Temporal Changes of CB1 Cannabinoid Receptor in the Basal Ganglia as a Possible Structure-Specific Plasticity Process in 6-OHDA Lesioned Rats

Abstract

The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration, neuroprotection and neuronal plasticity. The CB1 cannabinoid receptors are abundantly expressed in the basal ganglia, the circuitry that is mostly affected in Parkinson's Disease (PD). Some studies show variation of CB1 expression in basal ganglia in different animal models of PD, however the results are quite controversial, due to the differences in the procedures employed to induce the parkinsonism and the periods analyzed after the lesion. The present study evaluated the CB1 expression in four basal ganglia structures, namely striatum, external globus pallidus (EGP), internal globus pallidus (IGP) and substantia nigra pars reticulata (SNpr) of rats 1, 5, 10, 20, and 60 days after unilateral intrastriatal 6-hydroxydopamine injections, that causes retrograde dopaminergic degeneration. We also investigated tyrosine hydroxylase (TH), parvalbumin, calbindin and glutamic acid decarboxylase (GAD) expression to verify the status of dopaminergic and GABAergic systems. We observed a structure-specific modulation of CB1 expression at different periods after lesions. In general, there were no changes in the striatum, decreased CB1 in IGP and SNpr and increased CB1 in EGP, but this increase was not sustained over time. No changes in GAD and parvalbumin expression were observed in basal ganglia, whereas TH levels were decreased and the calbindin increased in striatum in short periods after lesion. We believe that the structure-specific variation of CB1 in basal ganglia in the 6-hydroxydopamine PD model could be related to a compensatory process involving the GABAergic transmission, which is impaired due to the lack of dopamine. Our data, therefore, suggest that the changes of CB1 and calbindin expression may represent a plasticity process in this PD model.

Reversal effect of simvastatin on the decrease in cannabinoid receptor 1 density in 6-hydroxydopamine lesioned rat brains

“…4) ultimately lead to glutamatergic excitotoxicity, oxidative stress, and eventual neuronal death in the SN [42]. Based on the observed evidence in this study and previous findings from other groups [7,42], we propose the possible mechanisms involved in CB1 receptors in the basal ganglia related disorders is schematically shown in Fig. 4.…”

“…However different findings were also observed; such as an elevation in CB1 receptor mRNA expression [41], up-regulation in CB1 binding [27], or no change identified [28]. The discrepancy for the contradictions may result from the following reasons: 1) different experimental approaches including the neurotoxin used; 2) different brain regions lesioned and origin of tissue samples; 3) and/or the various period times during the PD model [8]. Among these previous studies, the evidence revealing an elevation in CB1 receptor expression is supportive of a view that a general overactivity of CB1 receptors and their endocannabinoids are an event that develops when the degeneration of nigral dopaminergic neurons has progressed to a certain degree and that major parkinsonian symptoms are already evident [13].…”

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

“…D2Rs are G i/o protein coupled receptors that are located in striatopallidal neurons and their activation inhibits GABA release (Florán et al, 1997). However, other receptors, such as CB1R, are also present in these striatopallidal neurons (Chaves‐Kirsten et al, ; Herkenham et al, ; Julian et al, ). CB1R are also coupled G i/o proteins that inhibit GABA release (Gonzalez et al, ; Köfalvi et al, ) and they also contribute to the control of motor behavior, as was shown in the striatum and the globus pallidus (González et al, ; Kelsey et al, ; Souilhac et al, ).…”

Genome‐wide microarray analysis identifies a potential role for striatal retrograde endocannabinoid signaling in the pathogenesis of experimental l‐DOPA‐induced dyskinesia

“…Many recent researches focus on the role of dopaminergic receptor subtypes, ionotropic and metabotropic glutamate receptors in the pathophysiology of LID (Calabresi et al, 2008;Conn et al, 2005;Kumar et al, 2009). In addition, several experimental data lend support to the view that the dysfunction of the endocannabinoid (eCB) signaling system and their interaction with dopaminergic receptors and A 2A adenosine receptors may involve in the molecular mechanisms underlying LID and PD (Bonaventura et al, 2013;Chaves-Kirsten et al, 2013;Di Marzo et al, 2000;Hurley et al, 2003;Martinez et al, 2012). However, the prime cause of LID remains unclear.…”