Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model.
While levodopa therapy for Parkinson's disease (PD) may effectively relieve motor symptoms, many of the cognitive deficits experienced by PD patients (and in animal models of PD) are not effectively managed by this treatment. In contrast, previous work has shown positive effects of nicotinic therapies on cognition in PD models. The present study evaluated the effects of levodopa, nicotine and the nicotinic acetylcholine receptor agonist SIB-1553A alone and in combination on cognition in a non-human primate model of early PD. Three adult male Rhesus monkeys, previously administered low doses of the neurotoxin MPTP over several months to produce cognitive deficits, were trained to perform a modified spatial delayed response task in which the attentional demands of the task were manipulated by varying the duration of the cue presentation while keeping the memory demands of the task low and constant. Task performance was assessed after administration of levodopa, nicotine ditartrate, or SIB-1553A and after administration of drug combinations. Animals performed normally when task attentional load was low (i.e., with long cue durations) but performance was significantly impaired on short cue duration trials. Levodopa further impaired performance on short cue duration trials and induced a deficit on long cue duration trials. Nicotine and SIB-1553A improved performance on short cue trials and when co-administered with levodopa, counteracted levodopa-induced deficits. These results confirm that nicotinic therapies may be useful for treating cognitive deficits associated with PD and suggest that negative effects of levodopa on cognition may be amenable to correction with adjunctive nicotinic therapies.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, 521 JAH, Philadelphia, PA 19107, USA.
E
E
Decamp
J S
JS
Schneider
D000818:Animals; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004347:Drug Interactions; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000523:psychology; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D013647:Task Performance and Analysis
C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D015259:Dopamine Agents; D004338:Drug Combinations; D018722:Nicotinic Agonists; D010636:Phenols; D011759:Pyrrolidines; D007980:Levodopa; D009538:Nicotine