5-HT antagonists

These opposing effects of tryptamine and 5-HT are also seen when they are applied directly to cortical neurons by iontophoresis. Tryptamine is predominantly depressant while 5-HT is mainly excitatory. Surprisingly, the 5-HT antagonist metergoline is more effective against tryptamine and the depressant effects. When the medial Raphe nucleus... 

Antidepressants (MAOIs, TCAs, 5-HT and/or NE and/or DA reuptake inhibitors, 5-HT antagonists)... 

Using a standardized method for eliciting flexion (electrical stimulation of the base of the hindpaw) and a quantifiable method of contraction measurement (force transducer attached to the hindpaw), Nozaki et al. (136,137) found that LSD (10 Mg/kg) and tryptamine both increased the flexor reflex in acutely spinalized rats. Both these effects were blocked by pretreatment with the 5-HT antagonist cyproheptadine. A similar LSD effect was reported in spinal cats (118). 

Recent data utilizing a polysynaptic withdrawal reflex suggest that, in intact rats, a disinhibition hypothesis may be necessary to explain some of the facilitatory effects of hallucinogens. Low to moderate doses of the hallucinogen 5-MeODMT administered into the lateral ventricle facilitated (i.e., decreased the latency of) the tail flick response to radiant stimulation of the tail (22). Furthermore, either spinal transection alone or systemic administration of 5-HT antagonists in intact... 

The catecholamine-releasing agent beta-phenylethylamine (PEA) also produces the 5-HT syndrome (156) by direct activation of 5-HT receptors. The 5-HT antagonists methysergide and mianserin blocked the syndrome-producing effects of PEA, while depletion of 5-HT by PCPA or 5,7-DHT treatments was not effective. A possible role of catecholamines in the syndrome-producing effects of PEA cannot presently be discounted. 

TABLE 1. Putative 5-HT antagonists reported to attenuate a variety of hallucinogen-induced drug stimulia b c... 

TABLE 2. Comparison of the antagonism of various hallucinogenic-induced discriminative stimuli by two 5-HT antagonists... 

FIG. 1. Reversal by a 5-HT antagonist (methiothepin) of changes induced by LSD administration on indole levels in the whole brain of adult rats. LSD alone (2X1 mg/kg i.p. 120 and 100 min before death) induced a significant reduction of the 5-HIAA/5-HT ratio, indicating a marked decrease in 5-HT turnover. This effect was almost entirely suppressed by the combined treatment with the potent 5-HT antagonist methiothepin (20 mg/kg i.p. 110 min before death). Therefore, 5-hydroxyindole alterations due to LSD involve the direct stimulation of 5-HT receptors by the hallucinogen. Bar, mean SEM of six determinations. p < 0.05 when compared with saline-treated rats p < 0.05 when compared with rats treated with LSD alone. 

Drug-receptor interactions, and ability of 5-HT antagonists to attenuate DS properties of hallucinogens, 87-88... 

A large number of functional and electrophysiologic studies in transected animals support the conclusion that hallucinogens facilitate spinal MSRs and PSRs in both flexor and extensor muscles. Furthermore, these studies show that 5-HT antagonists effectively block the observed excitatory behavioral effects, suggesting mediation by spinal excitatory 5-HT receptors. 

In addition to the excitatory effects described above, there is some evidence that administration of hallucinogens can depress MSRs and PSRs in intact animals. These depressant effects, however, do not appear to be simply mediated by stimulation of inhibitory postsynaptic 5-HT receptors in the spinal cord, since they are blocked by 5-HT antagonists. 

Electrical stimulation in the vicinity of the raphe nuclei has been reported to produce depressant effects on MSRs (32,142). These depressant effects could be attributed to activation of postsynaptic inhibitory receptors analogous to those characterized in the forebrain, except for the fact that the depression was blocked by 5-HT antagonists. The effectiveness of the antagonists suggests that the receptor is more akin to the excitatory 5-HT receptor characterized on motoneurons (134,184). The depressant behavioral effects could result from... 

Since most of the effects of hallucinogens on unconditioned behavior are blocked by 5-HT antagonists, their effects can be attributed to actions at these excitatory postsynaptic receptors. These behaviors include most of the actions of hallucinogens on spinal reflexes, the excitatory effects of at least one hallucinogen (5-MeODMT) on acoustic startle, and the production of the 5-HT syndrome, limb flicks, and limb jerks. 

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