Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys.
Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with l-DOPA in treatment-naive and L-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and L-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of L-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and L-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure ("de novo" or after L-DOPA priming). Initial CE administration did not affect development of L-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to L-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on L-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.
Cao
Xuebing
X
Department of Neurology, Emory University, 6000 WMRB, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Liang
Li
L
Hadcock
John R
JR
Iredale
Philip A
PA
Griffith
David A
DA
Menniti
Frank S
FS
Factor
Stewart
S
Greenamyre
J Timothy
JT
Papa
Stella M
SM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001384:Azetidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
C523983:1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo(1,5-a)-(1,3,5)triazin-4-yl)-3-ethylaminoazetidine-3-carboxylic acid amide; D000978:Antiparkinson Agents; D001384:Azetidines; D043884:Receptor, Cannabinoid, CB1; D014227:Triazines; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine