Behavioral and Neurochemical Changes in Mesostriatal Dopaminergic Regions of the Rat after Chronic Administration of the Cannabinoid Receptor Agonist WIN55,212-2

Abstract

Background:The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat.Methods:Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments.Results:Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and increased D1 receptor mRNA and binding in nucleus accumbens. Furthermore, both dopamine receptor and transporter binding and mRNA levels were decreased in substantia nigra. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and substantia nigra.Conclusions:Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region-, dose-, and neurotransmitter-selective manner

Modulatory effects of cannabinoids on brain neurotransmission

“…Further studies have consistently repeated these results and have demonstrated that an acute administration of either Δ9‐THC, WIN55,212‐2, HU‐210 and CP55,940 results in a receptor‐specific activation of the ventral tegmental area and substantia nigra dopamine neurons in vivo and in vitro (Gessa et al ., ; Wu & French, ; Cheer et al ., ; Morera‐Herreras et al ., ; Ginovart et al ., ; Fanarioti et al ., ; Perdikaris et al ., ). These results have demonstrated that CB 1 agonists may act as dopamine agonist‐like in the meso‐cortical dopamine circuitry, known to be involved in the brain's reward mechanism (Chen et al ., ; Tanda et al ., ).…”

“…Accordingly, an administration of Δ9‐THC for 21 days has down‐regulated tyrosine hydroxylase mRNA expression in the substantia nigra and in the ventral tegmental area midbrain nuclei, but not in the cortex or striatum (Ginovart et al ., ). Further studies have replicated this result (Fanarioti et al ., ; Perdikaris et al ., ), and they have added that alterations to tyrosine hydroxylase expression was observed up to 7 days following cessation (Perdikaris et al ., ). Altogether, these studies show that following chronic treatment with CB 1 agonists there are some alterations in the activity of the dopaminergic‐neurons.…”

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

“…The absence of tolerance is quite remarkable since it is generally assumed that CB 1 receptors are prone to plasticity [13,16,36,40]. However, it has been previously reported that repeated administration of WIN55,212-2 does not lead to behavioral tolerance despite producing acute and sustained motor-suppressant effects [41]. Whereas chronic treatment with WIN results in slight CB 1 receptor desensitization in mice, it was much lower than when treated with Δ 9 -THC [65,66].…”

“…Similarly, evidence from rats with pentylenetetrazole (PTZ)-induced tonic-clonic seizures shows that chronic exposure to cannabinoids did not affect seizure susceptibility [67]. Therefore, the development of tolerance to CB 1 agonists seems to be dependent on several factors, including the used compound, experimental protocol, and dose [41,68].…”

“…However, CB 1 receptors have been reported to be prone to plasticity [13,16], and tolerance to cannabinoids on behavior, cognitive functioning, and EEG has been reported in humans [36][37][38] as well as in rodents [39,40]. However, in case of WIN, this is not entirely clear since repeated administration of this CB1 agonist did not lead to behavioral tolerance [41]. It is therefore of particular interest to investigate whether tolerance occurs regarding the effects of WIN on SWDs.…”