The speed of cocaine delivery determines the subsequent motivation to self-administer the drug.
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.
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
Ellie-Anna
EA
Minogianis
Daniel
D
Lévesque
Anne-Noël
AN
Samaha
D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D009042:Motivation / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012646:Self Administration; D013469:Sulpiride / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013997:Time Factors
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D017448:Receptors, Dopamine D2; C045105:iodosulpride; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013469:Sulpiride; D003042:Cocaine