Diminished responses of nigral dopaminergic neurons to haloperidol and morphine following lesions in the striatum

Abstract

Antipsychotics stimulate the synthesis 2a and metabolism 6 of dopamine (DA) in the striatum and increase the firing rates 4 of nigral DA cell bodies. Morphine affects these parameters in much the same manner 7,s,11,16. The effects of antipsychotics are attributed to the blockade of centr~tl DA receptors, while morphine blocks dopaminergic transmission other than the receptor blockade 15,16. Recent findings, however, indicated that changes in striatal DA turnover produced by DA receptor antagonists were not mediated by the classical postsynaptic receptor but by 'presynaptic' autoreceptors 5 located at the nerve terminals of DA neurons. Increase in DA turnover after administration of antipsychotics was not affected after lesions had been produced in the striato-nigral pathway ~2 and in the striatum 10. The increased firing rates of nigral DA neurons produced with systemic injections of haloperidol or morphine are also seen when these drugs are microinjected into the striatum ~6. Therefore, such alterations in the activity of the cell bodies of DA neurons may be produced via a feedback pathway connected with the striatum. We report herein that when lesions were inflicted by injecting kainic acid into the striatum, administration of haloperidol or morphine no longer stimulated the firing of nigral DA cells. Male, albino rats weighing 150-250 g were anesthetized with halothane and artificially ventilated following immobilization with gallamine triethiodide. The procedures for extracellular recording of single cell unit potentials and of spike rates of spontaneously firing DA neurons in the zona compacta of the substantia nigra (SNC) were as described previously 16. In brief, a glass micropipette filled with 2 M NaC1 and lithium carmine dye (impedance 3-6 Mf~) was inserted into the SNC (coordinates, A 2.0 to 2.4; L 1.4 to 2.0; H --1.8 to --2.8) according to K6nig and Klippers method 2°. The cells in which characteristics matched the following criteria were considered to be DA neurons4, la,16: (1) these neurons fired spontaneously at a low steady state (2-9 Hz); (2) their action potentials were wide (4-5 msec); (3) the audible