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

Abstract

Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evidence suggests that this increase in activity is produced by disinhibition following the inhibition of GABAergic (“non-dopaminergic”) cells in the ventral tegmental area. We hypothesized that the activation of A10 cells by muscimol is likely to be at least partly caused by the action of excitatory afferents. 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 subthalamic nucleus (or just anterior to the subthalamic nucleus), electrolytic 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 appeared to make little intrinsic contribution to muscimol-induced excitation, although the results suggested that part of the excitation which originates in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was investigated using electrolytic lesions of documented sources of excitatory amino acidergic afferents to the ventral tegmental area: the medial prefrontal cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again produced inhibition, an effect qualitatively and quantitatively similar to that in the hemisected groups. Habenular lesions blocked muscimol-induced excitation 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 counteracts and exceeds the direct inhibitory effects of muscimol on the activity of A10 dopaminergic neurons. Furthermore, this activation appears to be produced by the action of excitatory (probably excitatory amino acidergic) afferents arising from the medial prefrontal cortex, and possibly the lateral habenular nucleus. Insofar as the excitation of A10 dopaminergic neurons, which is produced by certain drugs of abuse, and which may play a crucial role in their sustained use, has its basis in excitation following disinhibition, this excitation may provide a novel target for therapeutic intervention in addiction.