Methamphetamine-induced loss of striatal dopamine innervation in BDNF heterozygote mice does not further reduce D3 receptor concentrations.

Depletion of dopamine (DA) reduces D(3) receptor number, but D(3) receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of DA fibers produced by methamphetamine were additive in their impact on D(3) receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen DA concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, DA transporter (DAT), and DA D(3) receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen DA concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D(3) receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D(3) receptor expression, but also indicate that a methamphetamine-induced depletion of DA fibers fails to produce an additive effect with lowered BDNF for control of D(3) receptor expression. In addition, the reduction of D(3) receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice.

Loss of D3 receptors in the zitter mutant rat is not reversed by L-dopa treatment.

In Parkinson's disease (PD) and animal models of parkinsonism the destruction of nigrostriatal (NSB) system results in a marked loss of the dopamine D(3) receptor and mRNA in the islands of Calleja (ICj) and the nucleus accumbens shell (NAS). In animal models, it has been reported that both measures are elevated by repeated intermittent administration of L-dopa. However, a large proportion of PD cases are resistant to L-dopa-induced elevation of D(3) receptor number. The zitter mutant (Zi/Zi) rat replicates the slow progressive degeneration of the NSB observed in PD and also exhibits a loss of D(3) receptor number in the NAS or ICj. To test if this could be reversed with subchronic L-dopa treatment, injections of carbidopa (10 mg/kg i.p.) were followed an hour later with injection of L-dopa (100 mg/kg i.p.) twice a day for 10 days. In control Sprague-Dawley (SD) and zitter heterozygote (Zi/-) rats that do not show a loss of D(3) receptors with vehicle treatment, L-dopa produced no change in D(3) receptor number or in DA terminal density as measured by dopamine transporter (DAT) binding and tyrosine hydroxylase immunoautoradiography (TH-IR). There was a marked loss of DAT and TH-IR in caudate-putamen (CPu) and NA, as well as D(3) receptors in NAS and ICj in Zi/Zi rats but no further change with L-dopa treatment. To determine if the resistance to L-dopa-induced increase in D(3) receptor was due to a deficiency in expression of cortical BDNF or its receptor, TrkB, in CPu and NAS, we examined BDNF mRNA by ISHH in frontal cortex and TrkB mRNA in frontal cortex, CPu, and NA. The loss of the NSB in the Zi/Zi did not alter levels of BDNF or TrkB mRNA, nor did L-dopa administration alter levels BDNF or TrkB mRNA. Thus, unlike in 6-hydroxydopamine-treated rats, in Zi/Zi rats administered L-dopa does not reverse the loss of BDNF mRNA or lead to an elevation of D(3) receptor number.

Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent, S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a comparison to ropinirole.

The novel naphtoxazine derivative and preferential D(3) vs D(2) receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency superior to those of two further, preferential D(3) receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP(+) and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.