Cannabinoid CB1 receptor mediates METH-induced electrophysiological and morphological alterations in cerebellum Purkinje cells

Abstract

Our previous studies on cannabinoid type1 receptor (CB1R) activation on Methamphetamine (METH)-induced neurodegeneration and locomotion impairments in male rats suggest an interaction between CB1Rs and METH. However, the role of these receptors in METH-neurotoxicity has not been fully identified. Therefore, the purpose of the present study is to investigate the involvement of CB1Rs in these effects. We conducted an electrophysiological study to evaluate functional interactions between METH and CB1Rs using whole-cell patch current clamp recording. Furthermore, we designed the Nissl staining protocol to assess the effect of METH on the basic cerebellar Purkinje cell structure. Our findings revealed that METH significantly increased the action potential half-width, spontaneous interspike intervals, first spike latency, and decreased the rebound action potential and spontaneous firing frequency. Using CB1R agonist and antagonist, our results showed a significant interaction with some of the electrophysiological alterations induced by METH. Further, Nissl staining revealed that the exposure to the combination of METH and SR141716A resulted in the necrotic cell death. Results of the current study raises the possibility that METH consumption profoundly affect the intrinsic membrane properties of cerebellar Purkinje neurons and cannabinoid system manipulations may counteract some of these effects. In summary, our findings provide further insights into the modulatory role of the endocannabinoid system in METH-induced neurologic changes, which can be used in the development of potential therapeutic interventions for METH dependence.

Inflammasome Inhibition Prevents Motor Deficit and Cerebellar Degeneration Induced by Chronic Methamphetamine Administration

“…It has been established that the PC is a unique kind of neuron that represents the only efferent neuron in the cerebellar cortex, essential for cerebellar function (Schonewille et al, 2021). It is well documented that the PC number is reduced in response to METH (Ramshini et al, 2021). Consistent with this study, we found a decline in PC number in mice cerebellum after METH intoxication, which could be alleviated by 10 and 20 mg/kg of MCC950.…”

“…It has been established that the nigrostriatal dopaminergic system is vulnerable to METH exposure since METH can be transferred into the cytoplasm by dopamine transporters (Huang et al, 2020). A recent study indicated that METH might lead to electrophysiological and morphological alternations of cerebellar PC (Ramshini et al, 2021). In the present study, we demonstrated that chronic METH could influence behavioral performance and cerebellar neurodegeneration involving a decrease in the number of PC, α-syn and p-Tau accumulation, axon degeneration, myelin sheath destruction and glial activation.…”

“…Methamphetamine may cause cerebellar degeneration, characterized by motor coordination deficits and a decrease in the number of PCs (Boroujeni et al, 2020;Ramshini et al, 2021). However, the precise mechanism by which METH causes cerebellar pathology is unknown.…”

The Involvement of the NLRP3 Inflammasome and Pyroptosis in Methamphetamine-Induced Neurotoxicity: Effects on Hippocampal Structure and Memory

“…Previous studies have also reported mitochondrial dysfunction and increased neuronal death in the hippocampus after high doses of methamphetamine (41), however, lower doses have been found to be neuroprotective (42). Another study showed that methamphetamine treatment decreased the number of Purkinje cells in the cerebellum (43).…”

Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice

“…Etomidate-induced sedation was increased and prolonged by activation of the CB1 receptor in vivo in mice [19]. Importantly, numerous evidences show that cerebellar Purkinje cell expresses abundant CB1 receptors, suggesting that etomidate may modulate Purkinje cell activity via activation of CB1 receptors [20][21][22][23]. Our previous results show that etomidate facilitates CB1 receptors in the absence of GABA A receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via protein kinase A (PKA) signaling pathway in mouse cerebellar granular layer [24].…”