Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease.
Recent studies have demonstrated a loss of cannabinoid CB1 receptors in the postmortem basal ganglia of patients affected by Huntington's disease (HD) and in transgenic mouse models for this disease. These studies have led to the notion that substances that increase the endocannabinoid activity, such as receptor agonists or inhibitors of endocannabinoid uptake and/or metabolism, might be useful in the treatment of hyperkinetic symptoms of this disease. In the present study, we employed a rat model of HD generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP), a toxin that selectively damages striatal GABAergic efferent neurons. These rats exhibited biphasic motor disturbances, with an early (1-2 weeks) hyperactivity followed by a late (3-4 weeks) motor depression. Analysis of GABA, dopamine, and their related enzymes, glutamic acid decarboxylase and tyrosine hydroxylase, in the basal ganglia proved marked decreases compatible with the motor hyperkinesia. In addition, mRNA levels for CB1 receptor, neuronal-specific enolase, proenkephalin, and substance P decreased in the caudate-putamen of 3-NP-injected rats. There were also reductions in CB1 receptor binding in the caudate putamen, the globus pallidus, and, to a lesser extent, the substantia nigra. By contrast, mRNA levels for tyrosine hydroxylase in the substantia nigra remained unaffected. Interestingly, the administration of AM404, an inhibitor of endocannabinoid uptake, to 3-NP-injected rats attenuated motor disturbances observed in the early phase of hyperactivity. Administration of AM404 also tended to induce recovery from the neurochemical deficits caused by the toxin in GABA and dopamine indices in the basal ganglia. In summary, morphological, behavioral, and biochemical changes observed in rats intrastriatally lesioned with 3-NP acid were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to that occurring in the brain of HD patients. As expected, a loss of CB1 receptors was evident in the basal ganglia of these rats. However, the administration of substances that increase endocannabinoid activity, by inhibiting the uptake process, allowed an activation of the remaining population of CB1 receptors, resulting in a significant improvement of motor disturbances and neurochemical deficits. These observations might be relevant to the treatment of hyperkinetic symptoms in HD, a human disorder with unsatisfactory symptomatic treatment for most patients.
Lastres-Becker
Isabel
I
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Hansen
Henrik H
HH
Berrendero
Fernando
F
De Miguel
Rosario
R
Pérez-Rosado
Alberto
A
Manzanares
Jorge
J
Ramos
José A
JA
Fernández-Ruiz
Javier
J
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000819:agonists*; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D063388:Endocannabinoids; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006948:Hyperkinesis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D003292:Convulsants; D063388:Endocannabinoids; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005680:gamma-Aminobutyric Acid; C015392:3-nitropropionic acid; D004298:Dopamine; C107594:N-(4-hydroxyphenyl)arachidonylamide