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Serotonin releasing agent
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Serotonin releasing agent
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.
SRAs, for instance fenfluramine, dexfenfluramine, and chlorphentermine, have been used clinically as appetite suppressants. However, these SRAs were withdrawn from the market due to toxicity in the 1990s and no SRAs were available or employable for clinical study for many years. In any case, a low-dose formulation was reintroduced for treatment of Dravet syndrome in 2020 and this allowed clinical and research use of SRAs in humans once again.
Aside from use as appetite suppressants, SSRAs have been proposed as novel antidepressants and anxiolytics, with the potential for a faster onset of action and superior effectiveness relative to the selective serotonin reuptake inhibitors (SSRIs).
A closely related type of drug is a serotonin reuptake inhibitor (SRI), for instance fluoxetine.
A number of somewhat selective SRAs have been well-studied, for instance fenfluramine and meta-chlorophenylpiperazine (mCPP). Although fenfluramine and mCPP are efficacious SRAs, they are also highly potent agonists of serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and particularly 5-HT2C receptors. 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. Similarly, mCPP is an extremely potent agonist of the serotonin 5-HT2C receptor and produces robust effects thought to be 5-HT2C receptor-mediated in in animals and humans, such as anxiety and panic. In addition to serotonin receptor agonism, fenfluramine is also a norepinephrine releasing agent with several-fold lower potency compared to serotonin release. 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.
The 2-aminoindane MMAI, and certain cathinones, have increased selectivity for serotonin release compaired 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. 4-Methylthioamphetamine (4-MTA) was originally described as a selective SRA, 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. Whereas the SSRI fluoxetine can increase serotonin levels in the hypothalamus in rats by up to 4-fold, the SRA dexfenfluramine can increase serotonin levels as much as 9- to 16-fold or more. Relatedly, genetic ablation of the serotonin transporter (SERT), which results in complete loss of SERT-mediated serotonin reuptake, is associated with 4- to 6-fold elevations in brain serotonin levels. 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.
Certain SRAs, such as fenfluramine and chlorphentermine, do not produce locomotor activation (a stimulant-like effect) in animals. Moreover, fenfluramine robustly inhibits the locomotor hyperactivity and rewarding effects induced by psychostimulants like amphetamine and phentermine. Whereas amphetamine and phentermine produce strong locomotor stimulation in rodents, combination of fenfluramine and phentermine results in only weak locomotor activation and substantial reduction in conditioned place preference (CPP). Fenfluramine also suppresses the subjective effects and positive mood effects of amphetamine and phentermine in humans.
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Serotonin releasing agent
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.
SRAs, for instance fenfluramine, dexfenfluramine, and chlorphentermine, have been used clinically as appetite suppressants. However, these SRAs were withdrawn from the market due to toxicity in the 1990s and no SRAs were available or employable for clinical study for many years. In any case, a low-dose formulation was reintroduced for treatment of Dravet syndrome in 2020 and this allowed clinical and research use of SRAs in humans once again.
Aside from use as appetite suppressants, SSRAs have been proposed as novel antidepressants and anxiolytics, with the potential for a faster onset of action and superior effectiveness relative to the selective serotonin reuptake inhibitors (SSRIs).
A closely related type of drug is a serotonin reuptake inhibitor (SRI), for instance fluoxetine.
A number of somewhat selective SRAs have been well-studied, for instance fenfluramine and meta-chlorophenylpiperazine (mCPP). Although fenfluramine and mCPP are efficacious SRAs, they are also highly potent agonists of serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and particularly 5-HT2C receptors. 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. Similarly, mCPP is an extremely potent agonist of the serotonin 5-HT2C receptor and produces robust effects thought to be 5-HT2C receptor-mediated in in animals and humans, such as anxiety and panic. In addition to serotonin receptor agonism, fenfluramine is also a norepinephrine releasing agent with several-fold lower potency compared to serotonin release. 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.
The 2-aminoindane MMAI, and certain cathinones, have increased selectivity for serotonin release compaired 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. 4-Methylthioamphetamine (4-MTA) was originally described as a selective SRA, 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. Whereas the SSRI fluoxetine can increase serotonin levels in the hypothalamus in rats by up to 4-fold, the SRA dexfenfluramine can increase serotonin levels as much as 9- to 16-fold or more. Relatedly, genetic ablation of the serotonin transporter (SERT), which results in complete loss of SERT-mediated serotonin reuptake, is associated with 4- to 6-fold elevations in brain serotonin levels. 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.
Certain SRAs, such as fenfluramine and chlorphentermine, do not produce locomotor activation (a stimulant-like effect) in animals. Moreover, fenfluramine robustly inhibits the locomotor hyperactivity and rewarding effects induced by psychostimulants like amphetamine and phentermine. Whereas amphetamine and phentermine produce strong locomotor stimulation in rodents, combination of fenfluramine and phentermine results in only weak locomotor activation and substantial reduction in conditioned place preference (CPP). Fenfluramine also suppresses the subjective effects and positive mood effects of amphetamine and phentermine in humans.
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