Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT₂ Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

Abstract

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT 2 receptor subtypes (5-HT 2A R, 5-HT 2B R, and 5-HT 2C R) in acute cocaineevoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT 2A R agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT 2C R antagonist SDZ SER-082 [(ϩ)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT 2A R antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT 2 R ligands were ineffective. When any of the 5-HT 2 R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT 2A R and 5-HT 2C R exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.Cocaine enhances dopamine (DA), serotonin (5-hydroxytryptamine; 5-HT), and norepinephrine neurotransmission through inhibition of their respective reuptake inhibitors (Koe, 1976). Enhancement of DA, particularly within the DA mesoaccumbens ("reward") pathway, is important in the locomotor-stimulant, reinforcing, and discriminative stimulus effects of cocaine (Pettit et al., 1984;Delfs et al., 1990;Callahan et al., 1997). However, the 5-HT system has also been shown to play a vital role in the modulation of DA mesoaccumbens pathways (Schmidt et al., 1992;De Deurwaerdere and Spampinato, 1999;Di Matteo et al., 1999;Gobert et al., 2000) and has been implicated in the mediation of cocaine-evoked behaviors, including cocaine-induced hyperactivity (McCreary and

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

“…Recent work characterized the downstream targets of the MHb-IPN pathway and show that serotonergic raphe nuclei receive dense innervation from vMHbinnervated IPN neurons (Quina et al 2017). The MHb also densely expresses the 5-HT3A, -4, -5A and -5B receptors, suggesting that it receives serotonergic inputs, potentially from the same raphe-serotonergic population receiving innervation from the IPN (Filip et al 2004;Ichikawa et al 2005;Wagner et al 2014). It is possible that these inputs may be directly, but differentially, modulated by cocaine and nicotine.…”

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…Administration of the 5-HT2A antagonist SR 46349B (1.0 mg/kg or less) attenuates hyperactivity induced by either the acute or repeated administration of cocaine (Filip et al, 2004). Treatment with M100907 reversed behavioral deficits in locomotor activity and prepulse inhibition of acoustic startle in DAT knockout mice (Barr et al, 2004).…”

“…Recent studies have shown that systemic administration of the 5-HT2C antagonists SB 242084 and SDZ SER-082 enhances cocaine-induced locomotor activity (Fletcher et al, 2002;Filip et al, 2004;Liu and Cunningham, 2006), the discriminative stimulus effects of cocaine (Filip et al, 2006) and cocaine self-administration (Fletcher et al, 2002). Likewise, systemic administration of 5-HT2C agonists (MK-212, Ro 60-0175 or mCPP) attenuates cocaine-induced locomotor activity (Grottick et al, 2000;Liu and Cunningham, 2006), responding for both food and cocaine (Grottick et al, 2000), and the discriminative stimulus effects of cocaine (Callahan and Cunningham, 1995;Frankel and Cunningham, 2004).…”

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…On the other hand, intra-NAc shell injections of 5-HT 2C R agonists and antagonists have been shown to respectively increase and decrease the hyperlocomotive and discriminative stimulus effects of cocaine (Filip and Cunningham, 2002;McMahon et al, 2001). Thus, in contrast to the overall inhibitory influence of systematically administered 5-HT 2C R compounds on DA-dependent behaviors (Callahan and Cunningham, 1995;Filip et al, 2004;Fletcher et al, 2002;Frankel and Cunningham, 2004;Grottick et al, 2000), these results suggest that NAc 5-HT 2C Rs exert an excitatory control on accumbal DA function (Bowers et al, 2000;Dremencov et al, 2005;Yan, 2000). Furthermore, considering that cocaine-induced behavior is thought to result from increased DA efflux in the NAc (Di Chiara, 2002;Dunnett and Robbins, 1992), these data suggest the existence of a functional opposite control of cocaineinduced accumbal DA outflow by 5-HT 2C Rs in the VTA (inhibition) and NAc (excitation) (Filip and Cunningham, 2002).…”