The selective alpha1 adrenoceptor antagonist HEAT reduces L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.
In Parkinson's disease (PD), the long term use of L-DOPA results in major adverse effects including dyskinesia or abnormal involuntary movements. The present study focuses on the effect of the selective alpha(1) adrenoceptor antagonist HEAT (2-[[beta-(-4-hydroxyphenyl)ethyl]aminomethyl]-1-tetralone) in the 6-hydroxydopamine rat model of L-DOPA-induced dyskinesia. We demonstrate that the selective alpha(1) adrenoceptor antagonist HEAT (1 and 2 mg kg(-1)), the alpha(2) adrenoceptor antagonist idazoxan (9 mg kg(-1)), and the nonselective beta(1)/beta(2) adrenoceptor antagonist propranolol (20 mg kg(-1)) alleviate dyskinetic movements induced by L-DOPA. Furthermore, the adrenoceptor antagonists at the doses used did not influence exploratory behavior in the open field system indicating that the antidyskinetic effect is not due to a reduction in general motor activity. Intrastriatal administration of the selective alpha(1) adrenoceptor agonist cirazoline via reverse in vivo microdialysis did not induce dyskinesia. Additionally, we measured plasma, brain, and CSF levels of HEAT. HEAT is a CNS active compound with a brain/plasma and CSF/plasma ratio of 4.29 and 0.15, respectively, which is appropriate for the investigation of alpha(1)-mediated mechanisms in CNS disorders. In conclusion, these results demonstrated for the first time that a alpha(1) adrenoceptor antagonist reduced L-DOPA-induced dyskinesia in a rat model. Further studies assessing the risk benefit in comparison to existing therapies are needed before considering alpha(1) adrenoceptor antagonists as a target for the development of new antidyskinetic compounds.
Buck
Kerstin
K
Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH and Co. KG, 88397 Biberach, Germany.
Ferger
Boris
B
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D019329:Idazoxan / Q000494:pharmacology; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D010949:Plasma / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D044024:Tetralones / Q000493:pharmacokinetics / Q000494:pharmacology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000978:Antiparkinson Agents; D018340:Receptors, Adrenergic, alpha-1; D044024:Tetralones; C010652:BE 2254; D007980:Levodopa; D016627:Oxidopamine; D011433:Propranolol; D019329:Idazoxan