Administration of SCH 23390 into the Medial Prefrontal Cortex Blocks the Expression of MDMA-Induced Behavioral Sensitization in Rats: An Effect Mediated by 5-HT2C Receptor Stimulation and not by D1 Receptor Blockade

Abstract

Akin to what has been reported for cocaine, systemic administration of the dopamine D1 receptor antagonist, SCH 23390 ((R)-( þ )-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), blocks the expression but not the induction of 3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization. Since the medial prefrontal cortex (mPFC) appears to regulate the expression of sensitization to cocaine, this study examined whether microinjection of SCH 23390 into the mPFC would alter the expression of MDMA sensitization. Saline or MDMA was administered for 5 consecutive days. After 12 days of withdrawal, rats received a bilateral intra-mPFC microinjection of SCH 23390 or saline followed by an intraperitoneal (i.p.) challenge dose of MDMA. While SCH 23390 enhanced locomotion in MDMA-naïve rats, it completely suppressed the expression of sensitization in MDMApretreated animals. Since, SCH 23390 has a fairly good affinity for 5-HT 2C receptors, we went further to study the role of mPFC D1 and 5-HT 2C receptors in this, apparently, paradoxical effect shown by SCH 23390. Thus, the microinjection of both SKF 81297 (R-( þ )-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) and MK 212 (6-chloro-2-(1-piperazinyl)pyrazine hydrochloride), a D1 and 5-HT 2C receptor agonist, respectively, blocked MDMA sensitization. By contrast, the 5-HT 2C receptor antagonist, RS 102221 (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro [4,5]decane-2,4-dione hydrochloride), had no effect in MDMA-naïve or MDMA-sensitized animals, but reversed the effects of SCH 23390 in MDMApretreated rats. These results demonstrate that suppression of MDMA-induced sensitization by SCH 23390 is mediated by 5-HT 2C receptor stimulation in the mPFC and not by the blockade of mPFC D1 receptors. Furthermore, these data indicate that stimulation of 5-HT 2C receptors by SCH 23390 is not a minor issue and should be considered when interpreting future data.

Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: Implications for understanding the neurobiology of addiction

“…Thus, alterations in accumbal DA and/or glutamate levels consequent to stimulation of mPFC 5-HT 2C R may be one mechanism by which the 5-HT 2C R modulates the neurochemical and behavioral effects of psychostimulants. Intra-mPFC infusion of 5-HT 2C R agonists have been shown to block the hypermotive and discriminative stimulus effects of cocaine (Filip and Cunningham, 2003), and block the expression of sensitization (the progressive enhancement of the hypermotive effects of a drug following repeated drug exposure) to 3,4-methylenedioxymethamphetamine (MDMA; Ramos et al, 2005). Intra-mPFC infusion of a 5-HT 2C R antagonist, on the other hand, enhanced cocaine-induced hyperactivity and increased recognition of the stimulus effects of cocaine (Filip and Cunningham, 2003) in the absence of overt effects of intra-mPFC 5-HT 2C R ligands alone.…”

“…The PFC is densely innervated by serotonin (5-HT) neurons of the midbrain (Van Bockstaele et al, 1993) and actions via the family of 5-HT 2 receptors (5-HT 2 R) provides an important modulatory influence over PFC function (Pompeiano et al, 1994;Clemett et al, 2000;Lopez-Gimenez et al, 2001). Recent reports have outlined an inhibitory role for the PFC 5-HT 2C R in mediating the behavioral effects of psychostimulants such as cocaine (Filip and Cunningham, 2003) and 3,4-methylenedioxymethamphetamine (MDMA; Ramos et al, 2005). While both transcript and protein for the 5-HT 2C R have been localized in PFC (Pompeiano et al, 1994;Clemett et al, 2000;Lopez-Gimenez et al, 2001;Pandey et al, 2006), a better understanding of the mechanisms of action through which the PFC 5-HT 2C R controls stimulant-induced behaviors is required, and a first step in this analysis is to gain a more complete understanding of the localization of the 5-HT 2C R protein in PFC.…”

Cocaine Withdrawal Impairs Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Nucleus Accumbens

“…5 A, B,D). Ramos et al (2005) showed that administration of SCH23390 into the medial prefrontal cortex (mPFC) prevents the expression of 3,4-methylenedioxymethamphetamine-induced behavioral sensitization through the blockade of serotonin 5-HT 2C , but not D 1 -like receptors. To exclude a role for the 5-HT 2C receptor in the development of cocaine-induced impairment of DHPG-LTD, we administered the specific 5-HT 2C receptor antagonist RS102221 (2 mg/kg) before the daily injection of cocaine.…”

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

“…Several groups of investigators have demonstrated that the repeated administration of MDMA also results in long-term neuroadaptations in the mesolimbic DA pathway that are manifested as an enhancement of the locomotor stimulating effect of MDMA, i.e., behavioral sensitization (Kalivas et al, 1997;McCreary et al, 1999;Ramos et al, 2005). Kalivas et al (1997) also have shown that the repeated administration of MDMA results in cross-behavioral sensitization to the locomotor stimulating effect of cocaine.…”