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

Abstract

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 quinpirole-mediated Gα(i/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.

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

“…A notable exception is Mantsch et al (2004), who showed that escalation occurs earlier at higher doses (2 versus 0.5 mg/kg/injection). This is in line with a number of studies that have failed to see escalation of cocaine intake at lower drug doses (0.25-0.6 mg/kg/injection) (Ferrario and Robinson, 2007, Kippin et al, 2006, Mantsch et al, 2004and Minogianis et al, 2013. Escalation is also facilitated by a rapid speed of cocaine onset.…”

“…However, a more recent study suggests that this lack of effect might be restricted to the initial stages of drug self-administration (the first 3-4 sessions following acquisition of the drug self-administration task). Bouayad-Gervais et al (2014) showed that, consistent with prior studies (Crombag et al, 2008, Minogianis et al, 2013and Wakabayashi et al, 2010, varying the speed of i.v. cocaine injection (5 or 90 s) has no effect on intake during the first 3-4 self-administration sessions.…”

“…Some studies show that rapid i.v. injections of cocaine or nicotine lead to greater drug intake within each time-limited session (Kato et al, 1987, Schindler et al, 2011and Schindler et al, 2009, other studies do not show this effect (Crombag et al, 2008, Minogianis et al, 2013, Sorge and Clarke, 2009and Wakabayashi et al, 2010. This suggested that the speed of drug onset might not critically influence drug intake during short, FR1 sessions.…”

“…This prompted us and others to ask whether the speed of drug delivery plays a role in the propensity to escalate drug consumption. Work on this issue showed that when daily access to cocaine is increased from 1 to 6 h, rats given access to rapid (5-45 s) versus slower (90 s) injections of cocaine take more drug and are also more likely to escalate their consumption over days (Bouayad-Gervais et al, 2014, Minogianis et al, 2013and Wakabayashi et al, 2010. Fig.…”

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

“…administration experiments were based on used faster pumps that delivered 1.6 ml/minute [95], compared to ours that infuse drug at approximately 1.0 ml/minute. The relatively slow speed of the self-administration pumps could have lowered the efficacy of the cocaine delivery system, as faster speeds of delivery results in increased motivation during self-administration in rats [120,121] and humans [122,123]. This explains why all routes of cocaine absorption used by humans facilitate concentrated, rapid delivery of concentrated drug doses into the bloodstream [124,125].…”