Introduction receptors regulate DA function in the mPFC. For example,

Brain Research 888 2001 51–59 www.elsevier.com locate bres Research report M100,907, a selective 5-HT antagonist, attenuates dopamine release 2A in the rat medial prefrontal cortex a , a,b a a a E.A. Pehek , H.G. McFarlane , K. Maguschak , B. Price , C.P. Pluto a Department of Psychiatry , Case Western Reserve University School of Medicine, Kenyon College, Gambier, OH 43022, USA b Department of Psychology , Kenyon College, Gambier, OH 43022, USA Accepted 19 September 2000 Abstract Previous research has suggested that serotonin 5-HT receptors modulate the functioning of the mesocortical dopamine DA pathway. 2A However, the specific role of 5-HT receptors localized within the medial prefrontal cortex mPFC is not known. The present study 2A 1 21 employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K -stimulated Ca -dependent DA release. The selective 5-HT antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a 2A 1 concentration-dependent blockade of K -stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT agonist, 1-2,5-dimethoxy-4-iodophenyl-2-aminopropane DOI. These 2A 2C 21 findings demonstrate that local 5-HT antagonism has an inhibitory effect on stimulated, Ca -dependent DA release. They suggest that 2A cortical 5-HT receptors potentiate the phasic release of mesocortical DA.  2001 Elsevier Science B.V. All rights reserved. 2A Theme : Neurotransmitters, modulators, transporters and receptors Topic : Interactions between neurotransmitters Keywords : Antipsychotic; In vivo; Mesocortical DA pathway; Microdialysis; Schizophrenia; Serotonin; DOI

1. Introduction receptors regulate DA function in the mPFC. For example,

administration of the atypical antipsychotic drug clozapine, The mesocortical dopamine DA system has been a potent 5-HT antagonist [20], increases extracellular DA 2 implicated in a wide range of emotional, motivated, and concentrations in vivo when administered either sys- cognitive behaviors. Neurons in this pathway originate in temically or directly into the mPFC [15,21,28]. In addition, the ventral tegmental area of the midbrain and terminate in systemic administration of amperozide, a 5-HT antago- 2A the medial prefrontal cortex mPFC [40]. Several in vivo nist [33,37], and intracortical administration of ritanserin, a studies have demonstrated that cortical DA neurochemistry 5-HT antagonist, were both found to elevate dialysate DA 2 is modulated by serotonin 5-HT receptors [5,10,12]. levels in the mPFC [15,24,29,30]. Thus, each of these Examination of the interactions between DA and 5-HT is potent 5-HT antagonists increased cortical DA efflux 2A thus central to the understanding of psychotropic drug suggesting that 5-HT receptors inhibit DA release from 2A action in the prefrontal cortex. the mesocortical DA system. In vitro and in vivo neurochemical studies in the dorsal Although there are three known subtypes of the 5-HT 2 and ventral striatum indicate that 5-HT receptors regulate receptor, the 2A, the 2B, and the 2C [32], many of the 2 DA function [9,26]. There is also evidence that 5-HT studies that have attempted to examine the role of these 2 receptors in mesocortical DA function have used ligands that are not subtype selective. Those experiments that have used selective ligands have generally employed the sys- Corresponding author. VA Medical Center GMHB, 10000 Breck- temic administration of such agents [7,10]. Since sys- sville Rd., Brecksville, OH 44141, USA. Tel.: 11-440-526-3030 ext. temically administered drugs can have actions at multiple 6610; fax: 11-440-546-2713. E-mail address : eap6po.cwru.edu E.A. Pehek. sites in the brain, the literature remains unclear as to the 0006-8993 01 – see front matter  2001 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 3 0 0 4 - 3 52 E specific role of cortical 5-HT receptors in the modulation before the start of the experiments, microdialysis probes 2A of mesocortical DA function. were lowered carefully through the guide cannulae into In the present study, we examined the role of pre- awake rats and secured in place with Krazy Glue Gel E. frontocortical 5-HT receptors through the use of the Immediately following probe implantation, animals were 2A highly selective antagonist M100,907 R-1-a-2,3- placed in clear Plexiglas test chambers and tethered to dimethoxyphenyl - 1 - [2 - 4 - fluorophenylethyl] - 4 - piper - counterbalance arms that permitted relatively free move- idine-methanol. This ligand has 100 fold selectivity for ment. They remained there with food and water until the the 5-HT Ki50.36 nM over the 5-HT Ki5105 nM start of the experiments. 2A 2C receptor [25] and has negligible affinity for DA receptors A micro-infusion pump PHD 2000 E, Harvard Ap- Ki.540 nM [14]. M100,907 was infused directly into paratus and liquid swivels were used to perfuse the buffer the mPFC through reverse microdialysis. Effects on both through the probes at a constant rate. Although each 1 basal and potassium K -stimulated DA release were experiment is self-contained with its own appropriate examined. Additionally, the effects of intracortical controls, perfusion flow rates differed between some M100,907 on alterations in DA release produced by the experiments. An initial experiment Experiment 2 em- systemic administration of 1-2,5-dimethoxy-4- ployed a flow rate of 1.5 ml min. In order to increase the iodophenyl-2-aminopropane DOI, a 5-HT agonist, recovery of DA, the flow rate was decreased to 1.0 ml min 2 were investigated. We hypothesized that intracortical infu- in all subsequent experiments. Dialysate samples were sion of a selective 5-HT antagonist would increase DA collected every 30 min until basal DA concentrations were 2A release in the mPFC. stable for at least 3 baseline samples. Drugs or artificial cerebrospinal fluid aCSF buffers with altered ionic compositions were then administered by manually switch-

2. Materials and methods ing tubing connections. This was performed rapidly and