Research ReportCocaine self-administration and locomotor activity are altered in Lewis and F344 inbred rats by RTI 336, a 3-phenyltropane analog that binds to the dopamine transporter
Introduction
Cocaine abuse is a major problem in the United States today, and pharmacotherapy is one treatment approach. Because of the evidence that cocaine exerts many of its behavioral effects by increasing synaptic dopamine (DA) levels [20], [42], many pharmacotherapies have targeted this system. Different approaches have been suggested, such as DA antagonists as blocking agents [22], [27], antidepressants to treat withdrawal-related depressive symptoms, or DA agonists as substitution agents [27]. There are two advantages to a substitution agent: (1) reduction in cocaine use perhaps by blocking “withdrawal” symptomatology such as “craving” that would increase compliance with behavioral treatment interventions [3]; (2) reduction in the effects of cocaine if an addict relapses. Theoretically, cocaine use would be reduced through extinction of the learned contingency between cocaine cues and cocaine reinforcement. An ideal substitution agent would have a slower onset and longer duration of action than cocaine. These characteristics should be associated with low abuse liability, given that the euphoric effects of cocaine are related, in part, to its rapid onset of action [11]. The potential treatment agent needs to be non-toxic, preferably reduce cocaine toxicity, and be acceptable to the addict.
The ability of cocaine to inhibit DA uptake presynaptically, via its actions at the DA transporter (DAT), resulting in an accumulation of DA in the synapse of the nucleus accumbens (NAc) [34] relates to its reinforcing [4], [29] and subjective [37] effects. Accordingly, pretreatment with DA reuptake inhibitors, such as GBR 12909, decreases cocaine self-administration and cocaine-induced reinstatement of responding in rats and primates [12], [31], [33]. However, GBR 12909 only reduced self-administration of high cocaine doses that may reflect rate-disruptive rather than reinforcement reduction effects [31].
Several tropane analogs of cocaine that are potent and selective inhibitors of DAT and have a long duration of action and slow onset have been developed and assessed in rodents and primates. Some of these compounds, such as RTI-31, RTI-32, and RTI-55, substitute for cocaine in a drug discrimination procedure causing minimal disruptions in response rate [2], [7]. Pretreatment with another cocaine analog, RTI-113, causes a downward shift in the cocaine dose–response function in self-administration in rats that could be interpreted as a decrease in cocaine reinforcement [8]. RTI-113 also decreased cocaine self-administration under a second-order schedule of reinforcement in squirrel monkeys [18]. In both rats [8] and monkeys [40], significant effects of RTI-113 on cocaine self-administration were seen under conditions of high levels of DAT occupancy. Recently, a novel phenyltropane analog, 3β-(4-Chlorophenyl) tropane-2β-[3-(4′-methylphenyl) isoxazol-5-yl] Hydrochloride (RTI 336), has been characterized and shown to be a potent and selective DAT inhibitor [5]. At high doses (>3 mg/kg), RTI 336 induces locomotor activity and stereotypy in mice and substitutes for the cocaine discriminative stimulus in rats [5], [6], but its effects on cocaine self-administration have not been assessed.
Inherent differences in DAT levels may exist in individuals prone to drug addiction as suggested by studies in inbred rat strains [21]. Fischer 344 (F344) and Lewis rats differ in acquisition and maintenance of cocaine self-administration [16], [24] and in protein levels in mesolimbic DA system such as tyrosine hydroxylase, glial fibrillary acidic protein (GFAP), neurofilament proteins, and Giα G-protein-coupled to D2 receptors [10], [15]. Specifically, Lewis rats show enhanced acquisition of cocaine self-administration, compared to F344 rats [24], and lower DAT levels and DA D2 and D3 densities in NAc with no strain differences in D1 densities [10]. Consistent with these mesolimbic DA protein profiles, we showed previously that pretreatment with D1 and D2 agonists (SKF38393, quinpirole) and antagonists (SCH23390, eticlopride) differentially alters cocaine self-administration in these strains [16]. The purpose of this study was to determine whether RTI 336, a potent and selective DAT inhibitor [5], would differentially affect cocaine self-administration in Lewis and F344 inbred rats given the strain differences in NAc DAT levels. We tested the effects of RTI 336 on maintenance of cocaine self-administration under a fixed-ratio schedule of reinforcement and examined its effects on cocaine-induced locomotor activity and drug discrimination.
Section snippets
Subjects
Male Lewis and Fischer 344 inbred rats (Harlan, Indianapolis IN) weighing 300–350 g served as subjects in these studies. Rats were housed singly in stainless-steel, hanging, wire-mesh cages in a temperature- and humidity-controlled colony room maintained on a 12:12 light/dark cycle (lights on at 07:00). Food and water were available ad libitum except during studies utilizing operant responding for food. All procedures were approved by the Institutional Animal Care and Use Committee in
Experiment 1: cocaine self-administration
The effects of RTI 336 on numbers of infusions self-administered across the different cocaine doses are shown in Fig. 1 for both Lewis and F344 rats. The overall three-way interaction of RTI 336 × strain × cocaine dose shows a trend towards significance, F(2,20) = 3.00; P < 0.09. This likely reflects, in part, that the effect of cocaine dose does not differ between strains. Both Lewis and F344 rats self-administer decreasing numbers of infusions across increasing doses of cocaine under baseline
Discussion
The 3-phenyltropane analog, RTI 336, that binds potently and selectively to the dopamine transporter (DAT) [5], leads to more pronounced effects on cocaine self-administration and locomotor activity in Lewis compared to F344 rats. In general, RTI 336 decreases levels of cocaine-induced responding in Lewis rats and increases such responding in F344 rats. These effects of RTI 336 are consistent with known strain differences in protein levels in the mesolimbic dopamine (DA) system [10], [15].
Acknowledgments
This research was supported by SPIRCAP: Novel Pharmacotherapy for Treatment of Cocaine Addiction (NIDA U19 DA133326), the VA New England Mental Illness Research Education and Clinical Center, and by the Yale IWHR Scholar Program on Women and Drug Abuse (1K12DA14038). The authors gratefully acknowledge the technical assistance provided by Diane Lendroth, Adriane Myers, and Hayde Sanchez.
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