Analysis of the effect of cannabinoids on GABAergic neurotransmission in the substantia nigra pars reticulata

Abstract.

The CB₁ cannabinoid receptor is widely distributed in the central nervous system. The substantia nigra pars reticulata (SNR) belongs to the brain regions with the highest density of CB₁ receptors. According to anatomical studies, most of the CB₁ receptors in the SNR are localized on terminals of striatonigral GABAergic neurons. The aim of the present study was to clarify the function of these receptors.

Electrophysiological properties of SNR neurons were studied in brain slices with the patch-clamp technique. Inhibitory postsynaptic currents (IPSCs) were elicited in parasagittal slices by electrical stimulation in the internal capsule. The mixed CB₁/CB₂ cannabinoid receptor agonist WIN55212-2 (1 µM and 10 µM) concentration dependently decreased the amplitude of IPSCs. CP55940, another mixed CB₁/CB₂ cannabinoid receptor agonist, also lowered IPSC amplitude. Superfused alone, the CB₁-selective antagonist SR141716A (1 µM) increased the amplitude of IPSCs. In interaction experiments, SR141716A (1 µM) prevented the inhibition produced by WIN55212-2 (1 µM). WIN55212-2 (1 µM) had no effect on GABAergic currents elicited by ejection of muscimol (1 mM) to the surface of the slices. WIN55212-2 (10 µM) did not influence the frequency and amplitude of spontaneously occurring IPSCs (sIPSCs) and the firing rate of SNR neurons.

The results show that activation of CB₁ cannabinoid receptors inhibits GABAergic neurotransmission in the SNR. The likely mechanism is presynaptic inhibition of GABA release, since cannabinoids had no effects on currents evoked by direct stimulation of GABA_A receptors by muscimol and on the amplitude of sIPSCs. The enhancement of IPSCs by the cannabinoid antagonist probably reflects continuous inhibition of GABAergic neurotransmission by an endogenous cannabinoid. SNR neurons receive GABAergic input from three sources: from the corpus striatum, the globus pallidus and from neighbouring SNR neurons. The observed inhibition of GABAergic neurotransmission was probably due to depression of the transmission between striatonigral axons and SNR neurons. No direct actions of cannabinoids on SNR neurons were observed in addition to this synaptic effect.