Rats Self-Administer Intravenous Nicotine Delivered in a Novel Smoking-Relevant Procedure: Effects of Dopamine Antagonists Robert E. Sorge and Paul B. S. Clarke Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada Received April 2, 2009; accepted May 14, 2009 ABSTRACT Attempts to explain tobacco addiction have relied heavily on the assumption that each cigarette puff delivers a bolus of nicotine to the brain within seconds. However, nicotine transits from lungs to brain much more gradually than once thought. Nevertheless, animal self-administration studies continue to use rapid (e.g., 3-s) infusions, as well as high unit doses of nicotine (e.g., 15–30 g/kg/infusion), each equivalent to one to two cigarettes. Here, we report that nicotine is self-adminis- tered across a range of infusion durations (3, 30, 60, and 120 s) in rats. Slow (30-s) infusions were preferred over fast (nominal 3-s) infusions and were self-administered across several rein- forcement schedules, at doses as low as 3 g/kg/infusion, equivalent to one to two puffs. A conventional “fast/high” self- administration procedure (3 s-30 g/kg/infusion) was then compared with our new “slow/low” procedure (30 s-3 g/kg/ infusion) in rats trained on a progressive ratio schedule and acutely challenged with dopamine receptor antagonists. The D 1 antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) (6 –25 g/kg s.c.) reduced intake in both procedures and in rats self-administering cocaine (0.5 mg/kg/infusion). The D 2 antag- onists spiperone (3–30 g/kg s.c.) and sulpiride (5–20 mg/kg i.p.) increased intake of fast/high nicotine and cocaine, but markedly reduced intake of slow/low nicotine. In a final test, in which only infusion speed was varied, an acute spiperone challenge produced the same differential effect on nicotine self-administration. In conclusion, our new slow/low nicotine self-administration procedure, designed to better mimic smok- ing-associated nicotine intake, is pharmacologically distinct from the conventional fast delivery/high-dose procedure. The nicotine addiction field has been underpinned by the pervasive belief that nicotine reaches the brain in 7 to 10 s after a single puff of a cigarette and that this rapid “bolus” of nicotine is necessary for tobacco dependence (Russell and Feyerabend, 1978). Recent empirical evidence, however, in- dicates that arterial concentrations of nicotine rise gradually and do not peak until 20 to 30 s after each cigarette puff (Rose et al., 1999), with brain nicotine concentrations peaking ap- proximately 2 min after a puff (Rose et al., 2006). It is interesting that, when nicotine is delivered intravenously to human subjects at high rates (e.g., via 10-s infusions), it can serve as a reinforcer (Rose et al., 2003; Harvey et al., 2004), but it is often misidentified as cocaine or as another stimu- lant (Henningfield et al., 1983; Jones et al., 1999). However, a critical review of the literature uncovered no convincing evidence that nicotine must be delivered rapidly to be rein- forcing in human subjects (Dar and Frenk, 2007), and accord- ing to a recent report, human subjects will self-administer relatively slow (30-s) intravenous infusions of nicotine (So- fuoglu et al., 2008). Despite the evidence outlined above, researchers studying nicotine self-administration in animals continue to use ultra- rapid (1– 4-s) bolus infusions of nicotine that inadequately represent the kinetics of nicotine obtained from cigarette smoking (Matta et al., 2007). To date, the effect of infusion rate has been studied systematically only in rhesus monkeys (Wakasa et al., 1995). Here, infusions of 6 and 24 s, but not 100 s, were found to support self-administration. Comparable evidence in rats is fragmentary. For example, Valentine et al. (1997) commented informally that infusion durations longer than 2 to 3 s were poorly reinforcing, particularly at low-unit doses, and studies that have reported a failure to obtain nicotine self-administration in adult rats have used slower (6-s) infusions (Belluzzi et al., 2005). In animal studies, nicotine infusion doses of 15 or 30 g/kg typically generate maximal responding and are hence widely used (Corrigall and Coen, 1989; Matta et al., 2007). In con- trast, cigarette smokers extract only 1 to 3 g/kg nicotine per This study was supported by a Natural Science and Engineering Research Council of Canada postdoctoral fellowship (to R.E.S.); the Canadian Institutes of Health Research of Canada [Grant MOP-10516] (to P.B.S.C.); and a Cana- dian Tobacco Control Research Initiative ICE Team grant (to P.B.S.C.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.154641. ABBREVIATIONS: DA, dopamine; FR, fixed ratio; PR, progressive ratio; SCH 23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine; ANOVA, analysis of variance; DAergic, dopaminergic. 0022-3565/09/3302-633–640$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 330, No. 2 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 154641/3495121 JPET 330:633–640, 2009 Printed in U.S.A. 633 at ASPET Journals on December 11, 2016 jpet.aspetjournals.org Downloaded from