Methamphetamine-induced serotonergic neurotoxicity using 4-¹⁸F- ADAM in rat brain

Objectives: Methamphetamine (METH), a psychostimulant, have neurotoxic effects on dopamine and serotonin systems. This experiment investigates METH-induced serotonergic neurotoxicity in rat brain using N, N-dimethyl-2- (2- amino- 4-[¹⁸F]-fluorophenylthio) benzylamine, i.e. 4-[¹⁸F]-ADAM, to image serotonin transporters (SERT).

Methods: Male adult rats were subcutaneously (s.c.) treated with either 5 mg/kg (n=7) or 10 mg/kg (n=6) METH for 4 separate administrations set at one hour interval. The controls were treated with normal saline (n=5). 4-[¹⁸F]-ADAM brain imaging was achieved 30 days after METH treatment using micro-PET (Concorde MicroSystems, Knoxville, TN). The specific uptake ratios (SURs) of 4-[¹⁸F]-ADAM were determined by drawing the volumes of interest in various brain regions of the rats with reference to the cerebellum. Tissue immunohistochemistry was carried out 7 days after the scans. Integrated optical density (IOD) ratios of target regions to corpus callosum were also measured.

Results: In the controls, 4-¹⁸F-ADAM uptake was measured in the midbrain, thalamus,hypothalamus, caudate putamen, hippocampus and frontal cortex with average SURs of 4.16, 3.63, 4.06, 3.76, 2.83 and 2.52, respectively at 30-60 min post-injection. The SURs of 4-[¹⁸F]-ADAM significantly reduced in all brain regions by 30 days after the METH- treatment; the effect is more prominent in the group treated with 10 mg/kg Meth (57% ~ 42% decreased compared to the controls; p< 0.05, each). Significant decrease of the tyrosine hydroxylase immunostaining and IOD ratios in caudate putamen, nucleus accubems, Substantia nigra pars compacta and Substantia nigra pars reticulata were also noted in the METH treated rats (50%,50%,41% and 21%; decreased compared to the controls; p< 0.01, each. ).

Conclusion: METH treatment may cause a dose-dependent loss of central SERT that can be evaluated by using 4-[¹⁸F]-ADAM micro-PET images. Research Support: Grants MOST 103-2314-B-075 -088 -MY3-3, NSC-99 and 100-2623-7016-001.