Serotonin modulation of catalepsy induced by N(G)-nitro-L-arginine in mice.

N(G)-(Nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in mice. The objective of the present work was to investigate if serotonergic drugs are able to modulate this effect. Results showed that the cataleptogenic effect of L-NOARG (40 mg/kg) in male albino-Swiss mice was enhanced by pre-treatment with (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY-100135, 5 or 10 mg/kg), a 5-HT1A-selective receptor antagonist, and by ketanserin (5 or 10 mg/kg), a 5-HT2A receptor and alpha1-adrenoceptor antagonist. Prazosin (3 or 5 mg/kg), an alpha1-adrenoceptor antagonist, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3-dimet hyl-indole-1-carboxamide HCl (BRL-46470A, 0.05 or 0.5 mg/kg), a 5-HT3 receptor antagonist, did not interfere with L-NOARG-induced catalepsy. Ritanserin (3 or 10 mg/kg), a 5-HT2A and 5-HT2C receptor antagonist, tended to enhance the effect of L-NOARG. These results confirm that interference with the formation of nitric oxide induces catalepsy in mice, and suggest that this effect is modulated by 5-HT1A and 5-HT2A receptors.

Late embryonic ritanserin exposure fails to alter normal responses to immune system stimulation in young chicks.

Prior studies in our laboratory have demonstrated that prenatal treatment with the serotonin2 (5-HT2) antagonist ritanserin is effective in blocking some of the lethal, dysmorphic, cardiovascular, and behavioral consequences of excessive direct or indirect stimulation of 5-HT2 receptors in the developing chicken. The efficacious dose range for ritanserin in these studies had very little or no effect on the above measures of toxicity when administered alone. In the present study, we extend our characterization of ritanserin's potential toxicity, or lack thereof, to include the normal behavioral and endocrine responses to immune system stimulation by the endotoxin lipopolysaccharide (LPS). LPS administration induces a syndrome collectively known as sickness behavior, manifest as altered thermoregulatory processes leading to fever, and increased serum concentrations of neuroendocrine hormones, including corticosterone. These survival-promoting responses to LPS were assessed in young chickens that had been treated with doses of ritanserin ranging from 0 to 2.7 mg/kg on embryonic day 17 (E17). When sickness behavior was assessed in 5-7-day-old chicks 1 h post-LPS injection, E17 ritanserin-treated subjects did not differ from controls. At 4-6 h post-LPS, 4-day-old chicks displayed a robust fever, and E17 ritanserin did not affect the magnitude of this response. Similarly, E17 ritanserin treatment failed to affect corticosterone concentrations 2 h post-LPS in 14-day-old chicks. Thus, ritanserin treatment during late embryogenesis, a time when it is effective against direct and indirect acting 5-HT2 agonists, failed to modify the survival promoting and beneficial interactions between the nervous, endocrine, and immune systems that are elicited following immunostimulation.

Relationships between midembryonic 5-HT2 agonist and/or antagonist exposure and detour learning by chickens.

The importance of serotonin (5-HT) as both a transmitter and a regulatory signal during development of many species is well established. The availability of 5-HT receptor subtype agonists and antagonists will enable pharmacological dissection of the importance of one or more of the 5-HT receptors for their involvement in the mediation of developmental insults by drugs that are less selective but include actions upon serotonergic function. Such insults include exposure to cocaine or opiate withdrawal, both of which are blocked or attenuated by 5-HT2 antagonists. The 5-HT2 receptor agonist dimethoxyiodophenylaminopropane (DOI), like cocaine, causes vasoconstriction during embryogenesis, herniated umbilici in hatchlings, and altered detour learning by young chickens after injection into eggs at late stages of embryogenesis. The 5-HT2 antagonist ritanserin (RIT) blocks or significantly attenuates these effects. This study describes an effect of DOI on posthatch detour learning when injected earlier during embryogenesis (i.e., on embryonic day 12, E12) which is opposite its effect when injected later (i.e., on E15). Both effects are blocked by an inactive dose of RIT (0.3 mg/kg egg) and by a higher dose of RIT (0.9 mg/kg egg), which itself retards posthatch detour learning following E12 injection. Thus, excessive stimulation or blockade of 5-HT2 receptors around midembryogenesis can cause a similar behavioral teratogenic outcome. The data are discussed in relation to the likelihood that potential use of 5-HT2 antagonists for treating pregnant women and their fetuses who are not at risk is nil.

Behavioral and neuroendocrine assessment of ritanserin exposure in the developing chicken: lack of toxicity at effective doses.

The 5-HT2 antagonist ritanserin (RIT) is undergoing Phase III clinical trials for the treatment of substance abuse disorders. RIT has also shown preclinical therapeutic potential for attenuating or blocking lethal and/or toxic effects of exposure to cocaine or the selective 5-HT2 agonist dimethoxyiodophenyl-aminopropane (DOI) in the developing chicken. To assess the potential toxicity ("side effects") of RIT itself during development, we exposed chicken embryos to 0, 0.1, 0.3, 0.9, or 2.7 mg RIT/kg egg by injecting the drug into eggs with 14-day-old embryos (E14). Voltage generated by spontaneous embryonic activity (motility) was measured on E15 to assess short-term effects of RIT; none were observed. There was no overall effect of these RIT doses on hatchability, though sample sizes were small (n = 13-15 per group). One to 2 weeks after hatching, chicks' acquisition of a detour learning response was tested. There were no observable effects of any RIT dose on detour learning. To assess potential effects of RIT on responsiveness to stress, some chicks were exposed to isolation stress approximately 3 weeks after hatching and killed 15 min later. Blood was assayed for serum corticosterone. There was no effect of any embryonic RIT dose on corticosterone concentrations in nonstressed subjects. Although corticosterone was elevated in all stressed groups, the group exposed to the highest embryonic RIT dose (2.7 mg/kg egg) showed a stress-induced elevation greater than other groups. Thus, except for the highest RIT dose (six to seven times greater than a therapeutically effective dose used in earlier work), embryonic RIT exposure on E14 had no effect on embryonic behavior, hatchability, posthatch learned behavior, and basal serum corticosterone concentrations. At a supraefficacious dose it appears to have modified the responsiveness of the neuroendocrine axis to mild stress.