Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism

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Abstract

We have observed that systemic administration of cannabinoid CB1 antagonists exerts antiparkinsonian effects in rats with very severe nigral lesion (>95% cell loss), but not in rats with less severe lesion (85–95% cell loss). Local injections into denervated striatum and corresponding globus pallidus reduced parkinsonian asymmetry. Infusions into lesioned substantia nigra enhanced motor asymmetries, but this effect was absent after very severe nigral lesion. At the striatal level, CB1 antagonists act enhancing dopamine D1 receptor function and reducing D2 receptor function. Striatal dopaminergic denervation did not affect cannabinoid CB1 receptor coupling to G proteins. These results suggest that (i) systemic administration of CB1 antagonists in rats with severe nigral degeneration is ineffective because striatopallidal-mediated motor effects are antagonized by nigra-mediated activity, and (ii) CB1 antagonists exert antiparkinsonian effects after very severe nigral degeneration because nigra-mediated inhibition disappears. CB1 receptor antagonists that lack psychoactive effects might be of therapeutic value in the control of very advanced stage of Parkinson's disease in humans.

Introduction

Brain cannabinoid CB1 receptors are expressed in neural areas that contribute to movement such as the basal ganglia, where their density is high and they co-localize with dopamine D2 and D1 receptors in striatal projection neurons (Herkenham et al., 1990, Herkenham et al., 1991, Surmeier et al., 1996, Tsou et al., 1998). It is known that there is a continual intracerebral release of endogenous cannabinoid receptor agonists such as anandamide (AEA) exhibiting neuromodulatory function (Baker et al., 2000, Giuffrida et al., 1999), and that the endocannabinoid system is an activity-dependent modulator of nigrostriatal dopaminergic neurotransmission (Beltramo et al., 2000, Cadogan et al., 1997, Glass et al., 1997, Pertwee, 1999). Endogenous cannabinoid CB1 activation seems to act as a brake of dopaminergic activity on dorsal striatum, and it has been proposed that it is a homeostatic counter-regulatory mechanism in the basal ganglia (Rodriguez de Fonseca et al., 1994, Rodriguez de Fonseca et al., 1998).

The interdependence between striatal CB1 and DA receptors have led to propose that cannabinoid CB1 ligands could be of value for improving motor deficits in degenerative diseases such as Parkinson's disease (PD) (Consroe, 1998, Glass et al., 1997, Rodriguez de Fonseca et al., 1998). The involvement of the endocannabinoid system in Parkinson's disease is also supported by recent findings describing up-regulation of CB1 receptors in the striatum after dopaminergic denervation, both in animals and humans (Lastres-Becker et al., 2001, Romero et al., 2000), associated with changes in striatal anandamide (AEA) levels. In this context, either enhancement of striatal AEA levels caused by a decrease in AEA degradation (Gubellini et al., 2002), or reduction of AEA levels have been reported (Ferrer et al., 2003). Hence, the nature of the changes in anandamide levels after striatal dopaminergic denervation remains controversial.

Cannabinoid CB1 receptor antagonists seem to be good candidates as antiparkinsonian tools. Nonetheless, blockade of CB1 receptors has been shown to enhance dopamine D2 receptor-mediated facilitation of motor behaviors (Giuffrida et al., 1999). Most cannabinoid antagonists available not only block endogenous CB1-mediated effects, but they also exhibit inverse cannabinomimetic effects (Pertwee, 1999), pointing to a possible efficacy of these compounds for enhancing basal dopaminergic transmission. In this regard, SR141716A has proved to be effective in ameliorating rigidity in the reserpine Parkinson's model in rats (DiMarzo et al., 2000), but it is ineffective in MPTP-induced parkinsonian monkeys (Meschler et al., 2001), indicating that the antiparkinsonian efficacy of these compounds is also controversial.

In the present study, selective CB1 antagonists have been tested in a rat PD model based on the unilateral destruction of nigral dopaminergic neurons. This animal model parallels human disorder well, and produces an hemiparkinsonian syndrome that includes motor asymmetries, sensorimotor neglect, akinesia, and forepaw use deficit (Cenci et al., 2002, Fornaguera et al., 1994, Schwarting and Huston, 1996). The cannabinoid ligand N-(4-hydroxyphenyl)-arachidonamide (AM404), which is an indirect agonist of CB1 receptors through anandamide reuptake and degradation inhibition, was used to reverse the effects of CB1 antagonists in order to verify the mediation of CB1 receptors.

Section snippets

Subjects

Male Wistar rats (275–325 g) from the breeding colony of the Faculty of Medicine of the University of Seville, Spain, were used. Laboratory temperature was kept at 22 ± 1°C, and a 12-h light–dark cycle (lights on at 08:00 h) was maintained throughout the experiment. Food (lab chow) and water were available ad libitum.

Unilateral 6-hydroxydopamine-induced nigra lesion

Thirty minutes before 6-hydroxydopamine (6-OHDA, RBI) lesion, rats were injected with the antibiotic ceftriazone (10 mg/0.3 ml IM), and desipramine (15 mg/kg IP) in order to

Induction of hemiparkinsonism

Rats were rendered hemiparkinsonian by injecting the toxin 6-hydroxydopamine into the left substantia nigra. Those animals that showed a strong ipsiversive rotational behavior after the administration of amphetamine (>420 turns per hour), indicative of dopamine depletion in the striatum higher than 95%, were selected for the study (Fornaguera et al., 1994, Schwarting and Huston, 1996). These animals presented an overt hemiparkinsonian syndrome characterized by drug-induced turning, spontaneous

Systemic cannabinoid CB1 antagonists exert antiparkinsonian effects only in rats with strong nigral degeneration

The data indicated that, within a dose range (0.1–0.5 mg/kg for SR141716A and around 5 mg/kg for AM251), the systemic administration of cannabinoid CB1 antagonists exerted antiparkinsonian effects in animals with very severe nigral degeneration. In this group of rats, nigral TH+ cell loss was higher than 95% of normal (analogue of last stage of human PD), and turning, akinesia, sensorimotor neglect (both ligands) and right forepaw use (SR141716A) were significantly ameliorated. In the remainder

Acknowledgments

This study was supported by grants to EFE from Spanish Ministerio de Ciencia y Tecnologia (SAF2002-1689), Plan Andaluz de Investigacion (CVI-127), Laboratorios Dr. Esteve (Barcelona), and Plan Nacional sobre drogas, and to FRF from Spanish Ministerio de Ciencia y Tecnologia (SAF2000-0101), FIS (2000/0654) and RED CIEN C03/06. Grants from Instituto Carlos III (FIS, RED de Trastornos adictivos, G03/05) and Junta de Andalucia (Acciones coordinadas) supported both EFE and FRF. The authors thank

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