Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson's disease

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) display time-dependent impairments in olfactory, emotional, cognitive and motor functions associated with disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, lithium (Li) and valproate (VPA) are two primary drugs used to treat bipolar mood disorder that have recently emerged as promising neuroprotective agents. The present data indicates that the pretreatment with Li (47.5 mg/kg) or VPA (200 mg/kg) by intraperitoneal route during 7 consecutive days was able to prevent olfactory discrimination and short-term memory impairments evaluated in the social recognition and step-down inhibitory avoidance tasks in rats infused with a single intranasal (i.n.) administration of MPTP (0.1 mg/nostril). Despite the absence of clear depressive-like responses following the current MPTP dose, Li and VPA treatment presented an antidepressant profile reducing the immobility time in the forced swimming test. Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, Li and VPA prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats. These results provide new insights in experimental models of PD, indicating that Li and VPA may represent new therapeutic tools for the management of olfactory and cognitive symptoms associated to early preclinical phases of PD, together with their neuroprotective potential demonstrated in previous research.