The behavioral effects of the stereoisomers of 4-methylaminorex, a psychostimulant, in the rat.
In this study, we examined the effect of the isomers of the psychostimulant 2-amino-4-methyl-5-phenyl-delta 2-oxazoline (4-methylaminorex or 4-MAX) on behavior in rats. The s.c. administration of the stereoisomers of 4-MAX, trans-4S,5S, cis-4R,5S, cis-4S,5R and trans-4R,5R (0.3-3 mg/kg), produced a dose-dependent increase in locomotor activity. However, at a dose of 10 mg/kg, the isomers of 4-MAX produced an initial increase in locomotor activity followed by the appearance of stereotyped behaviors (continuous sniffing, chewing, head bobbing, etc.) then a subsequent phase of rebound-enhanced locomotor activity all over a time course of 4 hr. The rank order of potency for the stereoisomers of 4-MAX was: 4S,5S > 4R,5S =4S,5R < 4R,5R. To determine what neurotransmitter systems may mediate the action of 4-MAX, the ability of various receptor antagonists to block or attenuate the effect of trans-4S,5S-4-MAX (3 mg/kg s.c.) on locomotor activity was examined. The selective dopamine (DA) D1 antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo- [d]naph-thio[2,1b]azepine (SCH 39166) and the D2 receptor antagonist (-)-eticlopride significantly, attenuated the behavioral action of trans-4S,5S-4-MAX, whereas antagonists to serotonergic and adrenergic receptors were ineffective. These results suggest that the ability of 4S,5S-4-MAX to induce locomotor hyperactivity and stereotypical behaviors and to increase rearing durations is primarily mediated by DA receptors. To determine whether the action of 4-MAX is dependent upon 5-hydroxytryptamine or DA concentrations in nerve terminals, rats were pretreated with either reserpine, alpha-methyl-p-tyrosine or d,l-p-chlorophenylalanine. Both reserpine and alpha-methyl-p-tyrosine pretreatment markedly attenuated the locomotor activity produced by trans-4S,5S-4-MAX. Moreover, L-dopa partially reversed the inhibitory action of alpha-methyl-p-tyrosine on 4S,5S-4-MAX-induced behavioral activation. In contrast, the administration of d,l-p-chlorophenylalanine did not alter the behavioral responses produced by trans-4S,5S-4-MAX. Taken together, our results suggest that 4-MAX may increase several locomotor behaviors by inducing neuronal DA release, which subsequently interacts with dopaminergic receptors.
Batsche
K
K
Department of Psychiatry, State University of New York at Stony Brook, New York.
Ashby
C R
CR
Lee
C
C
Schwartz
J
J
Wang
R Y
RY
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism; D019805:alpha-Methyltyrosine
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D008781:Methyltyrosines; D010080:Oxazoles; D011954:Receptors, Dopamine; D012702:Serotonin Antagonists; C058081:ecopipam; D019805:alpha-Methyltyrosine; C000081:4-methylaminorex; D010134:Fenclonine