Response of the Ventral Pallidal/Mediodorsal Thalamic System to Antipsychotic Drug Administration: Involvement of the Prefrontal Cortex Antonieta Lavin, Ph.D., and Anthony A. Grace, Ph.D. Intracellular recordings were obtained from rat ventral pallidal received ibotenic acid lesions of the prefrontal cortex (PFCtx) (VP) and mediodorsal thalamic (MD) cells in vivo and the 4–8 weeks prior to recording, cells in the VP exhibited similar effects of antipsychotic drugs on their basal and evoked changes in firing frequency in response to haloperidol electrophysiological characteristics were assessed. administration as those in the intact rats. However, in contrast Administration of either haloperidol or clozapine caused a to the intact rats, MD cells recorded from rats with PFCtx significant decrease in the average firing rate, accompanied by lesions exhibited a significant increase in firing rate after a hyperpolarization of the membrane potential in the VP cells haloperidol administration. The results from this study suggest recorded. However, neither drug induced a substantial change that the prefrontal cortex plays a role in modulating the in the other basic membrane properties of the MD cells or VP response of the thalamus to antipsychotic drugs. cells tested. In addition, in 50% of the MD cells tested, both [Neuropsychopharmacology 18:352–363, 1998] antipsychotic drugs caused a change in spike discharge from an © 1998 American College of Neuropsychopharmacology. oscillatory pattern to a tonic discharge mode. In rats that had Published by Elsevier Science Inc. KEY WORDS: Mediodorsal thalamic nucleus; Ventral Haber et al. 1985; Lavin and Grace 1994; Young et al. Pallidum; Haloperidol; Clozapine; Schizophrenia; 1984; Zahm and Heimer 1987) and the reticular thalamic Prefrontal cortical lesions nucleus (RTN) (Cornwall et al. 1990; Jones 1985; Lavin The ventral pallidum (VP) is a ventral extension of the and Grace 1994), thus forming a loop that encompasses globus pallidus, and together with its projection to the the prefrontal cortex–nucleus accumbens–VP–thalamus– mediodorsal thalamic nucleus (MD) are integral parts cortex. The MD thalamic nucleus has attracted a great of the limbic system within the basal ganglia. The VP is deal of interest due to its proposed role in the integration the major synaptic target of nucleus accumbens neu- of information flow between the limbic system and cen- rons, and in return influences higher cortical structures ters of higher cognitive function. The MD nucleus has via its projections to the MD (Cornwall and Phillipson also been an area of interest due to its potential involve- 1988; Gröenewegen 1988; Gröenewegen et al. 1993; ment in schizophrenia, both in its role as a major corti- cal relay of the limbic system and because of its inter- connections with the prefrontal cortex (Divac et al. 1978; From the Departments of Neuroscience and Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania. Goldman-Rakic et al. 1984; Goldman-Rakic and Porrino Address correspondence to: Dr. Antonieta Lavin, Department of 1985; Markowitsch 1982; O’Donnell et al. 1997). Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pitts- Models of cortical function suggest that the thalamo- burgh, PA 15260. Received March 25, 1997; revised July 20, 1997; accepted August cortical system, in conjunction with the RTN, serves as a 7, 1997. gate for cortical input or cortico-cortical integration. Re- NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 5 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(97)00165-6 NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 5 VP/MD System and Antipsychotic Drugs 353 sults of anatomical (Cornwall et al. 1990; Jones 1985; tory Animals published by the USPHS, and the specific O’Donnell et al. 1997) and electrophysiological (Lavin protocols used were approved by the University of and Grace 1994) studies suggest that the limbic system Pittsburgh Institutional Animal Care and Use Commit- output to the thalamus is positioned to exert a strong in- tee. Most of the methods used have been described pre- fluence on prefrontal cortical activity via its projection to viously (Lavin and Grace 1994). the MD and the RTN. Therefore, information arising from cortical and limbic sites is integrated within the In Vivo Intracellular Recording and ventral striatum under the modulatory influence of Drug Administration dopamine, which then exerts regulatory control over MD and RTN activity via the ventral striatal projection Sprague-Dawley albino male rats were anesthetized with to the VP and the medial segment of the globus pallidus chloral hydrate (400 mg/kg IP) and fixed in a stereotaxic (Gröenewegen 1988; Young et al. 1984). Like the MD, the apparatus (Narishige model SN-2). In experiments using VP itself is thought to play a significant role in the cogni- animals with cortical lesions, the recordings were per- tive and motor skills necessary to perform reward-medi- formed 4–6 weeks after the lesion. Supplemental doses of ated behaviors (Grace 1995; Mogenson and Yang 1991; chloral hydrate and test drugs were administered IV via Richardson and DeLong 1991; Wilson and Rolls 1990) a lateral tail vein cannula. The scalp was exposed and and represents the main output of the limbic system. holes drilled in the skull overlying the VP (coordinates: Because of this potential relationship between corti- AP 5 20.4mm; L 5 21.9 mm; V 5 7.5–8.5 mm), the MD cal-subcortical interactions and schizophrenia, many thalamic nucleus (coordinates: AP 5 23.4 mm; L 5 20.5 studies have examined the mode of action of antipsy- mm; V 5 5.2–5.6 mm), and the prefrontal cortex (coordi- chotic drugs by testing their effects on basal ganglia nates: AP 5 2.7 mm; L 5 21.6 mm; V 5 2.5 mm, accord- neurons. However, comparatively less effort has been ing to Paxinos and Watson 1986). Body temperature was expended to examine how classical and atypical anti- maintained at 37 6 0.58C by a thermostatically controlled psychotic drug treatment affects the output sites of the heating pad. Intracellular recordings were performed us- limbic system and their subsequent impact on thalamo- ing electrodes pulled from 1.0 mm O.D. Omegadot glass cortical activity. For example, Deutch et al. (1995) found tubing (WPI) using a Flaming-Brown P-80/PC electrode that clozapine administration increases the number of puller and filled with either: (1) 3 M K 1 acetate (resis- cells expressing Fos-like immunoreactivity and the tance 5 60–120 MV), or (2) 10% Lucifer yellow in 0.1 M amount of Fos protein in the paraventricular thalamic LiCl (resistance 5 100–250 MV). nucleus, but D2-like or D1-like antagonists did not in- All electrophysiological recordings were digitized us- duce Fos in this nucleus. Furthermore, extracellular re- ing a NeuroData Neurocorder and stored on VHS video- cordings of VP neuron activity revealed that systemic cassettes for subsequent off-line analysis with a custom- administration of haloperidol produced a suppression in designed data analysis program (Neuroscope). Input their firing rate (Napier et al. 1991a). In this article, we resistance, time constant, firing pattern, and evoked re- examined the spontaneous and evoked activity of neu- sponses from VP or MD stimulation were examined for rons that comprise the output sites of the limbic system each cell recorded. Electrical stimulation of the VP or MD (i.e., the VP and the MD thalamic nucleus) in response nuclei was performed using bipolar concentric electrodes to acute administration of two drugs with distinct phar- (Kopf, model SNE-10). Single pulses (0.3 ms duration, 0.1 macological profiles that are known to have potent to 1.5 mA) were delivered at approximately 1 Hz. Spon- therapeutic actions in schizophrenia: the classical anti- taneous and evoked responses were sampled from single psychotic drug haloperidol and the atypical antipsy- cells before and after drug administration. The input re- chotic drug clozapine (Chouinard and Annable 1976; sistance was determined by injecting a series of hyperpo- Gerlach et al. 1974, 1975; Racagni et al. 1980). The im- larizing current pulses of increasing amplitude into the pact of lesions of the prefrontal cortex on these re- neuron and measuring the resultant changes in mem- sponses was also examined as a way of evaluating brane potential. The drugs used were: haloperidol (0.5 whether the hypofrontality that is reported to be mg/kg) (McNeil Pharmaceutical), or clozapine (20 mg/ present in schizophrenics (Ingvar and Franzen 1974; kg, dissolved in 1N HCl, pH 5 4.5) (RBI). The final vol- Pettegrew et al. 1989, 1991; Williamson et al. 1991; ume was adjusted using isotonic saline. Only haloperidol Weinberger et al. 1986) may alter the effects of antipsy- was tested in the animals with prefrontal cortical lesions. chotic drugs when compared to the intact system. In the cases in which the effects of drugs were examined, only one cell per animal was recorded. METHODS Prefrontal Cortical Lesions All animals were handled in accordance with the proce- Lesions of neurons intrinsic to the PFCtx were produced dures outlined in the Guide for the Care and Use of Labora- in Sprague-Dawley (Zivic-Miller) albino male rats weigh- 354 A. Lavin and A.A. Grace NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 5 ing 200–250 g. The rats were anesthetized with Equithesin rior cingulate cortex and prelimbic cortex, as illustrated (0.3 ml/0.1 kg) followed by local bilateral injection of the in Figure 1. excitotoxin ibotenic acid (5 mg/0.5 ml/side) into the pre- frontal cortex (coordinates: AP 13.2; L 60.7; V 3.2 mm, Histology according to Paxinos and Watson 1986) using a glass micropipette (75–100 mm tip diameter). After the mi- In a subset of experiments, the location of the cells was cropipette had remained in position for at least 5 min, verified by staining the cells after recording via intracel- ibotenic acid was introduced by pressure ejection over a lular injection of the fluorescent dye Lucifer yellow 2.5-min period.