Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha 4 nicotinic receptorsubunit knockout mice

1 The present study examined the effect of a range of doses of chronic nico tine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striat al dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA ; 10 mug intrastriatal unilaterally) in rats; and the effects of acute nico tine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induc ed by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. 2 In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [H-3]-mazindol autoradiography. 3 In rats, chronic nicotine infusion delivered by osmotic minipump implante d subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced si gnificant and dose-related protection against 6-OHDA-induced neurodegenerat ion. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg( -1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degenera tion. 4 In wild-type mice, acute nicotine treatment produced significant inhibiti on of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit kn ockout mice, acute nicotine treatment failed to inhibit methamphetamine-ind uced neurodegeneration. 5 Nicotine is capable of protecting dopaminergic neurons against Parkinsoni an-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activati on of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprot ective. Further, neuroprotection is absent in a4 nAChR subunit knockout mic e. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effe ct of nicotine upon Parkinsonian-like damage in vivo.