Transgenic and pharmacological assessment of the contributions of norepinephrine, serotonin and dopamine to cocaine's aversive effects

Although cocaine's potent hedonic value dominates its affective experience, reports indicate that cocaine also has aversive effects, the neurochemical basis of which remains poorly understood. Although research has addressed this issue using either a genetic or pharmacological approach; the following series of studies combined both methodologies along with a preparation thar is thought to specifically assess the aversive properties of a compound. In Experiment 1, cocaine-induced taste aversions were examined in transgenic subjects lacking one of the respective monoamine transporters, dopamine (DAT), norepinephrine (NET) or serotonin (SERT). Attenuated aversions were only observed among NET and SERT knock-out subjects with the strongest effects in response to NE transporter deletion. However, since normal neurological pathways have been shown to be significantly altered in these types of transgenic subjects, the generalizability of these findings may be limited. Accordingly, Experiment 2 assessed the aversiveness of selective dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporter inhibitors. Only the NET inhibitor (nisoxetine) approximated the aversive strength of cocaine. Finally, Experiment 3 compared the effects of pretreatment of each of the selective inhibitors on the development of cocaine-induced taste aversions. Although pretreatment with cocaine, nisoxetine and fluoxetine all led to significantly attenuated aversions, the strongest preexposure effect was observed with fluoxetine pretreatment. Combined, the results of these three investigations indicate little or no involvement of dopaminergic systems in the molecular mechanisms responsible for cocaine-induced taste aversions. There is also the strong indication that NE contributes most substantially to the aversive component of cocaine's affective experience, with non-noradrenergic systems, particularly serotonin, having significant modulatory involvement.