Amphetamine maintenance therapy during intermittent cocaine self-administration in rats attenuates psychomotor and dopamine sensitization and reduces addiction-like behavior

Abstract

D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine's effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine's potency at the DAT. Male rats self-administered cocaine intermittently (5 min ON, 25 min OFF x10; 5-h/session) for 14 sessions, with or without concomitant D-amphetamine maintenance therapy during these 14 sessions (5 mg/kg/day via s.c. osmotic minipump). We then assessed responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. We also assessed the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core using fast scan cyclic voltammetry ex vivo. IntA cocaine self-administration produced psychomotor (locomotor) sensitization, strong motivation to take and seek cocaine, and it increased cocaine's potency at the DAT. D-amphetamine coadministration suppressed the psychomotor sensitization produced by IntA cocaine experience. After cessation of D-amphetamine treatment, the motivation to take and seek cocaine was also reduced, and sensitization of cocaine's actions at the DAT was reversed. Thus, treatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Dopamine “Ups and Downs” in Addiction Revisited

“…Finally, IntA experience also produces psychomotor sensitization [37,56,57,58], which has been related to increased DA neurotransmission [9], and psychomotor sensitization often predicts later motivation for cocaine [57,58]. Interestingly, amphetamine maintenance therapy during IntA cocaine decreases subsequent motivation for cocaine and the expression of psychomotor sensitization, while reversing the sensitization of cocaine's action at the DAT [59]. The latter effect is opposite that seen after LgA, where amphetamine maintenance reverses the tolerance to cocaine's effects at the DAT produced by LgA cocaine [60].…”

Dopamine ‘ups and downs’ in addiction revisited

“…In the context of therapeutic approaches, this indicates that when targeting the DA system, treatments should aim to mitigate this sensitized DA state [12]. Indeed, d-amphetamine maintenance therapy decreases cocaine use in humans [129,130,131,132,133], and a recent study in rats shows that d-amphetamine maintenance during IntA cocaine self-administration decreases the expression of psychomotor sensitization and subsequent motivation for cocaine, while reversing the sensitization of cocaine's action at the DAT [134]. While many questions remain to be addressed (see Outstanding Questions), this emerging literature suggests that treatments that mitigate cocaine-induced sensitization of DA systems may blunt the motivation to take the drug.…”

D-amphetamine maintenance therapy reduces cocaine use in female rats

“…In people with cocaine addiction, damphetamine in long-acting, sustained-release formulations is both safe and effective in reducing cocaine use (Grabowski et al, 2001(Grabowski et al, , 2003Greenwald et al, 2010;Lile et al, 2020;Nuijten et al, 2016;Rush et al, 2010). D-amphetamine also reduces cocaine use in nonhuman primates (Czoty et al, 2010(Czoty et al, , 2011Lile et al, 2020;Negus, 2003;Negus & Mello, 2003) and laboratory rats (Abreu, 1988;Allain et al, 2021;Chiodo et al, 2008;Chiodo & Roberts, 2009;Morgane et al, 2013;Siciliano et al, 2018;Zimmer et al, 2014).…”

“…Still, virtually all rat studies on the anti-addiction effects of damphetamine have included males only (Allain et al, 2021;Chiodo et al, 2008;Chiodo & Roberts, 2009;Siciliano et al, 2018;Zimmer et al, 2014). In parallel, while some studies in humans and nonhuman primates have included females, results were not analysed by sex (Grabowski et al, 2001;Greenwald et al, 2010;Lile et al, 2020;Negus & Mello, 2003;Rush et al, 2010Rush et al, , 2009, arguably because many of these studies were not sufficiently powered to do so.…”

“…Second, Siciliano et al (2019) studied the effects of acute d-amphetamine. While chronic d-amphetamine administration reduces cocaine reinforcement (Allain et al, 2021;Chiodo et al, 2008;Chiodo & Roberts, 2009;Czoty et al, 2010Czoty et al, , 2011Grabowski et al, 2001Grabowski et al, , 2003Greenwald et al, 2010;Lile et al, 2020;Negus, 2003;Negus & Mello, 2003;Nuijten et al, 2016;Rush et al, 2010;Shearer et al, 2003;Siciliano et al, 2018), acute d-amphetamine administration can increase cocaine taking and seeking (Barrett et al, 2004;Gerber & Stretch, 1975).…”