levels of the G Protein Subunits G_iα and G_oα in Discrete Regions of Rat Brain

Abstract

A possible role for G proteins in contributing to the chronic actions of cocaine was investigated in three rat brain regions known to exhibit electrophysiological responses to chronic cocaine: the ventral tegmental area, nucleus accumbens, and locus coeruleus. It was found that chronic, but not acute, treatment of rats with cocaine produced a small (approximately 15%), but statistically significant, decrease in levels of pertussis toxin-mediated ADP-ribosylation of Gi alpha and Go alpha in each of these three brain regions. The decreased ADP-ribosylation levels of the G protein subunits were shown to be associated with 20-30% decreases in levels of their immunoreactivity. In contrast, chronic cocaine had no effect on levels of G protein ADP-ribosylation or immunoreactivity in other brain regions studied for comparison. Chronic cocaine also had no effect on levels of Gs alpha or G beta immunoreactivity in the ventral tegmental area and nucleus accumbens. Specific decreases in Gi alpha and Go alpha levels observed in response to chronic cocaine in the ventral tegmental area, nucleus accumbens, and locus coeruleus are consistent with the known electrophysiological actions of chronic cocaine on these neurons, raising the possibility that regulation of G proteins represents part of the biochemical changes that underlie chronic cocaine action in these brain regions.

The Disruptive Effect of Cocaine on Prepulse Inhibition Is Prevented by Repeated Administration in Rats

“…Behavioral sensitization to cocaine is associated with enhanced D 1 -like receptor sensitivity in the nucleus accumbens (Henry and White 1991). Conversely, repeated treatment with selective D 2 -like receptor agonists appears to downregulate D 2 -like receptor density (Subramaniam et al 1992), reduce the level of D 2 -like receptor-coupled G i protein (Nestler et al 1990), and decrease the physiological response to D 2 -like agonists (Henry et al 1998) in the nucleus accumbens. Thus, cocaine-induced D 1 -like receptor enhancement with concurrent desensitization of D 2 -like receptors could account for the simultaneous sensitization of motor activity and tolerance to PPI disruption.…”

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

“…1). A consistent biochemical finding associated with exposure to different addictive drugs is a reduced signaling through G i/o protein-coupled receptors (Nestler et al, 1990;Terwilliger et al, 1991;Striplin and Kalivas, 1993;Self et al, 1994;Zhang et al, 2000;Hummel and Unterwald, 2003;Rahman et al, 2003;Bowers et al, 2004). Recent studies suggest that these drug-induced biochemical responses involve specific accessory proteins that regulate G i/o protein-coupled receptors, such as RGS9-2 and AGS3 (Rahman et al, 2003;Bowers et al, 2004).…”

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

“…In general, changes in the ventral tegmentum believed to be related to the initiation of sensitization are transient, such as decreased sensitivity of somatodendritic D2 subtype dopamine autoreceptors (Kamata and Rebec, 1984;White and Wang, 1984;Henry et al, 1989;Ackerman and White, 1990). In contrast, neurochemical changes in the nucleus accumbens accompanying sensitization are persistent (Wolf, 1998), such as increased D1 receptor electrophysiological responsiveness (Henry and White, 1991;Higashi et al, 1989) and upregulation of cAMP signal transduction (Nestler et al, 1990;Terwilliger et al, 1991). Some of the changes in the nucleus accumbens, such as augmentation of the increase in extracellular dopamine elicited by stimulants (Robinson et al, 1988;Kalivas and Duffy, 1990), require a withdrawal time interval to be manifest.…”