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

Abstract

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.

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

“…However, striatal levels of DA and DOPAC in GDNF ϩ/Ϫ mice were less than in WT mice at 12 months of age, despite persistent elevation in DAT activity, suggesting an imbalance in DA function that emerges as GDNF ϩ/Ϫ mice age. Greater loss of TH-IR in the lateral versus the medial striatum of wild-type mice after METH treatment confirms previous reports (Joyce et al, 2004;O'Callaghan and Miller, 1994;Koike et al, 2005) and extends this observation to the striatum of mice 9.5 months after METH treatment. The reason for less TH-IR loss in the medial versus lateral striatum of WT mice is unknown, but may be attributable to a greater density of DAT normally in the lateral striatum of rodents (Ciliax et al, 1995;Watanabe et al, 2004;Zhu et al, 2005).…”

The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease

“…BDNF is known to be responsible for the development of D3 receptors and the maintenance of their expression [12,22,39], and both BDNF and D3 receptors are involved in the development of drug induced dyskinesias in PD [13]. Dopaminergic stimulation of D1 and D5 receptors in the frontal cortex induces BDNF mRNA expression, which acts on its receptors (TrkB) in striatal neurons to increase D3 receptor expression [12].…”

Brain-derived neurotrophic factor and cocaine addiction

“…Further, bdnf +/− mice show similar depletions in tyrosine hydroxyalse immunoreactvity and DA tissue concentrations in response to a neurotoxic regimen of METH (Boger et al, in press; Dluzen et al, 2001). However, in one report (Joyce et al, 2004), DAT binding and TH-ir were less affected in bdnf +/− mice than in WT mice after a high dose METH binge (mortality, thermal response, age, and sex of the mice were not reported).…”