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, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. 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.

Figure 1

Mean (+/- SEM) absolute saccharin consumption for subjects conditioned with 18, 32 and 50 mg/kg of vanoxerine on Trials 1-4, along with saline and cocaine controls. *Denotes significant difference from subjects conditioned with saline ^#Denotes significant difference from subjects conditioned with cocaine.

Figure 2

Mean (+/- SEM) absolute saccharin consumption for subjects conditioned with 18, 32 and 50 mg/kg of fluoxetine on Trials 1-4, along with saline and cocaine controls. *Denotes significant difference from subjects conditioned with saline ^#Denotes significant difference from subjects conditioned with cocaine.

Figure 3

Mean (+/- SEM) absolute saccharin consumption for subjects conditioned with 18, 32 and 50 mg/kg of nisoxetine on Trials 1-4, along with saline and cocaine controls. *Denotes significant difference from subjects conditioned with saline ^#Denotes significant difference from subjects conditioned with cocaine.

Figure 4

Mean (+/- SEM) absolute saccharin consumption for subjects conditioned with 18, 32, and 50 mg/kg of vanoxerine, fluoxetine and nisoxetine on Trial 4

Figure 5

Mean water consumption for subjects preexposed to saline, cocaine, fluoxetine, nisoxetine or vanoxerine

Figure 6

Mean (+/- SEM) absolute saccharin consumption for subjects conditioned with 32 mg/kg of cocaine (Upper panel) or saline (Lower panel) following preexposure to various doses of either saline, cocaine, fluoxetine, nisoxetine or vanoxerine. *Denotes significant difference from the saline-preexposed group