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

Abstract

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (V max ), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced V max and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine selfadministering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerveterminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

One month of cocaine abstinence potentiates rapid dopamine signaling in the nucleus accumbens core

“…While some studies report that a history of cocaine self-administration reduces electrically-evoked DA concentration (Calipari et al, 2014; Ferris et al, 2015; Mateo et al, 2005; Siciliano et al, 2015), the experimental designs differed markedly from our own. For example, Calipari and colleagues (2014) assessed presynaptic DA signaling parameters in the NAc core to determine the effects of cocaine self-administration on DA release and uptake in the absence of drug.…”

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

“…Therefore, whereas adolescent methylphenidate treatment increases DAT function in mPFC of SHR (Somkuwar et al 2013a), adolescent AMPH treatment may reduce DAT expression and function. Although effects of adolescent AMPH on mPFC DAT in SHR are not yet confirmed, acute AMPH infusions reduce DAT function and expression in the nucleus accumbens of adult outbred rats (Ferris et al 2015). It is also worth noting that adolescent atomoxetine treatment did not increase DAT function in mPFC of adult SHR, but rather reduced DAT function in orbitofrontal cortex of adult SHR (Somkuwar et al 2013b).…”

“…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).…”

“…Unlike methylphenidate, d-amphetamine is a substrate at DAT and NET, reversing neurotransmitter transport from inside the neuron terminal to the extracellular space, in addition to being a substrate at serotonin and vesicular monoamine-2 transporters (Sulzer et al 2005). Importantly, d-amphetamine decreases DAT function in nucleus accumbens of adult outbred rats (Ferris et al 2015). Thus, we hypothesized that adolescent d-amphetamine would not increase cocaine self-administration behaviors in adulthood in the SHR model.…”

Adolescent d -amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

“…We hypothesize that chronic treatment with damphetamine during adolescence produces long-term decreases in DAT function and expression, similar to that observed after atomoxetine treatment. Although the effect of damphetamine on PFC DAT function in SHR is unknown, recently, acute amphetamine infusions were found to reduce DAT function and expression in nucleus accumbens of adult outbred rats [117]. Importantly, activation of post-synaptic D1 and D2 receptors in mPFC facilitates flexible learning [118], as infusion of D1 and D2 antagonists in mPFC impairs set shifting performance in outbred rats [119,120].…”