Cannabinoids depress excitatory neurotransmission between the subthalamic nucleus and the globus pallidus (original) (raw)
Related papers
Mechanisms of Cannabinoid Inhibition of GABAASynaptic Transmission in the Hippocampus
2000
The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABA A receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212-2 (EC 50 of 138 nM). This effect was blocked by the CB1 receptor antagonist SR141716A (1 M) but not by the opioid antagonist naloxone. In contrast, evoked GABA B -mediated IPSCs were insensitive to the CB agonist. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), mea-sured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VD-CCs) by cadmium also eliminated the effect of WIN 55,212-2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212-2. The presynaptic effect of WIN 55,212-2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212-2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABA A -but not GABA B -mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.
Cannabinoids inhibit striatonigral GABAergic neurotransmission in the mouse
Neuroscience, 2002
The substantia nigra pars reticulata (SNR) belongs to the brain regions with the highest density of CB(1) cannabinoid receptors. Anatomical studies indicate that the great majority of CB(1) receptors in the SNR are localized on terminals of GABAergic axons arriving from the caudate-putamen (striatonigral axons). The aim of the present experiments was to clarify the role of CB(1) receptors on terminals of striatonigral axons. Oblique sagittal slices, including the caudate-putamen and the substantia nigra, were prepared from brains of young mice. Electrical stimulation in the caudate-putamen elicited GABAergic inhibitory postsynaptic currents (IPSCs) in the SNR, which were studied by patch-clamp techniques. The long latency of IPSCs (14+/-1 ms) suggests that striatonigral axons were indeed activated within the caudate-putamen. The synthetic CB(1)/CB(2) cannabinoid receptor agonist WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-nap...
Journal of Neuroscience, 2006
It is widely accepted that cannabinoids regulate GABA release by activation of cannabinoid receptor type 1 (CB1). Results obtained from a variety of brain regions consistently indicate that cannabinoid agonists can also reduce glutamatergic synaptic transmission. However, there are still conflicting data concerning the role of CB1 in cannabinoid-induced inhibition of glutamatergic transmission in cortical areas. Here, we provide direct evidence that activation of CB1 on terminals of principal neurons controls excitatory synaptic responses in the forebrain. In slices of the basolateral amygdala, the CA1 region of the hippocampus, and the primary somatosensory cortex of wild-type mice, application of the CB1 agonist (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; WIN) (5 M) reduced evoked excitatory postsynaptic responses. In contrast, in slices obtained from conditional mouse mutants lacking CB1 in all principal forebrain neurons but not in GABAergic interneurons (CB1 f/f;CaMKII␣Cre ), WIN no longer affected glutamatergic synaptic transmission in any of the brain regions tested. Compatible with a presynaptic mechanism, WIN did not change the sensitivity to focally uncaged L-glutamate. WIN reduced glutamatergic responses in slices obtained from mice lacking CB1 exclusively in GABAergic neurons (CB1 f/f;Dlx5/6-Cre ), thus excluding the involvement of CB1 expressed on GABAergic neurons in this effect of the drug. The present data strongly indicate that excitatory synaptic transmission in forebrain areas is directly modulated by CB1 expressed on presynaptic axon terminals originating from glutamatergic neurons.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2002
The CB 1 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 CB 1 receptors. According to anatomical studies, most of the CB 1 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 CB 1 /CB 2 cannabinoid receptor agonist WIN55212-2 (1 µM and 10 µM) concentration dependently decreased the amplitude of IPSCs. CP55940, another mixed CB 1 /CB 2 cannabinoid receptor agonist, also lowered IPSC amplitude. Superfused alone, the CB 1selective 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 CB 1 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.
Journal of Neurophysiology, 2001
The effect of cannabinoids on excitatory transmission in the substantia gelatinosa was investigated using intracellular recording from visually identified neurons in a transverse slice preparation of the juvenile rat spinal cord. In the presence of strychnine and bicuculline, perfusion of the cannabinoid receptor agonist WIN55,212-2 reduced the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Furthermore, the frequency of miniature EPSCs (mEPSCs) was also decreased by WIN55,212-2, whereas their amplitude was not affected. Similar effects were reproduced using the endogenous cannabinoid ligand anandamide. The effects of both agonists were blocked by the selective CB1 receptor antagonist SR141716A. Electrical stimulation of high-threshold fibers in the dorsal root evoked a monosynaptic EPSC in lamina II neurons. In the presence of WIN55,212-2, the amplitude of the evoked EPSC (eEPSCs) was reduced, and the paired-pulse ratio was increased. The reduc...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2001
Despite the role of excitatory transmission to the nucleus accumbens (NAc) in the actions of most drugs of abuse, the presence and functions of cannabinoid receptors (CB1) on the glutamatergic cortical afferents to the NAc have never been explored. Here, immunohistochemistry has been used to show the localization of CB1 receptors on axonal terminals making contacts with the NAc GABAergic neurons. Electrophysiological techniques in the NAc slice preparation revealed that cannabimimetics [WIN 55,212,2 (WIN-2) and CP55940] strongly inhibit stimulus-evoked glutamate-mediated transmission. The inhibitory actions of WIN-2 were dose-dependent (EC(50) of 293 +/- 13 nm) and reversed by the selective CB1 antagonist SR 141716A. In agreement with a presynaptic localization of CB1 receptors, WIN-2 increased paired-pulse facilitation, decreased miniature EPSC (mEPSC) frequency, and had no effect on the mEPSCs amplitude. Perfusion with the adenylate cyclase activator forskolin enhanced glutamaterg...
European Journal of Pharmacology, 1993
Doses of 3 or 30/zg of A9-tetrahydrocannabinol markedly increased the ability of 25 ng of muscimol to delay the descent of rats from a horizontal bar (descent latency) when these drugs were coadministered bilaterally into the globus pallidus. Intrapallidal injections of 30/~g of the putative endogenous cannabinoid, anandamide, also increased the effect of muscimol on descent latency. These data indicate that the production of catalepsy by cannabinoids may depend at least in part on an ability to enhance GABAergic transmission in the globus pallidus and support the hypothesis that anandamide is indeed an endogenous ligand for the cannabinoid receptor.
Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat
Journal of Neurophysiology, 2014
The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M 1 -type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M 1 receptors. Alternatively, some M 1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M 1 . In addition, we found that some pallidal neurons have functional postsynaptic M 1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB 1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.