Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model

Abstract

While levodopa therapy for 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.

Smoking, nicotine and neuropsychiatric disorders

“…Moreover, a recent prospective study found that current smoking (compared with nonsmoking) at PD onset is associated with a more rapid cognitive deterioration in accordance with results of two previous cohort studies (Weisskopf et al, 2007;Ebmeier et al, 1990;Levy et al, 2002). The symptom-alleviating effect of NIC is also contradictory in animal models of PD, although some results from both primate and rodent models of PD show that NIC may reduce L-DOPA-induced dyskinesias or L-DOPA-induced cognitive deficits (L-DOPA is the gold standard for treating PD) Bordia et al, 2008;Janhunen and Ahtee, 2007;Abdel-Salam, 2008;Decamp and Schneider, 2009). In partial contrast to the results discussed above, some case-reports and studies found that NIC has symptomalleviating and cognition-improving effects in PD.…”

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function

“…Previous studies in monkeys generated support for the hypothesis that stimulation of α4β2* nAChRs, in combination with potentially relatively low doses of levodopa, benefits the non-motor symptoms of PD (Decamp and Schneider, 2009; Schneider et al, 1998, 1999, 2003). In our rat model (Kucinski et al, 2013), co-administration of the α4β2* nAChR agonist ABT-089 (Arneric et al, 1997), levodopa and benserazide, reduced falls across testing conditions on the MCMCT by approximately 50% (Kucinski et al, 2012).…”

The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis

“…A number of animal models have been employed in order to better understand the mechanisms involved in PD, including primates (Decamp and Schneider 2009), rodents (Lindgren et al, 2010), and Drosophila melanogaster (Bayersdorfer et al 2010). These models are mainly based on the neurotoxic induction of PD-like symptoms using different agents, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP; Xu et al 2010), 6-OHDA (Chuang et al 2010), rotenone (Hu et al 2010), and paraquat (DinisOliveira et al 2006;Jimenez-Del-Rio et al 2008).…”