Comparison of systemic and local methamphetamine treatment on acetylcholine and dopamine levels in the ventral tegmental area in the mouse

• Published in: Neuroscience 2008-10, Vol.156 (3), p.700-711
• Main Authors: Dobbs, L.K, Mark, G.P
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; addiction; Analysis of Variance; Animals; Biological and medical sciences; Central Nervous System Stimulants - administration & dosage; Chromatography, High Pressure Liquid - methods; Dopamine - metabolism; Dose-Response Relationship, Drug; Drug Administration Routes; Fundamental and applied biological sciences. Psychology; Male; Medical sciences; mesolimbic system; Methamphetamine - administration & dosage; Mice; Mice, Inbred C57BL; microdialysis; Microdialysis - methods; Motor Activity - drug effects; Neurology; Neuropharmacology; Pharmacology. Drug treatments; pontine tegmentum; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; psychostimulants; reward; Ventral Tegmental Area - drug effects; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.07.052

Abstract Acetylcholine (ACh) is an important mediator of dopamine (DA) release and the behavioral reinforcing characteristics of drugs of abuse in the mesocorticolimbic pathway. Within the ventral tegmental area (VTA), the interaction of DA with ACh appears to be integral in mediating motivated behaviors. However, the effects of methamphetamine on VTA ACh and DA release remain poorly characterized. The current investigation performed microdialysis to evaluate the effects of methamphetamine on extracellular levels of ACh and DA. Male C57BL/6J mice received an i.p. injection (saline, 2 mg/kg, or 5 mg/kg) and an intra-VTA infusion (vehicle, 100 μM or 1 mM) of methamphetamine. Locally perfused methamphetamine resulted in no change in extracellular ACh compared with vehicle, but caused a strong, immediate and dose-dependent increase in extrasynaptic DA levels (1240% and 2473% of baseline, respectively) during the 20-min pulse perfusion. An i.p. injection of methamphetamine increased extrasynaptic DA to 275% and 941% of baseline (2 mg/kg and 5 mg/kg, respectively). Systemic methamphetamine significantly increased ACh levels up to 275% of baseline for 40–60 min (2 mg/kg) and 397% of baseline for 40–160 min (5 mg/kg) after injection. ACh remained elevated above baseline for 2–3 h post injection, depending on the methamphetamine dose. Methamphetamine-induced locomotor activity was dose-dependently correlated with extrasynaptic VTA ACh, but not DA levels. These data suggest that methamphetamine acts in the VTA to induce a robust and short-lived increase in extracellular DA release but acts in an area upstream from the VTA to produce a prolonged increase in ACh release in the VTA. We conclude that methamphetamine may activate a recurrent loop in the mesocorticolimbic DA system to stimulate pontine cholinergic nuclei and produce a prolonged ACh release in the VTA.