Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine.
This experiment attempted to determine the mechanism by which amphetamine reduces locomotor hyperactivity in neonatal rats given brain dopamine (DA)-depleting 6-hydroxydopamine (6-OHDA) injections. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular (i.v.t.) injections of 6-OHDA following desmethylimipramine (DMI) pretreatment. Control rats received DMI and i.v.t. injections of the 6-OHDA vehicle solution. Rats given the 6-OHDA treatment displayed 7-fold increases in locomotor activity compared to controls during days 16-55 of life. Throughout this period, amphetamine (1 mg/kg) reduced locomotor hyperactivity in 6-OHDA-treated rats but increased locomotor activity in control rats. The reduction of hyperactivity caused by amphetamine (0.5-4 mg/kg) was dose-related and was not accompanied by stereotyped behavior. Like amphetamine, methylphenidate (4 mg/kg) reduced locomotor hyperactivity in rats given 6-OHDA. The DA antagonist, spiroperidol (50-200 micrograms/kg) failed to attenuate the hyperactivity-reducing effect of amphetamine in 6-OHDA-treated rats at doses which abolished the stimulant effect of amphetamine in control rats. However, the serotonin antagonist methysergide (0.5-4 mg/kg) produced dose-dependent antagonism of the effect of amphetamine in 6-OHDA-treated rats. Pretreatment with propranolol ((5 mg/kg), phentolamine (5 mg/kg), atropine (0.5 mg/kg) or naloxone (10 mg/kg) failed to alter the reduction in locomotor hyperactivity caused by amphetamine. The serotonin releasing agent, fenfluramine (3 mg/kg), and the serotonin agonist, quipazine (0.5-4 mg/kg), both reduced locomotor hyperactivity in 6-OHDA-treated rats while not altering locomotion in control rats. These results confirm previous observations that amphetamine reduces locomotor hyperactivity caused by neonatal 6-OHDA administration and suggest that this effect is mediated by increased serotonergic neurotransmission.
D000818:Animals; D001921:Brain / Q000187:drug effects*; D003891:Desipramine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006892:Hydroxydopamines / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D009115:Muridae; D016627:Oxidopamine; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D006892:Hydroxydopamines; D008774:Methylphenidate; D012701:Serotonin; D016627:Oxidopamine; D003891:Desipramine; D003913:Dextroamphetamine; D004298:Dopamine