Assessment of monoamine transporter inhibition in the mediation of cocaine-induced conditioned taste aversion

Abstract

Although the mechanisms of cocaine reward have been well characterized, the pharmacological basis of cocaine's aversive effects is less understood. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of monoamine uptake inhibition in cocaine's aversive effects by comparing cocaine to three reuptake inhibitors with relative specificity for the transporters of dopamine (DAT; GBR 12909), norepinephrine (NET; desipramine) and serotonin (SERT; clomipramine). Specifically, 104 male Sprague–Dawley rats were given 20-min access to a novel saccharin solution followed immediately by a subcutaneous injection of cocaine, GBR 12909, desipramine, clomipramine (each at 18, 32 or 50 mg/kg; 12 groups) or drug vehicle (equivolume to the highest cocaine dose). Over trials, cocaine and desipramine each dose-dependently suppressed saccharin consumption and did so in an equivalent manner when matched by dose. However, both GBR 12909 and clomipramine conditioned weaker aversions than cocaine at the two lowest doses (18 and 32 mg/kg). At the highest dose (50 mg/kg), GBR 12909 produced equivalent suppression of saccharin consumption to cocaine while clomipramine's conditioned suppression remained relatively weak at this dose. These results suggest that cocaine's adrenergic actions resulting from NET inhibition may play a more significant role in the mediation of its aversive effects than its actions at DAT and SERT.

Introduction

Cocaine, like a number of other drugs of abuse, has been shown to possess both rewarding (Nomikos and Spyraki, 1988, Wise et al., 1992) and aversive (Ettenberg, 2004, Ferrari et al., 1991, Koob et al., 1997) properties. Although its rewarding effects appear to be mediated by monoamine transporter inhibition in the central nervous system (CNS; Ritz et al., 1987, Rocha, 2003), the basis for the aversive effects of cocaine is less well understood. Interest in the aversive properties of abused drugs stems from the notion that the acceptability and abuse potential of the drug may depend on a balance of its rewarding and aversive effects (Riley and Simpson, 2001). Understanding the physiological bases of cocaine's aversive effects as well as the conditions under which they occur may provide insight into a key vulnerability factor mediating the abuse potential of cocaine.

In the investigation of cocaine's behavioral effects, one area that has received considerable attention is its action on monoaminergic systems. Cocaine affects monoamine activity by acting as an indirect agonist for the three monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) via its blockade of their respective transporter proteins (Taylor and Ho, 1978, Woolverton and Johnson, 1992). To understand the relative roles of cocaine's actions on each of these monoamine systems in the expression of various behaviors (e.g., self-administration [SA], drug discrimination [DD]), researchers have employed pharmacological probes that act with relative specificity on each of the monoamine transporters and have compared the effects of these drugs to those of cocaine (Baker et al., 1993, Cunningham and Callahan, 1991, Tella, 1995). Although these assessments have provided insight into the rewarding (Tella, 1995) and discriminative stimulus (Baker et al., 1993, Cunningham and Callahan, 1991) effects of cocaine, this methodology has yet to be used to examine cocaine's aversive effects. There is some evidence that 5-HT transporter (SERT) inhibition with fluoxetine can induce a CTA (Berendsen and Broekkamp, 1994, Prendergrast et al., 1996), although no comparison was made to cocaine in these assessments. In addition, there appears to be a dopaminergic contribution to cocaine-induced CTAs as the DA receptor antagonist pimozide has been shown to attenuate a cocaine-induced CTA (Hunt et al., 1985). However, this demonstration did not assess the direct effect of DA transporter (DAT) inhibition on the induction of a CTA.

Recent work examining factors outside of cocaine's monoaminergic activity highlight the possibility that monoamine transporter inhibition may be mediating its aversive effects. Specifically, a report by Freeman et al. (2005) comparing the aversive effects of cocaine to the analogs procaine and cocaine methiodide in the conditioned taste aversion (CTA) preparation demonstrated that the full expression of cocaine's aversive effects do not appear to be singularly mediated by either sodium channel inhibition or activity in the peripheral nervous system (PNS). That is, neither the inhibition of sodium channels with procaine nor the cocaine-like actions in the PNS induced by peripherally administered cocaine methiodide produced aversions comparable in magnitude to cocaine when matched by dose, although each analog did induce some degree of aversion by itself. Given that neither of these compounds specifically allowed for an assessment of the contribution of monoamine transporter inhibition, there remains the possibility that one or more of the monoamine systems may be participating in the mediation of cocaine's aversive effects.

In order to make a systematic assessment of monoamine transport inhibition as a mediator of cocaine-induced CTA, the present study compared cocaine to three reuptake inhibitors, each of which possesses relative specificity for one of the three monoamine transporters, in their ability to induce a CTA. Specifically, rats were given access to a novel saccharin solution and injected with either cocaine, GBR 12909 (DAT inhibitor; Andersen, 1989), desipramine (NE transporter [NET] inhibitor; Tatsumi et al., 1997) or clomipramine (SERT inhibitor; Thomas and Jones, 1977) at one of three doses (18, 32 and 50 mg/kg).