Afferent input to midbrain dopamine neurones and its modulation : an electrophysiological study i vitro

Dopamine (DA) neurones of the ventral mesencephalon are involved in the control of reward related behaviour, cognitive functions and motor performances, and provide a critical site of action for major categories of neuropsychiatric drugs, such as antipsychotic agents, dependence producing drugs and anti-Parkinson medication. The midbrain DA neurones are mainly located in the substantia nigra pars compacta (SNPC) and the ventral tegmental area (VTA). Their activity is regulated by the intrinsic properties of the DA neurones as well as by the activity of the afferent inputs. The aim of the present work was to study the function and modulatory role of the glutamatergic and cholinergic afferent inputs in regulating the midbrain DAergic neuronal activity.

The slice preparation of the rat ventral mesencephalon in vitro was used and intracellular or whole-cell patch clamp recordings were performed from the DA neurones. Repetitive stimulation of the afferents in the slice preparation was shown to elicit a slow excitatory postsynaptic event that was blocked by application of the NMDA antagonist AP5. Moreover, the amplitude of the slow postsynaptic event was markedly reduced by L-type Ca2+ channel blockers such as nifedipine. Specific agonists to group I, II and III metabotropic glutamate receptors (mGluRs) were all shown to reduce the amplitude of both glutamatergic and GABAergic synaptic inputs to the DA neurones. A presynaptic site of action was indicated by a paired-pulse protocol. Also, muscarine depressed both glutamatergic and GABAergic synaptic transmission to the DA neurones. These effects were completely blocked by the M3/M1 receptor antagonist 4-DAMP, but not significantly affected by the M, receptor antagonist pirenzepine. Moreover, the postsynaptic responses to glutamate or GABA were not changed by muscarine. The nicotine-induced excitation of DA neurones was reduced in the presence of AP5 or the AMPA/kainate receptor antagonist CNQX. However, neither glutamate- nor GABA-mediated spontaneous synaptic transmission was affected by nicotine application.

The results demonstrate that NMDA-mediated glutamatergic synaptic transmission to midbrain DA neurones involves activation of presynaptic L-type Ca2+ channels. Moreover, mGluRs and muscarinic receptors mediate presynaptic inhibition of both glutamatergic and GABAergic synaptic inputs to the midbrain DA neurones. Finally, the nicotine-induced excitation of the DA neurones in the slice preparation seems essentially to be mediated through postsynaptically located nicotinic receptors.