Selectivities and serotonin increases A number of somewhat
selective SRAs have been well-studied, for instance
fenfluramine and
meta-chlorophenylpiperazine (mCPP). Direct activation of serotonin receptors such as the serotonin 5-HT2C receptor with fenfluramine has been shown to be therapeutically relevant in humans, as dexfenfluramine produces
appetite suppressant effects even when its serotonin release is blocked by concomitant treatment with the
selective serotonin reuptake inhibitor (SSRI)
fluoxetine. As such, the serotonin 5-HT2 receptor agonism and other actions of these agents may modify their effects, and a fully
selective SRA could produce very different effects. and certain
cathinones, have increased selectivity for serotonin release compared to fenfluramine and mCPP.
Chlorphentermine is also notable in being a highly selective SRA, including having negligible activity as an agonist of all three of the serotonin 5-HT2 receptors. but was subsequently found to efficiently induce dopamine release as well, and is also known to act as a potent
monoamine oxidase A (MAO-A)
inhibitor.
MMA has been found to act as a highly selective SRA, but has also been reported to produce psychedelic-like effects in both animals and humans. SRAs achieve far greater increases in serotonin levels than SRIs and have substantially more robust of effects, both in animals and in terms of subjective effects in humans. SRIs produce subtle interoceptive cues that are difficult for animals to recognize in
drug discrimination testing, whereas SRAs produce robust cues that are easily recognized and learned. In spite of the preceding however, it has also been reported that the SRA
dexfenfluramine weakly but
dose-dependently stimulates locomotor activity in rodents. As with reported findings with fenfluramine, whereas the SRA and serotonin 5-HT2C receptor agonist mCPP decreases locomotor activity normally, it increases locomotor activity in serotonin 5-HT2C receptor
knockout mice or with serotonin 5-HT2C receptor antagonism. This increased locomotor activity could be blocked by a serotonin
5-HT1B receptor antagonist. In contrast to fenfluramine and mCPP, the SSRI fluoxetine has no impact on locomotor activity alone or in combination with SB-242084. Moreover, this effect appears to be serotonin-dependent, as it can be blocked by pretreatment with SSRIs like fluoxetine (which prevent the serotonin-releasing effects of SRAs). In terms of
reinforcing properties, MDMA produces dose-dependent CPP, MDAI produces CPP, MBDB produces weak CPP, fenfluramine produces
conditioned place aversion (CPA), and MMAI has no effect on place conditioning at lower doses but produces CPA similarly to fenfluramine at high doses. mCPP had no effect on place conditioning, at least in one study. SSRIs have shown highly mixed effects on place conditioning, with fluoxetine producing CPP, zimelidine producing CPP or having no effect, and
citalopram producing CPA. Effects on
intracranial self-stimulation (ICSS) can be used to measure the reinforcing and misuse-related effects of drugs. ICSS is enhanced by amphetamine and is reduced by the serotonin 5-HT2C receptor agonist
Ro 60-0175, by the SRA and serotonin 5-HT2C receptor agonist fenfluramine, and by the
κ-opioid receptor agonist
U-69,593 in rats. These findings suggest that serotonin 5-HT2C receptor activation plays a major role in the anti-reinforcing effects of SRAs, but that other serotonin receptors may also be involved. The psychedelic effects of fenfluramine may be mediated by direct serotonin 5-HT2A receptor agonism, as other SRAs like
MDMA, PCA, and
chlorphentermine have been reported not to produce the head-twitch response in animals chlorphentermine shows very weak or negligible activity at the serotonin 5-HT2 receptors, In conflict with the preceding findings however, PCA has been reported to robustly induce the head-twitch response in animals in other studies, and this appeared to be dependent on induction of serotonin release as opposed to direct serotonin 5-HT2A receptor agonism, since it could be largely blocked by an SRI or by serotonin synthesis inhibitor.
Antidepressant-like effects SSRIs like fluoxetine, as well as non-selective SRIs, are used and claimed to be clinically effective in the treatment of
depression. SRAs produce far more robust of increases in serotonin levels than SRIs. In addition to its antidepressant-like effects, MMAI has shown
anxiolytic-like effects in animals.
α-methyltryptamine (αMT), which was previously marketed in the
Soviet Union under the brand name Indopan; fenfluramine, which has been clinically studied for depression but was never approved for this use; ==Examples and use of SRAs==