Reduction of the reinforcing effectiveness of cocaine by continuous d-amphetamine treatment in rats: importance of active self-administration during treatment period

Abstract

Rationale Continuous administration of d-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of d-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19 - 0.75 mg/kg/inf. Objectives The present study tested whether these effects were a reflection of pharmacological interactions between d-amphetamine and cocaine or if they resulted from associative learning mechanisms. Methods After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic mini-pumps filled with either d-amphetamine (5 mg/kg/day - groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with d-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions. Results In replication of previous studies, d-amphetamine treatment resulted in a significant (35%) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2). Conclusions Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous d-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking.

The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats

“…Conversely, cocaine self-administration recovered gradually over the course of seven days after termination of amphetamine treatment in rats and rhesus monkeys (Negus and Mello 2003a; Chiodo et al 2008). To the degree that these ICSS data can inform interpretation of self-administration data, these results support the view that slow recovery of cocaine self-administration after amphetamine treatment does not reflect slow recovery of cocaine effects, but rather may reflect learning processes such as those associated with reacquisition of self-administration after a period of extinction (Czoty et al 2010; Zimmer et al 2013). …”

Adolescent d-amphetamine treatment in a rodent model of attention deficit/hyperactivity disorder: impact on cocaine abuse vulnerability in adulthood

“…Interestingly, amphetamines show promise in the treatment of cocaine abuse. For example, in outbred rats with cocaine self-administration experience, concurrent AMPH produced downward shifts in cocaine dose-response functions (Chiodo et al 2008; Zimmer et al 2014), and reversed cocaine-induced deficits in DAT expression and function (Ferris et al 2015). Similarly, in non-human primates, concurrent AMPH reduced cocaine self-administration under PR and second-order schedules of reinforcement, and increased choice for food over cocaine (Czoty et al 2010; Negus 2003).…”

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

“…Continuous amphetamine administration delivered during cocaine selfadministration sessions is effective at reducing breakpoints on a progressive-ratio schedule (Negus and Mello, 2003a;Chiodo et al, 2008;Czoty et al, 2010;Zimmer et al, 2014), reducing second-order responding for cocaine (Negus and Mello, 2003b), and reducing preference for cocaine in a choice paradigm (Negus, 2003) in both rats and/or nonhuman primates. Similarly, oral d-amphetamine treatment has been shown to reduce cocaine use in human addicts (Grabowski et al, 2001(Grabowski et al, , 2004a.…”