Pii: S0306-4522(00)00036-1

The substantia nigra pars reticulata belongs to the brain regions with the highest density of CB1 cannabinoid receptors. Since the level of CB1 receptor messenger RNA is very low in the pars reticulata, most of the receptors are probably localized on terminals of afferent axons. The hypothesis was tested that terminals of glutamatergic afferents of substantia nigra pars reticulata neurons possess CB1 cannnabinoid receptors, the activation of which presynaptically modulates neurotransmission. Rat midbrain slices were superfused and the electrophysiological properties of substantia nigra pars reticulata neurons were studied with the patch-clamp technique. Focal electrical stimulation in the presence of bicuculline evoked excitatory postsynaptic currents mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors. The excitatory postsynaptic currents were reduced by the metabotropic glutamate receptor agonist (^)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 10-4 M). The mixed CB1/CB2 cannabinoid receptor agonists R( 1 )-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone (WIN55212-2; 1028–1025 M) and (2)-cis-3-[2-hydroxy-4-(1,1dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; 1026 M) also produced inhibition. The maximal inhibition by WIN55212-2 was 54^ 6%. The CB1 cannabinoid antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4methyl-3-pyrazole-carboxamide (SR141716A; 1026 M) prevented the effect of WIN55212-2, but had no effect when superfused alone. WIN55212-2 (1026 M) increased the amplitude ratio of two excitatory postsynaptic currents evoked with an interstimulus interval of 100 ms. Currents evoked by short ejection of glutamate on to the surface of the slices were not changed by WIN55212-2. The results show that activation of CB1 cannabinoid receptors inhibits glutamatergic synaptic transmission between afferent axons and neurons in the substantia nigra pars reticulata. The lack of effect of the cannabinoids on glutamate-evoked currents and the increase of the paired-pulse ratio indicate that the mechanism of action is presynaptic inhibition of transmitter release. q 2000 IBRO. Published by Elsevier Science Ltd.