TY - JOUR
T1 - Probable role of the hyperpolarization-activated current in the dual effects of CB1R antagonism on behaviors in a Parkinsonism mouse model
AU - Soti, Monavareh
AU - Ranjbar, Hoda
AU - Kohlmeier, Kristi Anne
AU - Razavinasab, Moazamehosadat
AU - Masoumi-Ardakani, Yaser
AU - Shabani, Mohammad
PY - 2022
Y1 - 2022
N2 - Recent evidence from genetic and pharmacological animal models of Parkinson's disease (PD) suggests alteration in activity of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) occurs following dopamine (DA) depletion. Further, based on data from our lab and others, the endocannabinoid system (ECBS) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of an intracerebroventricular (i.c.v.) injection of the cannabinoid receptor type 1 (CB1R) agonist WIN 55,212-2 (WIN) and selective antagonist AM251 (AM) on motor and non-motor symptoms (NMS) of PD in a mouse model generated by an i.c.v. injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link between CB1R and the hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological antagonism 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. The AM was also effective in reducing the 6-OHDA-induced TH level deficit. 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 spike half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih current was seen. Consistent with an effect of increasing Ih, WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency. In addition, greater amplitudes of sEPSPs were elicited. The effects of 6-OHDA on sag voltage, Ih current amplitude, and firing frequency were reversed by administration of AM. These results suggest that ECBs might be involved in some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD. In addition, the CB1R antagonistic mechanism could be effective in modulating the devastating effects of 6-OHDA.
AB - Recent evidence from genetic and pharmacological animal models of Parkinson's disease (PD) suggests alteration in activity of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) occurs following dopamine (DA) depletion. Further, based on data from our lab and others, the endocannabinoid system (ECBS) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of an intracerebroventricular (i.c.v.) injection of the cannabinoid receptor type 1 (CB1R) agonist WIN 55,212-2 (WIN) and selective antagonist AM251 (AM) on motor and non-motor symptoms (NMS) of PD in a mouse model generated by an i.c.v. injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link between CB1R and the hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological antagonism 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. The AM was also effective in reducing the 6-OHDA-induced TH level deficit. 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 spike half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih current was seen. Consistent with an effect of increasing Ih, WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency. In addition, greater amplitudes of sEPSPs were elicited. The effects of 6-OHDA on sag voltage, Ih current amplitude, and firing frequency were reversed by administration of AM. These results suggest that ECBs might be involved in some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD. In addition, the CB1R antagonistic mechanism could be effective in modulating the devastating effects of 6-OHDA.
U2 - 10.1016/j.brainresbull.2022.10.015
DO - 10.1016/j.brainresbull.2022.10.015
M3 - Journal article
C2 - 36283508
VL - 191
SP - 78
EP - 92
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
ER -