The medial prefrontal cortex plays an important role in the excitation of A10 dopaminergic neurons following intravenous muscimol administration

Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evide nce suggests that this increase in activity is produced by disinhibition fo llowing the inhibition of GABAergic ("non-dopaminergic'') cells in the vent ral tegmental area. We hypothesized that the activation of A10 cells by mus cimol is likely to be at least partly caused by the action of excitatory af ferents. To verify this, A10 cells were isolated from ipsilateral afferent sources which utilise excitatory amino acids (which play an important role in the activity of these neurons), using hemisections at the level of the s ubthalamic nucleus (or just anterior to the subthalamic nucleus), electroly tic lesions of the pedunculopontine tegmental nucleus, or a combination of both. Following hemisections, and hemisections combined with lesions of the pedunculopontine tegmental nucleus, muscimol inhibited rather than excited A10 dopaminergic neurons. The pedunculopontine tegmental nucleus itself ap peared to make little intrinsic contribution to muscimol-induced excitation , although the results suggested that part of the excitation which originat es in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was inv estigated using electrolytic lesions of documented sources of excitatory am ino acidergic afferents to the ventral tegmental area: the medial prefronta l cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again pr oduced inhibition, an effect qualitatively and quantitatively similar to th at in the hemisected groups. Habenular lesions blocked muscimol-induced exc itation without producing inhibition, whilst amygdalar lesions produced no significant: change in the effects of muscimol. The results suggest that under normal circumstances, an active excitation c ounteracts and exceeds the direct inhibitory effects of muscimol on the act ivity of A10 dopaminergic neurons. Furthermore, this activation appears to be produced by the action of excitatory (probably excitatory amino acidergi c) afferents arising from the medial prefrontal cortex, and possibly the la teral habenular nucleus. Insofar as the excitation of A10 dopaminergic neur ons, which is produced by certain drugs of abuse, and which may play a cruc ial role in their sustained use, has its basis in excitation following disi nhibition, this excitation may provide a novel target for therapeutic inter vention in addiction. (C) 1999 IBRO. Published by Elsevier Science Ltd.