Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine

Abstract

These data indicate that 5-HT(2C) receptors within the mPFC and the NAC modulate the reinforcing effects of cocaine and provide evidence that 5-HT(2C) receptor agonists could be a possible drug discovery target for the treatment of psychostimulant addiction.

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Furthermore, neither 5-HT 2A R agonists nor antagonists had any effect on the reward-facilitating effects of cocaine in intracranial stimulation studies (Katsidoni et al, 2011). The lack of effect of M100907 pretreatment on cocaine self-administration has been replicated in rhesus monkeys at doses that suppressed the self-administration of 3,4-methylenedioxymethamphetamine (Fantegrossi et al, 2002).…”

“…Intracranial microinjections of the 5-HT 2C R agonist MK 212 [2-chloro-6-(1-piperazinyl)-pyrazine hydrochloride] into the prelimbic and infralimbic regions of the mPFC attenuated both cocaine-and cue-induced reinstatement (Pentkowski et al, 2010). Moreover, intracranial microinjections of the 5-HT 2C R agonist WAY 161503 [8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride] into the mPFC or NAc increased the threshold for intracranial self-stimulation and attenuated the reward-facilitating effects of cocaine in rats (Katsidoni et al, 2011). Conversely, systemic administration of 5-HT 2C R antagonists exerts effects opposite to those after agonist administration, thus enhancing cocaine-induced hyperlocomotion (Fletcher et al, 2002(Fletcher et al, , 2006, the discriminative stimulus effects of cocaine (Fletcher et al, 2002;Filip et al, 2006), cocaine self-administration (Fletcher et al, 2002), and cocaine-induced reinstatement (Fletcher et al, 2002).…”

“…c Filip et al, 2004, 2006Filip, 2005. d Callahan andCunningham, 1995;Filip and Cunningham, 2003;Filip et al, 2004;Acosta, 2007. e Burbassi andCervo, 2008;Fletcher et al, 2008Fletcher et al, , 2011Grottick et al, 2000;Manvich et al, 2012a. f Navarra et al, 2008Cunningham et al, 2011Cunningham et al, , 2013Anastasio et al, 2014a. g Katsidoni et al, 2011 h SB242084 alone supported self-administration in squirrel monkeys (Manvich et al, 2012b).…”

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

“…In addition, both 5-HT2AR and 5-HT2CR that are expressed throughout the brain have been implicated in the pathophysiology of psychiatric disorders (Abramowski et al, 1995;Hoyer et al, 1986;Heisler et al, 2007;Mestre et al, 2013;Lyddon et al, 2013]. 5-HT2CRs for example, was shown to play a role in addiction and reward behavior via modulating dopamine transmission within the mesolimbocortical dopaminergic system (Katsidoni et al, 2011). Dysregulation of the reward-related neurotransmitter systems and behaviours could also contribute to the increased susceptibility to obesity in the recuperated offspring (Grissom et al, 2014) In summary, we report that elevated 5-HT in fetuses exposed to maternal protein restriction, may underlie a permanent reduction in 5-HT2CR expression and function and secondary counter-regulatory up-regulation of 5-HT2AR and increased sensitivity to 5-HT2AR agonist.…”

Reward processing by the dorsal raphe nucleus: 5-HT and beyond

“…Altering central 5-HT levels negatively affects reward effects elicited by natural rewarding stimuli Sanders et al 2007), addictive drug (Leccese and Lyness 1984;Smith et al 1986;Carroll et al 1990;McGregor et al 1993;Peltier and Schenk 1993), and electrical ICSS (Redgrave 1978;Bauer et al 2013). Reward inhibition by 5-HT appears to be mainly mediated by the 5-HT2C receptor (Higgins and Fletcher 2003;Cunningham et al 2011;Katsidoni et al 2011). In addition, infusion of 5-HT or 5-HT1B receptor agonists into the NAc decreases amphetamine self-administration (Fletcher et al 2002) and amphetamineconditioned reward response (Fletcher 1996;.…”