Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry

Abstract

The cannabinoid CB1 (CB1R) and dopaminergic D2 (D2R) receptors modify GABAergic transmission in the globus pallidus. Although dopaminergic denervation produces changes in the expression and supersensitization of these receptors, the consequences of these changes on GABAergic neurotransmission are unknown. The aim of this study was to show the effects of CB1R and D2R activation and coactivation on the uptake and release of [(3) H]GABA in the globus pallidus of hemiparkinsonian rats as well as their effects on motor behavior. The activation of CB1R blocked GABA uptake and decreased GABA release in the globus pallidus in the dopamine denervated side, whereas the co-activation of CB1R-D2R increased GABA release and had no effect on GABA uptake. A microinjection of the CB1R agonist ACEA into the globus pallidus ipsilaterally to a 6-OHDA lesion potentiated turning behavior that was induced by methamphetamine. However, a microinjection of the D2R agonist quinpirole did not modify this behavior, and a microinjection of a mixture of CB1R and D2R agonists significantly potentiated turning behavior. The behavioral effects produced after the activation of the CB1R and the co-activation of CB1R and D2R can be explained by increased GABAergic neurotransmission produced by a block of GABA uptake and an increase in the release of GABA in the globus pallidus, respectively.

The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra

“…Behavioral and pharmacological evidence exists for cooperation and cross-regulation of both Drd1 and Drd2 MSN function by CB 1 -R and some of these observations can be attributed to a presynaptic locus. Increased Drd2 expression occurs in CB 1 -R knockout mice [ 76 ], and CB 1 -R can also compensate for reduced Drd2 [ 77 , 78 ], and regulate Drd2 MSN release of GABA in the GP [ 79 , 80 ]. The existence of CB 1 -R and Drd2 heterodimers has also been postulated based on some of these observations [ 81 ].…”

Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection

“…Autoradiography investigations have convincingly reported that the basal ganglia encompass the highest levels of both mRNA expression and binding sites for the CB1 receptor [ 57 , 58 ]. Including striatum [ 59 ], other three regions that receive striatal efferent outputs, such as the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata (SNpr), contain high levels of CB1 receptor binding sites [ 20 , 60 , 61 ]. However, CB1 receptor mRNA transcripts are also present in the caudate-putamen, which is deficient of striatal outflow nuclei [ 62 ].…”

“…In fact, D1 and D2 dopamine receptors are co-localised with striatal CB1 receptors on GABAergic neurons of striatonigral and striatopallidal pathways [ 58 , 160 , 161 , 163 , 166 ]. A tentative interaction between CB1 and D1/D2 receptors at the level of the G-protein/adenylyl cyclase signaling mechanism has been reported [ 23 , 60 , 168 ]. United activation of D1 and CB1 receptors causes a decrease in adenylyl cyclase and a net decrease in the inhibitory activity of direct striatal projection neurons ultimately leading to an inhibited motor response due to increased neuron activity in the SNpr.…”

“…United activation of D1 and CB1 receptors causes a decrease in adenylyl cyclase and a net decrease in the inhibitory activity of direct striatal projection neurons ultimately leading to an inhibited motor response due to increased neuron activity in the SNpr. In contrast, co-stimulation of D2 and CB1 receptors increases adenylyl cyclase [ 59 , 60 , 169 ] which increases activity in the indirect striatal pathway that activates STN neurons leading to decreased motor activity [ 160 , 161 ]. This phenomenon of co-existence of macromolecular complexes composed of functional receptor units with biochemical properties that are different from those of its individual components is called receptor heteromers.…”

An integrative overview of the cannabinergic system and mental health

“…Moreover, it modulates the activity of the N and P/Q type calcium canals (inhibiting the entry of Ca++) and of the Kir and A type potassium canals (facilitating the currents flowing out of K+), resulting in a global state of inhibition of the cell (Kendall & Yudowski, 2017) (Figure 2). Likewise, Floran's group has suggested that CB1 can form a heterodimer with the D2 dopaminergic receptor, allowing the increase of AMPc, and consequently exciting the neuron (Muñoz-Arenas et al, 2015).…”