Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

• Published in: Psychopharmacology Vol. 213; no. 2-3; pp. 321 - 335
• Main Authors: Zayara, Avi E., McIver, Gregor, Valdivia, Paola N., Lominac, Kevin D., McCreary, Andrew C., Szumlinski, Karen K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2011
• Subjects: Aminopyridines - administration & dosage; Aminopyridines - pharmacology; Animals; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Cocaine - administration & dosage; Cocaine - pharmacology; Dopamine - metabolism; Dose-Response Relationship, Drug; Fluorobenzenes - administration & dosage; Fluorobenzenes - pharmacology; Glutamic Acid - metabolism; Indoles - administration & dosage; Indoles - pharmacology; Male; Microdialysis; Neuronal Plasticity - drug effects; Neurosciences; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Pharmacology/Toxicology; Piperidines - administration & dosage; Piperidines - pharmacology; Psychiatry; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A - drug effects; Receptor, Serotonin, 5-HT2A - metabolism; Receptor, Serotonin, 5-HT2C - drug effects; Receptor, Serotonin, 5-HT2C - metabolism; Serotonin 5-HT2 Receptor Antagonists - administration & dosage; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Nucleus accumbens; Psychosis; receptor; Dopamine; Addiction; Cocaine; Sensitization; 5-HT; Glutamate
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-1996-3

Rationale The serotonin 5-HT 2A and 5-HT 2C receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine’s addictive and psychotogenic properties. Objectives In the present study, we tested the hypothesis that NAC 5-HT 2A and 5-HT 2C receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days 1 and 7, 15 mg/kg; days 2–6, 30 mg/kg, i.p.). Methods The effects of intra-NAC infusions of the 5-HT 2A antagonist R -(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500 nM) or the 5-HT 2C antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500 nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100 nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC. Results Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization. Conclusions These data provide the first evidence that NAC 5-HT 2A and 5-HT 2C receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.