Chronic repeated cocaine administration alters basal and opioid‐regulated adenylyl cyclase activity

Abstract

Repeated daily cocaine injections have been shown to alter mu-opioid receptor densities in the caudate putamen and nucleus accumbens of rat brain (Unterwald et al., 1991, 1992). Adenylyl cyclase activity was measured in rat rostral caudate putamen and nucleus accumbens following repeated cocaine administration to determine the functional consequences of cocaine-induced opioid receptor changes. Male Fischer rats were injected daily for 14 days with saline or cocaine HCl (30 or 45 mg/kg/day, i.p.) in three equal doses at 1-hr intervals. Basal adenylyl cyclase activity and the effects of the selective mu- and delta-opioid agonists [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) and [D-penicillamine2,D-Penicillamine5]enkephalin (DPDPE), respectively, on adenylyl cyclase activity were examined 30 min after the last injection using a cAMP radioligand binding assay in crude membrane preparations. Basal adenylyl cyclase activity was 49% and 34% lower in the caudate putamen of animals treated with 30 and 45 mg/kg/day of cocaine, respectively, as compared to those receiving saline injections. Basal adenylyl cyclase activity was unchanged in the nucleus accumbens following cocaine treatment. DAMGO and DPDPE each maximally inhibited approximately 25% and 30%, respectively, of basal adenylyl cyclase in the caudate putamen and nucleus accumbens of saline-injected animals. Administration of cocaine attenuated the ability of DPDPE to inhibit adenylyl cyclase in both brain regions, but had no effect on the efficacy or potency of DAMGO for inhibiting adenylyl cyclase activity. These results suggest that chronic, repeated cocaine administration results in a selective impairment of delta-opioid receptor-mediated effector function in the caudate putamen and nucleus accumbens.

Differential desensitization of μ‐ and δ‐ opioid receptors in selected neural pathways following chronic morphine treatment

“…Both brain regions receive major dopaminergic innervation, the caudate putamen from nigrostriatal pathway and the nucleus accumbens from the mesolimbic tract. Moreover, it has been reported that chronic cocaine treatment also induces a selective impairment of b-opioid receptor-mediated effector function in the caudate putamen and the nucleus accumbens without change in A-receptor-mediated inhibitory activity (Unterwald et al, 1993). Thus the involvement of the dopaminergic system is strongly suggested.…”

Hemopressin is an inverse agonist of CB 1 cannabinoid receptors

“…For GTP␥S binding or adenylyl cyclase assay, membranes from striatum or spleen (10 g) were incubated with increasing concentrations (0 -1 M) of Hu-210 (cannabinoid agonist), SR141716, hemopressin, or a combination of different concentrations of Hu-210 without or with 10 M hemopressin or SR141716 as described (36,37).…”

Expression of Amphetamine-Induced Behavioral Sensitization after Short- and Long-Term Withdrawal Periods: Participation of μ- and δ-Opioid Receptors

“…We and others have reported changes in the expression levels of MOR in the NAc and other nuclei of the motive circuit, after intermittent injections of amphetamine or cocaine that induce behavioral sensitization (Unterwald et al, 1992(Unterwald et al, , 1994Vecchiola et al, 1999). Opioid-receptor-coupled adenylate cyclase activity was also found to be altered after repeated intermittent injections of cocaine (Sala et al, 1995;Unterwald et al, 1993;Unterwald and Cuntapay, 2000). In addition, the opioid antagonist naltrexone blocks the induction of amphetamine and cocaine-induced behavioral sensitization (Balcells-Olivero and Vezina, 1997;Sala et al, 1995), and Heidbreder et al (1996) reported the involvement of DOR in the induction but not the expression of cocaineinduced behavioral sensitization measured after a shortterm withdrawal period.…”