Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress

Abstract

Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (i.v.) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, s.c.) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg, 12 h apart; i.p.) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50-200 mg/ kg; i.p.) had no consistent effects on i.v. heroin self-administration (50 100 microg/kg per infusion) and, in experiment 3, that acamprosate (100-200 mg/ kg, i.p.) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, s.c.) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users.

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…The negative results reported here suggest that acamprosate does not have anti-opiate-dependence effects. These results actually are consistent with studies showing that acamprosate does not generalize to morphine in drug discrimination studies and does not block the reinforcing effects of heroin (Pascucci et al, 1999;Spanagel et al, 1998).…”

“…The present study was initiated to test the hypothesis that the anti-alcohol-dependence effects of acamprosate might generalize to opiate dependence. Indeed, one study showed that acamprosate attenuated the locomotor sensitization associated with repeated opiate administration (Spanagel et al, 1998). Acamprosate also did Conditioned place aversion in rats L Stinus et al not alter the expression of opiate withdrawal-induced place aversion.…”

The Endomorphin System and Its Evolving Neurophysiological Role

“…However, tolerance to other endomorphin effects needs to be elucidated. This study might be particularly interesting, as tolerance did not develop to all of the effects of morphine: for example, it did not occur to morphine-induced locomotor activity, which is linked to the physical dependence (Spanagel et al, 1998).…”

The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

“…Mice were subjected to 30 minutes of transient focal cerebral ischemia as described below followed by intraperitoneal treatment with either acamprosate (Sigmal-Aldrich, Taufkirchen, Germany; solved in NaCl) or standard saline (control) during reperfusion, at 3, 6, 9, 12, and 24 hours after stroke. Referring to previous studies, [15][16][17][18][19][20] mice received a modified injection protocol with a single intraperitoneal injection of acamprosate at a dose of 400 mg/kg bodyweight (BW). To exclude toxic side effects of acamprosate after high dosage bolus application, analysis of potential weight loss and blood count analysis was performed 1 day before stroke induction as well as on days 7 and 14 after stroke ( Table 1).…”