Chronic cocaine administration decreases the functional coupling of GABAB receptors in the rat ventral tegmental area as measured by baclofen-stimulated 35S-GTPγS binding

doi:10.1016/S0024-3205(01)01203-6

Life Sciences

Volume 69, Issue 9, 20 July 2001, Pages 1093-1102

https://doi.org/10.1016/S0024-3205(01)01203-6 Get rights and content

Abstract

Results of numerous studies indicate that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) modulates central dopamine systems, and that GABA_B receptors may play a primary role in decreasing dopamine release. To determine if chronic cocaine administration alters the functional coupling of GABA_B receptors to G-proteins in central dopamine systems, male F-344 rats received cocaine (15mg/kg/injection) or saline three times a day at hourly intervals for fourteen consecutive days. Rats were decapitated one hour after the last injection and crude membrane preparations were made from the substantia nigra, caudate-putamen, ventral tegmental area, nucleus accumbens, and frontal cortex of individual rats. The ability of the specific GABA_B receptor agonist baclofen to stimulate ³⁵S-GTPγS binding in each of these regions was determined for individual animals. Additionally, baclofen-stimulated ³⁵S-GTPγS binding in each of these regions in rats that received cocaine was compared to baclofen-stimulated ³⁵S-GTPγS binding in rats that received control injections of saline. The EC₅₀ of baclofen and maximal baclofen-stimulated ³⁵S-GTPγS binding over basal levels were determined in each brain region in the saline group and in the cocaine group. Two-way ANOVA revealed a significant decrease in GABA_B receptor-stimulated ³⁵S-GTPγS binding in the ventral tegmental area of the cocaine group compared to the saline group. These data suggest that chronic exposure to cocaine decreases the functional coupling of GABA_B receptors to G-proteins selectively in the ventral tegmental area. This finding may have implications in the augmented extracellular dopamine levels seen in the nucleus accumbens of rats that have been sensitized to cocaine.

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Citation Excerpt :
No significant group difference was shown for LICI at ISI of 100 ms at which LICI can be tested without overlap with the preceding LICF (Nakamura et al., 1997; Sanger et al., 2001). This finding is in apparent discord with preclinical studies suggesting that GABA(B) receptor-mediated transmission is persistently down-regulated (Kushner and Unterwald, 2001; Frankowska et al., 2008) and such a down-regulation would be expected to reduce LICI. This interpretation supports claims that that GABA(B) receptor agonists may be useful in the treatment of cocaine addiction (Brebner et al., 2002; Roberts, 2005; Sofuoglu and Kosten, 2005).
The effects of chronic cocaine dependence on cortical inhibitory/excitatory processes are not well characterized. Employing transcranial magnetic stimulation measures of motor cortical excitability, we have previously reported an elevation of motor threshold (MT) suggesting reduced excitability and an increased long-interval intracortical facilitation (LICF) suggesting increased excitability. In the current study, we used an expanded battery of TMS cortical excitability measures to further examine motor cortex excitability in a larger sample of well-characterized and closely monitored for drug use, abstinent cocaine-dependent subjects (N = 52) and healthy controls (N = 42). Furthermore, coil-to-cortex distance was assessed in a subsample of both groups. We verified that long-interval intracortical facilitation (LICF), possibly representing glutamatergic cortical neurotransmission, was significantly increased in cocaine-dependent patients. Significantly longer cortical silent periods (CSP) and elevated MT were also observed while there was no significant abnormality in long-interval intracortical inhibition (LICI). Increased LICF and CSP duration suggest increased cortical excitability and increased inhibition, respectively, of different neurotransmitter systems in cocaine-dependent patients. Increased MT might reflect an adaptation to those effects of cocaine abuse that enhance cortical excitability. Overall, the data point to the complex nature of chronic cocaine dependence on the balance of cortical inhibitory/excitatory mechanisms.
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Citation Excerpt :
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The serotonin_1B receptor knockout (5-HT_1B KO) mouse is a valuable animal model of addiction to psychostimulants. We previously found selective increases in dopamine (DA) turnover in the nucleus accumbens of these mice, in addition to several changes in their central serotonin system. Here, we searched for further DA adaptations by measuring D₁ and D₂ receptor as well DA plasma membrane transporter (DAT) sites by ligand binding autoradiography, and G-protein coupling to D₁ and D₂ receptors by [³⁵S]GTPγS autoradiography. Except for a slight increase in the lateral septum, D₁ receptor binding did not differ from wild-type in twenty-one other neocortical, limbic or basal ganglia regions examined in the KO. Nor were there changes in D₁ agonist-stimulated G-protein coupling in any of these regions, including the lateral septum. Increases in D₂ binding sites, presumably involving GABAergic projection neurons, were measured in the nucleus accumbens, olfactory tubercle and ventral tegmental area of the 5-HT_1B KO. However, no activation of the efficacy of D₂ receptor coupling to G-protein could be measured in these and other brain regions. Binding to DAT was unchanged throughout brain. Because of their implication in cocaine addiction, the functionality of μ-opioid and GABA_B receptors was also assessed by [³⁵S]GTPγS autoradiography. 5-HT_1B KO showed selective decreases in G-protein coupling to μ-opioid receptors in the paraventricular thalamic nucleus, and to GABA_B receptors in the basolateral nucleus of amygdala. It is likely that these latter changes underlie some aspects of the addictive behavior of the 5-HT_1B KO mouse.

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Original articlesChronic cocaine administration decreases the functional coupling of GABAB receptors in the rat ventral tegmental area as measured by baclofen-stimulated 35S-GTPγS binding

Abstract

Original articles
Chronic cocaine administration decreases the functional coupling of GABA_B receptors in the rat ventral tegmental area as measured by baclofen-stimulated ³⁵S-GTPγS binding