Dopamine, norepinephrine and serotonin transporter gene deletions differentially alter cocaine-induced taste aversion

Abstract

Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al. 2005b; Grupp 1977; Roberts & Fibiger, 1975). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, SERT) on cocaine’s aversive properties has yet to be performed (Uhl et al. 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT.

3,4-Methylenedioxypyrovalerone (MDPV)-induced conditioned taste avoidance in the F344/N and LEW rat strains

“…As noted above, 5-HT has also been implicated in cocaine-induced taste avoidance. For example, transgenic mice with SERT deletions display attenuated acquisition of cocaine-induced taste avoidance compared to wild-type and DAT knockout mice (Jones et al, 2010), although it should be noted that NET knockouts also produced significant attenuation of avoidance, precluding a solitary role of 5-HT in this behavioral effect. Additionally, Serafine et al (2010) reported that animals exposed to cocaine prior to taste avoidance conditioning with fluoxetine (a selective 5-HT reuptake inhibitor) displayed attenuated fluoxetine-induced taste avoidance, suggesting some adaptation to their common aversive effects (see Braveman, 1975; Cappell et al, 1975; for a review see Simpson and Riley, 2001).…”

“…Consistent with these results, animals exposed to the selective dopamine transporter (DAT) inhibitor GBR 12909 prior to taste avoidance conditioning with cocaine display weaker cocaine-induced CTAs (Serafine et al, 2012a), suggesting an adaptation to DA-mediated effects as a consequence of the preexposure and a role of DA in cocaine’s aversive effects (for a review of drug preexposure, see Riley & Simpson, 2001). Cocaine-induced taste avoidance is also weaker in knockout mice with a DAT deletion (although it should be noted that NET- and SERT-knockout mice showed stronger attenuation in this preparation; see Jones et al, 2010; for a complete discussion of monoamine regulation of cocaine-induced taste avoidance, see Serafine and Riley, 2013). It is clear from this evidence that DA plays some role in mediating taste avoidance induced by cocaine.…”

Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats

“…In contrast, adolescents have been consistently reported to be less sensitive to the anxiogenic and aversive effects of both acute drug treatment and withdrawal from drugs of abuse (Doremus et al, 2003; Infurna and Spear, 1979; O’Dell et al, 2007; Schramm-Sapyta et al, 2007; Schramm-Sapyta et al, 2006; Schramm-Sapyta et al, 2009; Shram et al, 2006). Serotonin contributes to the anxiogenic and aversive effects of drugs of abuse, so immature serotonergic function may play a role in adolescent insensitivity to the anxiogenic and aversive effects of these drugs (Ettenberg et al, 2011; Jones et al, 2010). There is a large body of literature showing that the extended amygdala mediates the aversive effects of withdrawal from drugs of abuse due to activation by neuromodulators such as corticotropin-releasing factor and norepinephrine (Koob and Volkow, 2010).…”

Cocaine decreases saccharin preference without altering sweet taste sensitivity

“…It also has been shown that knockout of both dopamine and serotonin transporters are required to abolish cocaine place preference, even though dopamine remains the primary neurotransmitter underlying the rewarding effects of cocaine (Sora et al , 2001). Similarly, mice with genetic deletion of transporters for serotonin or norepinephrine show altered responses to taste-selective behavior (Jones et al , 2010). Cocaine also has been shown to alter many aspects of appetite and ingestion (Cui and Lutter, 2013, Vicentic and Jones, 2007).…”