Rats Maintained Chronically on Buprenorphine Show Reduced Heroin and Cocaine Seeking in Tests of Extinction and Drug-Induced Reinstatement

Abstract

Buprenorphine is being introduced as a maintenance therapy in opioid addiction, but it is not clear how buprenorphine will affect co-use of cocaine in opioid users. We examined the effects of chronic buprenorphine (BUP0: 0.0 mg/kg/day; BUP1.5: 1.5 mg/kg/day; BUP3: 3.0 mg/kg/day) on the locomotor activity effects of acute heroin (0.25 mg/kg, subcutaneously (s.c.)) and cocaine (20 mg/kg, intraperitoneally (i.p.)). Buprenorphine had no effect on the stimulatory effect of heroin, but potentiated the locomotor response to cocaine. To investigate further the interactions between buprenorphine (BUP1.5 and BUP3), heroin (0.125, 0.25 and 0.375 mg/kg, s.c.), and cocaine (10, 20 and 30 mg/kg, i.p.), we used in vivo microdialysis and high-performance liquid chromatography to analyze extracellular levels of dopamine (DA) in the nucleus accumbens (NAc). Buprenorphine attenuated the heroin-induced rise in NAc DA, but greatly potentiated the cocaine-induced rise. Finally, we examined the potential of the highest dose of buprenorphine (BUP3) to reduce heroin and cocaine seeking in the presence of drug-associated cues under extinction conditions and in tests for reinstatement induced by heroin (0.25 mg/kg, s.c.), cocaine (20 mg/kg, i.p.), and 15-min footshock stress (0.8 mA, 0.5 s/shock, 40 s mean OFF time) in rats trained to selfadminister both drugs. Buprenorphine reduced heroin and cocaine seeking during extinction and following acute heroin and cocaine priming injections, but had no effect on stress-induced reinstatement. These results indicate that the suppression of responding following priming injections of drugs did not result from reduced motor activity, but possibly from a reduction in the salience of drug-associated cues induced by chronic buprenorphine treatment.

High-Dose Methadone Maintenance in Rats: Effects on Cocaine Self-Administration and Behavioral Side Effects

“…If anything, we observed a potentiation of this response, which is not surprising in light of known synergistic interactions between opiates and cocaine on the dopamine system (Brown et al, 1991;Hemby et al, 1999;Martin et al, 2006;Zernig et al, 1997). Furthermore, this effect of methadone was very similar to the effect of buprenorphine maintenance on cocaine-induced elevations in extracellular dopamine recently reported by Sorge et al, 2005 andStewart, 2006. Taken together, these results provide some support for the hypothesis that chronic maintenance on mu-opioid receptor agonists does not reduce, and can even enhance, some behavioral (Foltin et al, 1995;Foltin and Fischman, 1996;Leri et al, 2006;Preston et al, 1996) and neurochemical indexes of reinforcing effects of cocaine (Di Chiara and Imperato, 1988;Koob and Bloom, 1988;Wise and Bozarth, 1981).…”

“…The procedures used were similar to those reported previously by Sorge et al (2005). Different groups (n ¼ 4-12) of male Long-Evans rats (350-375 g) were used for each dose of methadone (0, 20 and 40 mg/kg/day) and each dose of cocaine (10, 20 or 30 mg/kg, i.p.).…”

“…Different groups (n ¼ 4-12) of male Long-Evans rats (350-375 g) were used for each dose of methadone (0, 20 and 40 mg/kg/day) and each dose of cocaine (10, 20 or 30 mg/kg, i.p.). The same doses of cocaine were used in previous studies examining interactions with buprenorphine (Sorge et al, 2005). An additional group of rats (n ¼ 9) was maintained on 30 mg/kg/day and challenged with 20 mg/kg cocaine because this dose combination was employed in our previous methadone-cocaine experiments.…”

“…The dialysate analysis has been described previously (Sorge et al, 2005). Briefly, dopamine and metabolites (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and 5-hydroxyindole acetic acid (HIAA)) were measured simultaneously on one of the two systems and were adjusted to allow for the separation and quantification of dopamine, DOPAC, HVA, and HIAA in a single run.…”

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…One possible reason for the low responding in methamphetamine-trained unpunished rats on day 2 is the induction of early withdrawal depressive-like states by extended access methamphetamine (Jang et al, 2013;McGregor et al, 2005), resulting in decreased responding to the drug-associated cues. Additional support for the idea that incubation of drug craving involves early withdrawal neuroadaptations that decrease cue-induced drug seeking comes from cocaine studies in which the duration of the training session and number of training days were manipulated (Pacchioni et al, 2011;Sorge et al, 2005). These studies indicate that extended cocaine exposure, which presumably leads to more profound neuroadaptations (Ahmed et al, 2005;Ben-Shahar et al, 2009), does not increase cue-induced drug seeking during late withdrawal but instead decreases cocaine seeking during early withdrawal.…”