The Speed of Cocaine Delivery Determines the Subsequent Motivation to Self-Administer the Drug

Neuropsychopharmacology (2013) 38, 2644–2656 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org The Speed of Cocaine Delivery Determines the Subsequent Motivation to Self-Administer the Drug Ellie-Anna Minogianis1, Daniel Lévesque2,3 and Anne-Noël Samaha*,1,3 1 Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; 2Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada; 3CNS Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada The rapid delivery of drugs of abuse to the brain is associated with an increased likelihood and severity of addiction. Here we evaluated the hypothesis that rapidly delivered cocaine facilitates the addiction process by promoting the development of enhanced motivation for the drug. Rats lever-pressed for cocaine delivered intravenously over 5 or 90 s under fixed ratio (FR) during 6-h sessions. The motivation for cocaine was subsequently assessed using a progressive ratio (PR) schedule, where each successive drug injection cost an exponentially greater number of lever presses, until the cessation of responding. Throughout all self-administration sessions, all rats could only take one injection every 90 s. The 5-s groups self-administered more drug than the 90-s groups across the FR sessions. Under PR, animals that had chronically self-administered rapidly delivered cocaine took more cocaine across a range of doses and regardless of whether the drug was delivered over 5 or 90 s during PR testing. The speed of delivery also determined the long-term neurobiological impact of cocaine. Fourteen days following cocaine withdrawal, caudate-putamen D2 levels were decreased only in the 90-s rats, and quinpirolemediated Gai/o-protein activation was increased to a greater extent in the 90- vs 5-s rats. Thus, rapid delivery promotes the pursuit of cocaine in the face of rising costs and alters cocaine-induced changes in striatal D2 receptor number and function. As such, rapidly delivered cocaine might facilitate addiction because it more readily alters brain motivation circuits in ways that contribute to the compulsive pursuit of the drug. Neuropsychopharmacology (2013) 38, 2644–2656; doi:10.1038/npp.2013.173; published online 7 August 2013 Keywords: speed of drug delivery; cocaine; extended access; progressive ratio; intravenous drug self-administration; dopamine D2 receptor INTRODUCTION It is thought that ‘The development of addiction depends on the interaction of agent, host and environmenty’ (O’Brien, 2008). Much research has shown that ‘host’- and environment-related factors can modulate the transition from controlled drug use to addiction (Badiani and Robinson, 2004; Le Moal, 2009). Much less attention has been paid to characteristics of the ‘agent’ and how these might accelerate or delay the progression to addiction. One such characteristic is the speed at which a drug reaches its target sites in the brain. Addiction to cocaine, amphetamine, methamphetamine, nicotine, or heroin is more likely and more severe in individuals who smoke or inject these drugs than in individuals who use slower routes of administration (eg, intranasal, oral, or transdermal administration). Individuals who smoke or inject drugs use drugs more frequently, for a longer time, spend more money on drugs, report a greater loss of control over drug taking, and are more likely to *Correspondence: Dr A-N Samaha, Department of Pharmacology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal, QC H3C 3J7, Canada, Tel: þ 514 343 6111 x. 32788, Fax: þ 514 343 2291, E-mail: Received 20 March 2013; revised 11 July 2013; accepted 15 July 2013; accepted article preview online 18 July 2013 overdose (Barrio et al, 2001; Carpenter et al, 1998; Ferri and Gossop, 1999; Gossop et al, 1992; Hatsukami and Fischman, 1996; Hughes, 1989; Rawson et al, 2007; Winger et al, 1992). Rapidly administered drugs are hypothesized to be more addictive, because they are more pleasurable such that the likelihood of continuing or escalating drug use is increased (de Wit et al, 1993; Hatsukami and Fischman, 1996). Indeed, rapid delivery enhances the positive subjective effects of drugs (Abreu et al, 2001; de Wit et al, 1993; Kollins et al, 1998), and this could contribute to drug use. A related hypothesis is that rapidly administered drugs are more addictive, because they are more reinforcing (Balster and Schuster, 1973; Kato et al, 1987; Panlilio et al, 1998). The idea is that because drug effects are more immediate with rapid drug delivery, associations formed between drugtaking behaviors and ensuing drug effects are stronger and the likelihood of repeating these behaviors is increased. However, animal studies on reinforcing efficacy have produced inconsistent findings. Some show that rapid intravenous delivery enhances the acute reinforcing effects of drugs (Balster and Schuster, 1973; Kato et al, 1987; Panlilio et al, 1998; Schindler et al, 2011; Wakasa et al, 1995; Woolverton and Wang, 2004), and others show that it does not (Crombag et al, 2008; Liu et al, 2005; Sorge and Clarke, 2009). The reasons for the discrepancy are not clear. However, the procedures often used (limiting drug access to Rapid delivery of cocaine increases motivation for the drug E-A Minogianis et al 2645 1–3 h/session; (Crombag et al, 2008; Panlilio et al, 1998; Pickens et al, 1969; Schindler et al, 2011; Sorge and Clarke, 2009)) are known to promote stable patterns of drug intake, rather than the progressive and deteriorating patterns of drug-taking behavior that define addiction (Ahmed, 2012; Roberts et al, 2007). Recently, the influence of the speed of drug delivery on drug reinforcement has been assessed using extended self-administration (SA) sessions (Wakabayashi et al, 2010), where animals self-administer during 6 h/session, and are subsequently more likely to develop patterns of drug taking relevant to addiction (Ahmed, 2012). This work has shown that under limited cocaine access (1 h/session), the speed of intravenous cocaine delivery (5, 45 or 90 s) does not influence the reinforcing properties of the drug (Wakabayashi et al, 2010). When access to cocaine is extended to 6 h, however, faster cocaine injections lead to greater drug intake and a more persistent vulnerability to drug-primed reinstatement of cocaine-seeking behavior (Wakabayashi et al, 2010). It has been proposed that regardless of whether rapid delivery might or might not make drugs more reinforcing, rapid delivery increases the potential for addiction because it facilitates the brain changes that promote excessive motivation for drugs (Liu et al, 2005; Samaha et al, 2002; Samaha and Robinson, 2005; Wakabayashi et al, 2010). Repeated drug use can trigger the development of pathological motivation for drug, leading to a state where drugs become progressively harder (...truncated)