Original ArticlesInteraction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo
Introduction
Antipsychotic drugs (APDs) are the most effective treatments available for schizophrenia. Unfortunately, these drugs can also cause extrapyramidal side effects [1], probably via their action on dopamine (DA) neurons [4] and at DA receptors [6] in the basal ganglia. One of these side effects is an acute dystonic reaction (ADR), which involves abnormal and tonic contractions of neck and facial muscles, often with torticollis and oculogyric crises [23]. Acute dystonic reactions occur only in the first 4 days of APD treatment, often in young males treated with high doses of high-potency neuroleptics such as haloperidol (HAL), fluphenazine or trifluoperazine. The treatment of ADRs is often achieved with antimuscarinic compounds such as benztropine (BENZ) 22, 23, 27, which also inhibits the DA transporter 8, 11, 15, 16. However, to date, the effects of this class of drugs on DA cell activity have not been investigated.
It has been known for some time that APDs affect the electrophysiological activity of DA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) [5]. When administered acutely, APDs increase DA cell firing rate and bursting activity by blocking somatodendritic DA autoreceptors [21]. In addition, DA neuron activity is affected by muscarinic drugs 17, 18 as well as dopamine transporter (DAT) inhibitors 2, 12, 13, 24. Given the effects of APDs, DAT inhibitors, and muscarinic drugs on midbrain DA neuron activity, and the efficacy of BENZ in the treatment of APD-induced ADRs, we investigated the interaction between BENZ and HAL on DA neuron activity in anesthetized rats. A portion of these data has been presented previously [25].
Section snippets
Materials and methods
All experiments were performed in strict accordance with the guidelines established in The Guide for the Care and Use of Animals in Research (USPHS) and were approved by the University of Pittsburgh Animal Care and Use Committee. Male Sprague-Dawley rats (Zivic-Miller, Allison Park, PA, USA) weighing 275–400 g were anesthetized with chloral hydrate (400 mg/kg, i.p.) and placed in a stereotaxic device (Narishige). The lateral tail vein was catheterized for administration of drugs or supplemental
Results
In control rats, BENZ caused a significant decrease in DA cell firing rate (n = 13, F(5,60) = 6.51, p < 0.01; Fig. 1A, Fig. 2, dotted line); however, the effects of BENZ on burst firing were baseline dependent. Cells that fired <15% of their spikes in bursts during the baseline period (“nonbursty controls”; n = 7) increased their burst firing in response to BENZ, whereas cells that fired >15% of their spikes in bursts during the baseline period (“bursty controls”; n = 6) decreased their burst
Discussion
Although the effects of DAT inhibitors 2, 12, 13, 24 and the antimuscarinic trihexiphenidyl [7] on DA cell activity in vivo have been reported previously, to our knowledge this is the first report of the actions of BENZ on DA cell activity in vivo. In this regard, it is interesting to note the differences between our results and previous results obtained with DAT inhibitors and muscarinic drugs in vivo. Dopamine transporter inhibitors have been shown to decrease SN and VTA DA cell firing rate 2
Acknowledgements
This study was supported by USPHS MH 01055, MH 29670 and MH 42217 (A.A.G.) and Undergraduate Research Fellowships from Howard Hughes Medical Institute and NIMH (C.L.T.). The authors thank Mark Antkowiak for technical assistance.
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