Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum

doi:10.1016/S0306-4522(97)00597-6

Neuroscience

Volume 85, Issue 2, 8 April 1998, Pages 395-403

https://doi.org/10.1016/S0306-4522(97)00597-6 Get rights and content

Abstract

Electrophysiological consequences of activation of cannabinoid receptors have been mostly investigated on neuronal cell lines and on cells transfected with cannabinoid receptors. The aim of the present experiments was to study cannabinoid effects on identified neurons in situ. Electrically-evoked postsynaptic currents and voltage-dependent calcium currents were investigated in the principal neurons of the corpus striatum, the medium spiny neurons, with the patch-clamp method for brain slices. These neurons were chosen because they produce messenger RNA for cannabinoid receptors and because the density of cannabinoid binding sites in the striatum is high. Activation of muscarinic receptors by carbachol (10⁻⁵ M) reduced inhibitory postsynaptic current amplitude by 67%. The synthetic cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphtalenyl)methanone (WIN55212-2; 10⁻⁸ to 10⁻⁵ M) dose-dependently reduced striatal inhibitory postsynaptic currents; the maximum effect, inhibition by 52%, was observed at 10⁻⁶ M. Another cannabinoid agonist, (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; 10⁻⁶ M), also reduced inhibitory postsynaptic currents, by 50%. The CB1 cannnabinoid receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide (SR141716A; 10⁻⁶ M) had no effect when given alone but abolished the effect of WIN55212-2 (10⁻⁶ M). WIN55212-2 (10⁻⁶ M) did not change the current evoked by the GABA_A-receptor agonist muscimol (10⁻⁶ M). Activation of muscarinic receptors by carbachol (10⁻⁵ M) inhibited voltage-dependent calcium currents by 21%, but the cannabinoid receptor agonist WIN55212-2 (10⁻⁶ M) was without effect.

The results show that activation of CB1 cannabinoid receptors reduces GABAergic inhibitory postsynaptic currents in medium spiny neurons of the corpus striatum: the likely mechanism is presynaptic inhibition of GABA release from terminals of recurrent axons of the medium spiny neurons themselves.

Section snippets

Experimental procedures

Patch-clamp recording from neurons in brain slices was performed as described by Edwards and Konnerth and Stuart et al.6, 47

Results

Patch-clamp recordings were made from the principal neurons, the medium spiny neurons, of the corpus striatum. The perikarya of these neurons were spindle-formed and measured 12–16 μm along the longer axis. Cell capacitance, input resistance, series resistance and membrane time constant were calculated (see [38]) using standard extracellular solution and the CsCl-based intracellular solution used for IPSC recording: they were 52±4 pF, 1 263±206 MΩ, 21±1 MΩ and 1.1±0.1 ms, respectively (n=15).

Discussion

The major finding of this study is that cannabinoids inhibited IPSCs in the corpus striatum. We interpret this observation as a CB1 cannabinoid receptor-mediated presynaptic inhibition of GABA release from terminals of recurrent axon collaterals of medium spiny neurons. Contrary to our expectation, activation of cannabinoid receptors had no effect on somadendritic voltage-dependent calcium channels in medium spiny neurons.

IPSCs were nearly abolished by tetrodotoxin and bicuculline, and the

Conclusion

Catalepsy is a typical cannabinoid effect in animals and is thought to be due to an interference of cannabinoids with extrapyramidal motor systems.1, 16The observed presynaptic inhibition of GABA release in the striatum and in striatal projection regions should be incorporated in any model aimed to explain extrapyramidal effects of cannabinoids.

Acknowledgements

This work was supported by a grant form the Deutsche Forschungsgemeinschaft (Sz-72/2-1).

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Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum

Abstract

Section snippets

Experimental procedures

Results

Discussion

Conclusion

Acknowledgements

Trends pharmac. Sci.

Biochem. Pharmac.

Neuroscience

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Trends Neurosci.

Neuroscience

Devl Brain Res.

Eur. J. Pharmac.

Eur. J. Pharmac.

Neuron

Brain Res.

Pharmac. Ther.

Life Sci.

Brain Res.

Neuroscience

Cellular and molecular characterization of Ca2+ currents in acutely isolated, adult rat neostriatal neurons

J. Neurosci.

Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a Pertussis toxin-sensitive mechanism

Br. J. Pharmac.

Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process

J. Pharmac. exp. Ther.

Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons

J. Neurophysiol.

Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors

Molec. Pharmac.

Electrically evoked acetylcholine release from hippocampal slices is inhibited by the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the cannabinoid antagonist, SR 141716A

J. Pharmac. exp. Ther.

Cellular and molecular characterization of Ca²⁺ currents in acutely isolated, adult rat neostriatal neurons