Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect
dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As
antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist,
WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]
indole], was evaluated in animal models of
schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to
clozapine,
WAY-163909 (1.7-30 mg/kg i.p.) decreased
apomorphine-induced climbing with little effect on stereotypy and no significant induction of
catalepsy.
WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced
phencyclidine-induced locomotor activity compared with
d-amphetamine with no effect on spontaneous activity.
WAY-163909 (1.7-17 mg/kg i.p.) reversed
MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-
imine (
dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding,
WAY-163909 (0.3-3 mg/kg i.p.; 1-17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT(2B/2C) receptor antagonist
SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]
indole].
WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of
WAY-163909 (1-10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist
WAY-163909 is similar to that of an atypical
antipsychotic and additionally may have rapid onset properties.