Cocaine alters mu but not delta or kappa opioid receptor‐stimulated in situ [³⁵S]GTPγS binding in rat brain

Abstract

Chronic cocaine administration produces alterations in mu and kappa opioid receptor density as well as striatal and accumbens opioid-regulated adenylyl cyclase activity, suggesting a psychostimulant responsive interaction between opioidergic and dopaminergic systems. Stimulation of G-protein-coupled opioid receptors inhibits adenylyl cyclase production of cyclic AMP. The present study employed in situ [(35)S]GTPgammaS binding to measure opioid receptor-stimulated activation of G-proteins in response to acute and chronic cocaine exposure. Male Fischer rats received acute (1 or 3 days) or chronic (14 days) binge pattern cocaine administration. Three and 14 days of cocaine injections resulted in greater increases in the ability of the mu receptor agonist DAMGO to stimulate [(35)S]GTPgammaS binding in both the core and the shell of the nucleus accumbens, all regions of the caudate putamen and the cingulate cortex compared with saline-matched controls. The greatest increases in DAMGO-stimulated [(35)S]GTPgammaS binding were observed in the dorsal areas of the caudate putamen in animals that received 14 days of cocaine. No significant changes in delta (DPDPE), or kappa (dynorphin A(1-17)) receptor-stimulated [(35)S]GTPgammaS binding were found in any brain region in response to cocaine administration. These results demonstrate that binge pattern cocaine administration induce changes in mu but not delta or kappa opioid receptor-mediated G-protein activity. This study provides support for the hypothesis that the addictive properties of both psychostimulants and opiates may share common neurochemical signaling substrates.

Time-Dependent Changes in Receptor/G-Protein Coupling in Rat Brain following Chronic Monoamine Transporter Blockade

“…35 S]GTP␥S binding in the same region. These results are similar to homologous desensitization observed after chronic opioid and cannabinoid treatment (Sim et al, 1996;Breivogel et al, 1999) but in contrast to reports of chronic cocaine treatment, where increases have been shown in both monoamine and nonmonoamine receptor signal transduction (Unterwald et al, 1996;Kushner and Unterwald, 2001;Schroeder et al, 2003). It is unlikely that these differences are due to pharmacological differences in the specificity of cocaine and WF-23, since both drugs block all three monoamine transporters, but may involve pharmacokinetic differences between the two transport inhibitors.…”

“…It is unlikely that these differences are due to pharmacological differences in the specificity of cocaine and WF-23, since both drugs block all three monoamine transporters, but may involve pharmacokinetic differences between the two transport inhibitors. The cocaine binge treatment used (Unterwald et al, 1996;Kushner and Unterwald, 2001;Schroeder et al, 2003) by many investigators produces temporary high increases in monoamine levels, whereas the long-acting WF-23 tropane analog may produce sustained increases in DA, 5-HT, and NE. Sustained elevations of these monoamines, in contrast to periodic high concentrations, may result in different responses by the receptors.…”

Cocaine reward and hyperactivity in the rat: Sites of mu opioid receptor modulation

“…In addition to its direct effects on monoamine neurotransmitters, cocaine impacts other neurotransmitter systems including the endogenous opioid system. Cocaine alters levels of endogenous opioid peptides (Hurd and Herkenham, 1993;Olive et al, 2001;Roth-Deri et al, 2003) and has profound effects on the expression and function of opioid receptors (Hammer, 1989;Unterwald et al, 1994;Izenwasser et al, 1996;Schroeder et al, 2003). Together, dopamine and opioid peptides modulate rewarding behaviors and locomotor activity (Fink and Smith, 1980;Roberts and Koob, 1982).…”

Cocaine-Induced Reinstatement Requires Endogenous Stimulation of μ-Opioid Receptors in the Ventral Pallidum

“…35 S]GTP␥S binding was measured in many cortical and subcortical forebrain regions (Schroeder et al, 2003). Although the Schroeder et al study did not specifically quantify receptor-regulated […”