Effects of d-Amphetamine and Buprenorphine Combinations on Speedball (Cocaine+Heroin) Self-Administration by Rhesus Monkeys

Abstract

The simultaneous i.v. administration of heroin and cocaine, called a 'speedball,' is often reported clinically, and identification of effective pharmacotherapies is a continuing challenge. We hypothesized that treatment with combinations of a monoamine releaser d-amphetamine, and a mu partial agonist, buprenorphine, might reduce speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine + 0.0032 mg/kg/inj heroin) and food (1 g banana-flavored pellets) were available during four daily sessions on a second-order schedule of reinforcement (fixed ratio (FR)2 (variable ratio (VR)16:S)). Monkeys were treated for 10 days with saline or ascending doses of d-amphetamine (0.0032-0.032 mg/kg/h) + buprenorphine (0.075 or 0.237 mg/kg/day) in combination. d-Amphetamine + both doses of buprenorphine produced an amphetamine dose-dependent decrease in speedball self-administration in comparison to the saline treatment baseline (Po0.01-0.001), but food-maintained responding did not change significantly. d-Amphetamine alone (0.032 mg/kg/h) significantly decreased both food (Po0.01) and speedball-maintained responding (Po0.05). During saline control treatment, speedball unit doses of 0.0032 mg/kg/inj cocaine + 0.001 mg/kg/inj heroin were at the peak of the speedball dose-effect curve. Daily treatment with 0.01 mg/kg/h d-amphetamine + 0.237 mg/kg/day buprenorphine produced a significant downward and rightward shift in the speedball dose-effect curve (Po0.01) and no significant effect on food-maintained responding. A significant decrease in speedball self-administration was sustained over 10 days of treatment. These findings are consistent with our previous reports and suggest that medication mixtures designed to target both the stimulant and the opioid component of the speedball may be an effective approach to polydrug abuse treatment.

Compulsive-Like Responding for Opioid Analgesics in Rats with Extended Access

“…At low doses buprenorphine acts as an antagonist at the kappa-receptor (Kajiwara et al, 1986). Antagonism of the kappa-receptor has previously been shown to inhibit self-administration of cocaine and other drugs of abuse (Cashman and Azar, 2014;Mello and Negus, 2007;Wee et al, 2009). At high doses, buprenorphine has weak agonist effects that might render buprenorphine aversive (Kajiwara et al, 1986;Sante et al, 2000) and similar to its effects at ORL-1, activation of kappa-receptors directly Figure 2 Rats were allowed to self-administer heroin (a), fentanyl (b), oxycodone (c), and buprenorphine (d) over the course of 14 sessions at low, intermediate, and high doses during short (ShA) or long (LgA) access conditions to evaluate the escalation of drug intake.…”

Evidence-based treatments of addiction

“…Buprenorphine, a partial opioid agonist, has been found to reduce cocaine self-administration in monkeys (Mello & Negus 2007), but studies in cocaine-dependent patients have yielded mixed results. A recent controlled study of buprenorphine in a population of combined opiate-and cocaine-dependent patients has shown a positive effect in reducing the use of both cocaine and opiates (Montoya et al 2004).…”

Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

“…Separate from the idea of a potential cocaine antagonist is the interest in DAT as a target for agonist-like substitution therapy (Grabowski et al, 2001; Negus and Mello, 2003; Grabowski et al, 2004; Negus et al, 2007; Mello and Negus, 2007); see also recent review by (Howell and Negus, 2014). There is promising pre-clinical and clinical evidence for efficacy of the DAT substrates d -amphetamine, d -phenmetrazine and sustained-release d -methamphetamine (Negus et al, 2009; Banks et al, 2013a; 2013c; Phillips et al, 2014), making a strong case for further work on this group of medications.…”