Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice.
The underlying mechanisms of ketamine-induced hyperlocomotion were examined in mice. An intraperitoneal (IP) injection of ketamine (3-150 mg/kg) increased locomotor activity in a dose-dependent fashion. A low dose of ketamine (30 mg/kg) produced peak locomotion within the first 10 min followed by a rapid decline. In contrast, a high dose (150 mg/kg) inhibited locomotor activity to the control level during the first 30 min. Thereafter the activity gradually increased and reached a peak at approximately 2 h followed by a gradual decline. The hyperactivities induced by both low and high doses of ketamine were inhibited by a low dose of haloperidol (0.10 mg/kg, IP), a dopamine (DA) receptor antagonist. However, neither a high dose of phenoxybenzamine (10 mg/kg, IP), an alpha-blocker nor a high dose of propranolol (20 mg/kg, IP), a beta-blocker inhibited the hyperactivities. Destruction of catecholaminergic terminals by 6-hydroxydopamine suppressed ketamine-induced hyperlocomotion. Regional brain monoamine assays revealed that, at peak locomotion, a low dose of ketamine (30 mg/kg) selectively increased DA turnover in the nucleus accumbens which is a forebrain region believed to be involved in the initiation and regulation of locomotor activity, while a high dose (150 mg/kg) increased not only DA but also norepinephrine and serotonin turnover in many regions of the brain. In vitro, ketamine slightly provoked [3H]DA release from nucleus accumbens and striatal slices to a similar extent, but inhibited synaptosomal uptake of [3H]DA in the nucleus accumbens to a greater degree than in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Irifune
M
M
Department of Pharmacology, Faculty of Medicine, Kagoshima University, Japan.
Shimizu
T
T
Nomoto
M
M
D000758:Anesthesia; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D006220:Haloperidol / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*
D015306:Biogenic Monoamines; D010643:Phenoxybenzamine; D007649:Ketamine; D016627:Oxidopamine; D011433:Propranolol; D006220:Haloperidol; D004298:Dopamine