Dual Effect of CB1R Antagonist on Motor and Psychological Behaviors in 6OHDA-Induced Parkinsonism Model: Probable Role of Ih Currents

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Based on data from our lab and others, the endocannabinoid system (ECB S ) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of the cannabinoid receptor type 1 (CB1R) WIN 55,212-2 (WIN) and selective antagonist (AM251), on motor and non-motor symptoms (NMS) of PD in a mice model generated by an intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link of CB1R with hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological blockage of CB1R ameliorated explorative behaviors, balance, muscle strength, and passive avoidance memory deficits induced by 6-OHDA, however, anxious, and depressive-like behaviors were heightened. 6-OHDA exposure induced severe alterations in the spontaneous and evoked firing behavior of DA neurons as evidenced by a significant increase in the mean number of spikes and a decrease in half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih currents was seen. WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency, as well as increasing sEPSP amplitudes. The effects of 6-OHDA on sag voltage, Ih currents amplitude, and firing frequency were reversed by administration of AM251. These results suggest that ECBs might underlie some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD and antagonist of this receptor could be effective in modulating the devastating effects of 6-OHDA.

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