Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion

Abstract

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning (Garcia, 1955). Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin.

Profound reduction in sensitivity to the aversive effects of methamphetamine in mice bred for high methamphetamine intake

“…In fact, multiple genes in the NAc are differentially expressed in drug naïve and MA-exposed MADR line mice, which could contribute to differential neuroadaptation. Drug naïve high and low line mice, for example, show differential expression of the gene that codes for the noradrenergic transporter, which is thought to contribute to the negative effects of psychostimulants (Jones et al, 2009; Schank et al, 2008). However, how this gene, or others that are differentially expressed in the MADR lines, contributes to sensitivity to anxiogenic and aversive effects of MA remains to be determined.…”

Dopamine mediates cocaine-induced conditioned taste aversions as demonstrated with cross-drug preexposure to GBR 12909

“…Antagonizing NE activity removes this inhibition allowing cocaine to induce stronger aversions. In support of this, Serafine and Riley (2009) have recently shown that preexposure to cocaine potentiated aversions induced by the NE transporter (NET) inhibitor desipramine (Serafine and Riley, 2009), suggesting that tolerance to cocaine during preexposure (likely through its actions on NET) resulted in the weakening of any inhibitory effects NE may have on desipramine’s aversive effects (for similar investigations and findings with mice; see Jones et al, 2009). Although collectively this work suggests that NE activity may limit the aversive effects of cocaine (and desipramine), preexposure to desipramine attenuated cocaine-induced CTAs (Serafine and Riley, 2009).…”

“…To date, no direct pharmacological studies have been conducted to assess the effects of 5-HT receptor activation (or antagonism) on the aversive effects of cocaine. Our laboratory has recently used the cross-drug preexposure preparation to assess the effects of exposure to the selective serotonin reuptake inhibitor (SSRI) fluoxetine on aversions induced by cocaine (and vice versa; Serafine and Riley, 2010; see also Jones et al, 2009 for a similar assessment with mice). Under these conditions, fluoxetine preexposure did not attenuate cocaine-induced CTAs, suggesting that the two do not share a common aversive effect, although higher doses of fluoxetine may attenuate cocaine-induced aversions.…”

“…This prediction is based on work utilizing the cross-drug preexposure preparation (De Beun et al, 1996; Gommans et al, 1998; Serafine and Riley, 2009) in which exposure to one compound is given prior to aversion conditioning with another. Under such conditions, aversions to the second compound are often weakened, an effect commonly interpreted as being due to cross tolerance (or adaptation) to the shared aversion-inducing effects of the two drugs (Berman and Cannon, 1974; Jones et al, 2009; LeBlanc and Cappell, 1974; Simpson and Riley, 2005; Serafine and Riley, 2009; 2010; for reviews and alternative interpretations, see Cappell and LeBlanc, 1977; Randich and LoLordo, 1979; Riley and Simpson, 2001). In one of the first demonstrations of the use of this procedure for investigations of common stimulus properties, De Beun and colleagues (1993) reported that CTAs induced by the selective serotonin (5-HT) agonist 8-OHDPAT were blocked by preexposure to compounds that also had 5-HT agonist activity (for the same receptor subtype, e.g., 5-HT 1A ; see De Beun et al, 1993).…”

“…Given that these compounds (ipsapirone, buspirone, RU-24969, sertraline, d-amphetamine, LSD, metergoline and idazoxane) were effective in blocking 8-OHDPAT-induced CTAs, De Beun and colleagues concluded that cross-drug preexposure could be used to assess the commonalities in aversion-inducing mechanism between different compounds (De Beun et al, 1993). Since this demonstration, several other investigations have also utilized this procedure to examine common mechanisms in the aversive effects of various compounds (see De Beun et al, 1996; Gommans et al, 1998; Jones et al, 2009; Kayir et al, 2008; Olivier et al, 1999; Van Hest et al, 1992; Serafine and Riley, 2009; 2010). …”