THE ROLE OF VENTRAL TEGMENTAL DOPAMINE NEURONS IN LOCOMOTOR SENSITIZATION FOLLOWING QUINPIROLE OR (+)-AMPHETAMINE: EX VIVO VOLTAMMETRIC EVIDENCE R. MUSCAT,*† M. M. IRAVANI‡ and Z. L. KRUK‡ ‡Department of Pharmacology, Medical Sciences, Queen Mary and Westfield College, Mile End Road, London E1 4NS, U.K. †Department of Biomedical Sciences, University of Malta, Msida MSD 06, Malta Abstract––Behavioural sensitization to the locomotor stimulating effects of (+)-amphetamine or quin- pirole was induced in rats by intermittent drug administration. Following expression of sensitization, locomotor activity scores on day 9 were: vehicle 879, (+)-amphetamine 1441227 and quinpirole 2078214. Electrically stimulated dopamine release was measured on day 12 in ventral tegmental slices using fast cyclic voltammetry. Dopamine release was significantly elevated in the (+)-amphetamine- and quinpirole-treated groups when compared to vehicle-treated controls over a wide range of stimulation frequencies (5–200 Hz) and pulses (1–200). Quinpirole (1 μM) in the perfusion fluid attenuated dopamine release following 40-pulse, 200-Hz electrical stimulation, by 31.62.8% in the ventral tegmental area of the vehicle-treated group, by 14.85.6% in the (+)-amphetamine-treated group and 87.3% in the quinpirole-treated group. This study shows that dopamine release is increased in the ventral tegmental area following sensitization with either a direct or indirectly acting dopamine agonist. The findings that dopamine release was elevated at all stimulation frequencies in sensitized animals, and that quinpirole only attenuated this release at the highest stimulation frequency, would suggest that in addition to D 2 autoreceptor subsensitivity, other mechanisms contribute to the enhanced release of dopamine in these animals. Key words: behavioural sensitization, ventral tegmental area, (+)-amphetamine, quinpirole, fast cyclic voltammetry, dopamine release. Intermittent repeated exposure to psychostimulant drugs in man can lead to dependence and addiction. In animals, similar patterns of exposure to the same drugs can lead to the phenomenon of behavioural sensitization, which is manifested when locomotor and other responses are increased on subsequent exposure to the drug. It is well established that increased locomotor activity following acute admin- istration of dopamine agonists arises from the activation of the mesolimbic dopamine system, as these effects may be blocked by neuroleptics or 6-hydroxydopamine lesions. 25,43 However, the mechanisms and sites through which dopamine ac- tivity is apparently enhanced following behavioural sensitization are imprecisely described and under- stood. It is not clear, for example, whether the changes occur in the mesolimbic dopamine system itself or whether the increase in dopamine activity results from an alteration in the activity of one of the many neurotransmitter systems that interact with this pathway. The dopamine input to the ventral striatum is from the ventral tegmental area (VTA), whereas the major output pathways from the ventral striatum project to the ventral pallidum, mediodorsal thala- mus, substantia nigra zona compacta and the VTA itself. 15,11,22 At the level of the VTA, it has been demonstrated that alterations in serotonin, GABA, glutamate, acetylcholine, noradrenaline, opiate, neurotensin and corticosteroid levels may influence the way in which the dopamine system operates. 7,10,17,20,35,40,50 Local changes in activity of the dopamine path- way may contribute to sensitization. It is frequently assumed that there is an increase in dopamine availability in the ventral striatum. It is suggested that the efficacy of the dopamine system may be enhanced by increases in the sensitivity of post- synaptic D 2 and D 1 receptors, or by decreases in the sensitivity of release regulating D 2 autoreceptors, both in the nucleus accumbens (NAc) and VTA. 21 We have shown that intermittent administration of either (+)-amphetamine or quinpirole leads to behav- ioural sensitization, but that these drugs produced different effects on endogenous dopamine release and on dopamine D 2 receptor sensitivity in the NAc. 28 Behavioural sensitization to quinpirole led to increased electrically stimulated dopamine release, †To whom correspondence should be addressed. A bbreviations: ACSF, artificial cerebrospinal fluid; FCV, fast cyclic voltammetry; NAc, nucleus accumbens; VTA, ventral tegmental area. Pergamon N euroscience Vol. 75, No. 4, pp. 1175–1184, 1996 IBRO Copyright  1996 Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306–4522/96 $15.00+ 0.00 PII: S0306-4522(96)00389-2 1175