Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT 2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies Patricia A. Broderick a,b,c,d, * , Opeyemi A. Olabisi a,c,1 , David N. Rahni a,e , Yueping Zhou a,2 a Department of Physiology and Pharmacology, CUNY Medical School, New York, NY 10031, USA b Doctoral Programs, Departments of Biology and Psychology, The City University of New York Graduate School, New York, NY, USA c MARC and MBRS Programs, City College of New York, New York, NY, USA d Department of Neurology, NYU School of Medicine, NYU Comprehensive Epilepsy Center, New York, NY, USA e Department of Chemistry and Physical Sciences, Pace University, Pleasantville, NY, USA Accepted 30 January 2004 Abstract It is well known that cocaine’s psychomotor stimulant properties derive from enhanced monoamines via synaptic transporter/reuptake inhibition and release mechanisms. However, to further understand mechanisms of action for cocaine, which may be receptor-related, ketanserin, a selective 5-HT 2A/2C antagonist was used to ascertain a possible mediation for 5-HT 2A//2C receptors in the monoamine and behavioral responses to cocaine. The studies were performed in the freely moving and behaving animal with In Vivo Microvoltammetry. Miniature carbon sensors, BRODERICK PROBER microelectrodes detected dopamine (DA) and serotonin (5-HT) concentrations in Nucleus Accumbens (NAcc) of male, Sprague – Dawley laboratory rats in separate signals and within seconds while at the same time, locomotor behavior was monitored with infrared photobeams. Synaptic release of each monoamine was detected because separate studies showed that the depolarization blocker, gamma-butyrolactone (gBL), decreased steady-state values [Pharmacol. Biochem. Behav. 40 (1991) 969]. Acute studies (Day 1) were performed; the animals received single injection of drug(s) in the faradaic behavioral chamber after a stable baseline during habituation behavior was achieved. After completion of the study, the animals were returned to their home cages. Subacute studies (Day 2) were also performed; these took place 24 h later in the faradaic behavioral chamber; same animal control was used and no further drug was administered. Day 2 data were compared to baseline (habituation data) on Day 1. Results showed that (1) Acute administration of Cocaine (10 mg/kg, i.p.) (N = 5) increased DA and 5-HT release above baseline ( p < 0.001) while locomotion was also increased above baseline ( p < 0.001). (2) In Subacute studies in the cocaine group, when no further drug was administered, DA release decreased ( p < 0.001) and decreases in 5-HT release also occurred throughout the time course ( p < 0.05). Locomotor behavior increased above baseline and showed a trend toward statistical significance ( p < 0.07). (3) Acute administration of Ketanserin/Cocaine (3 mg/kg s.c. and 10 mg/kg i.p., respectively) (N = 6) showed that ketanserin antagonized DA and 5-HT release ( p < 0.001), while locomotion was antagonized as well ( p < 0.001). (4) In Subacute studies, in the ketanserin/cocaine group, when no further drug was administered, DA decreased ( p < 0.001), but 5-HT increased ( p < 0.001), while locomotor activity increased above baseline and a trend toward statistical significance was seen ( p < 0.07). Additional saline controls were without effect ( p>0.05). In summary, Acute studies showed that cocaine produced its psychostimulant responses on monoamines and behavior and ketanserin antagonized these responses, likely via a 5-HT 2A/2C receptor mediation. Presynaptic and postsynaptic responses were not distinguished, suggesting, in addition, a role for 5-HT-ergic modulation 0278-5846/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.01.007 Abbreviations: AA, ascorbic acid; BSA, bovine serum albumin; DOPAC, 3,4-dihydroxyphenylacetic acid; DOI, [(F)-2,5-dimethoxy-4-iodoamphetamine hydrochloride]; DA, dopamine; DAT, dopamine transporter; DR, Dorsal Raphe; gBL, gamma-butyrolactone; g irradiation, gamma irradiation; HVA, homovanillic acid; 5-HIAA, 5-hydroxyindoleacetic acid; IACUC, Institutional Animal Care and Use Committee; i.p., intraperitoneal; i.v., intravenous; A 10 , mesolimbic pathway; A 10 , mesocorticolimbic neuronal pathway; A 9 , nigrostriatal neuronal pathway; NE, norepinephrine; NET, norepinephrine transporter; NAcc, Nucleus Accumbens; per os, oral; PET, Positron Emission Tomography; PEA, phosphotidylethanolamine; pA, picoamperes; PFC, Prefrontal Cortex; RR, Raman Resonance; SAD, sinoaortic denervated rat; 5-HT, serotonin; SERT, serotonin transporter; Ag/Ag/Cl, silver/silver chloride; SHR, spontaneously hypertensive rat; Str, striatum; 24-h follow-up studies, Subacute studies; s.c., subcutaneous; SERS, Surface Enhanced Raman Spectroscopy; TH, tyrosine hydroxylase; UA, uric acid; VTA, Ventral Tegmental Area; vlNAcc, ventrolateral Nucleus Accumbens. * Corresponding author. Department of Physiology and Pharmacology, The City University of New York Medical School, Convent Avenue and W. 138th Street, New York, NY 10031, USA. Tel.: +1-212-650-5479; fax: +1-212-650-7754. E-mail address: drpabroderick@cs.com (P.A. Broderick). 1 Presently at The Albert Einstein School of Medicine. 2 Presently at Johns Hopkins School of Medicine. www.elsevier.com/locate/pnpbp Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 547 – 557