Retrograde signaling changes the venue of postsynaptic inhibition in rat substantia nigra.

Both endocannabinoids through cannabinoid receptor type I (CB1) receptors and dopamine through dopamine receptor type D1 receptors modulate postsynaptic inhibition in substantia nigra by changing GABA release from striatonigral terminals. By recording from visually identified pars compacta and pars reticulata neurons we searched for a possible co-release and interaction of endocannabinoids and dopamine. Depolarization of a neuron in pars reticulata or in pars compacta transiently suppressed evoked synaptic currents which were blocked by GABA(A) receptor antagonists (inhibitory postsynaptic currents [IPSCs]). This depolarization-induced suppression of inhibition (DSI) was abrogated by the cannabinoid CB1 receptor antagonist AM251 (1 microM). A correlation existed between the degree of DSI and the degree of reduction of evoked IPSCs by the CB1 receptor agonist WIN55,212-2 (1 microM). The cholinergic receptor agonist carbachol (0.5-5 microM) enhanced DSI, but suppression of spontaneous IPSCs was barely detectable pointing to the existence of GABA release sites without CB1 receptors. In dopamine, but not in GABAergic neurons DSI was enhanced by the dopamine D1 receptor antagonist SCH23390 (3-10 microM). Both the antagonist for CB1 receptors and the antagonist for dopamine D1 receptors enhanced or reduced, respectively, the amplitudes of evoked IPSCs. This tonic influence persisted if the receptor for the other ligand was blocked. We conclude that endocannabinoids and dopamine can be co-released. Retrograde signaling through endocannabinoids and dopamine changes inhibition independently from each other. Activation of dopamine D1 receptors emphasizes extrinsic inhibition and activation of CB1 receptors promotes intrinsic inhibition.

Gamma-aminobutyric acid(B) autoreceptors in substantia nigra and neostriatum of the weaver mutant mouse.

The weaver mutation causes cell loss in the center of the substantia nigra, pars compacta. We compared the depression of gamma-aminobutyric acid (GABA)(A) synaptic currents by the GABA(B) agonist R-baclofen in pars compacta neurons of weaver mice which were largely spared from cell degeneration and of wild-type mice. In weaver neurons the suppression of GABA(A) synaptic currents by R-baclofen was reduced compared to wild-type neurons. The EC(50) of R-baclofen was 6.3 times higher in weaver than in wild-type mice. In the neostriatum, which is not a target of the mutation, such a difference did not exist. We conclude that in the pars compacta the weaver mutation leads to a reduced presynaptic autoinhibition through GABA(B) receptors which may promote survival of a subset of weaver neurons in the pars compacta.