Semax and neurotransmitters: dopamine, serotonin, and others

Semax wpływa na neuroprzekaźniki takie jak dopamina, noradrenalina i serotonina.

Semax acts on multiple neurotransmitter systems simultaneously. Documented effects include influences on serotonin, dopamine, GABA, glycine, acetylcholine, and norepinephrine, making it one of the most broadly acting synthetic peptides studied in modern neuroscience. Neurotransmitters are the chemical substances by which nerve cells communicate with each other. Each of them performs a different function – regulating mood, memory, movement, stress responses, and overall brain function.

Semax stands out due to its mode of action. It does not directly activate or block a single specific receptor, unlike most conventional drugs. It acts as a neuromodulator – meticulously regulating the sensitivity of existing neurotransmitter systems without overwhelming them with artificial signals. This can be compared to a dimmer switch rather than a simple on/off switch.

It is this ability for fine-tuning that is considered the basis of Semax's favourable safety profile, as well as its broad neuroprotective and cognitive action. The available scientific evidence primarily comes from animal studies, with a limited but promising number of clinical data from human trials. The involvement of individual neurotransmitter systems in the overall profile of Semax's action remains an active area of research.

Does Semax affect dopamine?

Semax affects the dopaminergic system, however, its action is indirect and modulatory – not direct or constant. Dopamine is a neurotransmitter closely linked to motivation, reward, movement and the brain's reaction to pleasurable experiences.

Under normal resting conditions, Semax administered alone does not significantly alter dopamine levels in either brain tissue or extracellular fluid. It also does not affect the levels of the two main dopamine breakdown products – DOPAC and HVA – in the striatum, the area of the brain responsible for movement and reward processing [1].

However, the situation changes when Semax is administered before a substance that activates the dopaminergic system. In microdialysis studies – a technique involving the implantation of a miniature probe into the brain to measure the composition of brain fluid in real-time – Semax administered 20 minutes before D-amphetamine caused significantly higher peak dopamine concentrations than amphetamine alone. Simultaneously, a more pronounced decrease in DOPAC levels was observed, indicating more intense dopamine release and utilisation [2].

The results of behavioural studies in mice confirmed these observations. The combination of Semax and D-amphetamine increased the animals’ motor activity to 261% of the baseline value, whilst amphetamine alone reached only 182% [2]. This confirms that Semax significantly enhances the dopamine system’s response to stimulation.

A simple analogy: Semax works like turning up the volume on a speaker. When music is playing, it sounds louder – but simply turning up the volume doesn't make the music start playing. The dopamine system becomes more reactive, but Semax doesn't cause the release of dopamine by itself.

This profile of action is consistent with the observation that Semax does not appear to induce addictive behaviours or lead to an increasing dependence of the dopaminergic system on its presence. The exact mechanism of this reinforcing effect has not yet been fully elucidated. Researchers suggest that it may involve melanocortin receptors influencing the excitability of dopaminergic neurons, or indirect effects via the serotonergic system, which regulates dopaminergic circuitry.

All current data regarding Semax and dopamine comes exclusively from animal studies. There is currently no direct evidence from human studies.

Does Semax affect serotonin?

Semax exerts measurable and repeatable effects on the serotonin system, with a particularly pronounced increase in serotonergic activity in the striatum. Serotonin is a neurotransmitter responsible for regulating mood, anxiety, sleep, and emotional well-being.

In rat striatal tissue, Semax administered at a dose of 0.15 mg/kg by intraperitoneal injection caused a significant increase in tissue levels of 5-HIAA of approximately 25% two hours after administration [1]. 5-HIAA is the main breakdown product of serotonin – higher levels of it indicate more intense production and consumption of serotonin.

Real-time measurements using microdialysis revealed an even more pronounced effect. Extracellular levels of 5-HIAA in the fluid surrounding brain cells rose gradually to approximately 180% of the baseline value within 1–4 hours after administration of Semax [1]. This sustained increase suggests that Semax enhances the release and metabolism of serotonin in this area of the brain, rather than merely slowing its clearance.

Serotonergic effects may partially explain the documented anxiolytic and antidepressant properties of Semax. In animal studies, chronic administration of Semax for 10–14 days induced behavioural changes in rats indicative of reduced anxiety and antidepressant-like effects. Researchers attributed this at least partly to the activation of the serotonergic system and increased production of BDNF in the hippocampus [3].

Furthermore, in a model where newborn rats were exposed to fluvoxamine – an SSRI drug that alters serotonin processing during early brain development – Semax administration reduced anxiety-like behaviours, improved learning abilities, and normalised disturbed brain chemical levels in the affected animals [4]. This suggests that Semax may help restore serotonin system balance when it has been disrupted during critical developmental periods.

The precise receptor mechanisms underlying this normalisation are not yet fully understood. All available data on the serotonergic action of Semax come from animal studies.

Does Semax affect GABA?

Semax directly modulates the GABAergic system – one of the main inhibitory neurotransmitter systems in the brain. GABA, or gamma-aminobutyric acid, is the brain's primary inhibitory neurotransmitter. It reduces nerve cell activity and helps maintain a state of calm and balance.

Evidence for Semax's action on GABA comes from two types of studies: electrophysiological, which measure the actual electrical activity of nerve cells, and radioligand binding studies, where radioactively labelled molecules allow us to determine where and how the substance binds to receptors.

In electrophysiological experiments on isolated rat brain neurons, Semax at a concentration of 1 micromole increased the GABA-evoked electrical currents in cerebellar Purkinje cells to approximately 147% of their normal level [5]. Purkinje cells are specialised nerve cells in the cerebellum – the part of the brain responsible for motor coordination and balance. The potentiating effect developed gradually and did not subside readily after Semax was removed from the preparation. This suggests a mechanism of action via intracellular signalling pathways, known as second-messenger systems, rather than through the direct opening of GABA-gated ion channels.

Radioligand binding studies have confirmed that Semax affects both high- and low-affinity binding sites for GABA on rat neuronal membranes. The effects were dose-dependent and differed depending on the specific binding site and whether the animal was under stress [6]. Under acute immobilization stress conditions, prior administration of Semax modified the stress-induced changes in GABA receptor binding, though it did not prevent them entirely [6].

It is worth noting that other synthetic peptides structurally related to Semax – including ACTH(6-9)PGP and ACTH(7-10)PGP – have also demonstrated activity at GABA receptors. This suggests that the ability to modulate the GABAergic system is a common feature of the entire class of ACTH-derived peptides, rather than a phenomenon exclusively characteristic of Semax [6].

GABAergic effects likely contribute to Semax's anxiolytic properties and its ability to protect brain cells during excitotoxic damage – a type of damage caused by excessive stimulation of neurons. However, this relationship requires further direct investigation. All data concerning GABA come from studies on animals and laboratory cell cultures.

Does Semax affect glycine?

Semax inhibits glycinergic neurotransmission in specific brain regions – which is an important complement to its potentiating effect on the GABAergic system. Glycine is another inhibitory neurotransmitter which, like GABA, reduces the activity of nerve cells, but it acts via different receptors and is particularly active in the hippocampus and spinal cord.

In the same electrophysiological study in which GABA currents were analysed, Semax at concentrations of 0.1 and 1 micromole reduced the amplitude of glycine-activated chloride currents in hippocampal pyramidal neurons – the brain’s main memory centre – to approximately 68% and 43% of their normal levels, respectively [5]. The effect was concentration-dependent: the higher the concentration of Semax, the greater the inhibition of glycine receptor activity.

Similar to the action on GABA, the inhibition developed slowly and was difficult to reverse, again pointing towards a second messenger-based mechanism rather than direct receptor blockade.

The fact that Semax simultaneously increases GABA activity in one brain region and inhibits glycine activity in another indicates a complex, regionally specific regulatory role. Instead of globally inhibiting or exciting the brain, Semax adjusts the balance of inhibitory neurotransmission depending on the area in which it acts. This may contribute to its specific effects on neuronal excitability and synaptic plasticity – the brain's ability to strengthen and weaken connections between nerve cells.

These results are based solely on electrophysiological data from isolated rat neurons.

Does Semax affect acetylcholine?

Semax modulates the cholinergic system – both through direct interaction with receptors and indirectly by influencing the survival of acetylcholine-producing neurons. Acetylcholine plays a crucial role in learning, memory, attention, and muscle control. It is also the neurotransmitter most affected in the course of Alzheimer's disease.

Radioligand binding studies using radioactively labelled acetylcholine confirmed that Semax modulates the binding of acetylcholine receptors in rat brain preparations in a dose-dependent manner [6]. At the cellular level, Semax increased the survival of cholinergic neurons in the basal forebrain – a group of nerve cells that produce acetylcholine, which are crucial for memory and attention – in primary cultures by about 1.5 to 1.7 times [7]. It also stimulated the activity of choline acetyltransferase – the enzyme responsible for the synthesis of acetylcholine within neurons – in basal forebrain tissue cultures at a concentration of 100 nanomolar [7]. Importantly, these effects were selective: Semax did not affect the total number of GABAergic neurons or other nerve cells in the same cultures, suggesting a specific targeting of cholinergic neurons.

Electrophysiological studies provided additional information. The inhibitory effect of Semax on the electrical activity of the cerebral cortex neurons in cats was associated with the stimulation of M-cholinergic receptors, also known as muscarinic receptors, in over half of the cases studied [8]. This suggests that muscarinic receptor activation plays a significant role in the neuromodulatory action of Semax at the cerebral cortex level.

The ability of Semax to support the survival of cholinergic neurons, increase acetylcholine synthesis, and modulate muscarinic receptors allows its cholinergic action to be considered a potentially important component of its procognitive effect – particularly in states of cholinergic deficiency. All available data originate solely from animal and cell culture studies.

Does Semax affect norepinephrine?

Evidence for Semax's effect on norepinephrine – also known as noradrenaline – is more limited and largely indirect compared to its impact on other neurotransmitter systems. Norepinephrine regulates alertness, attention, stress response, and blood pressure.

Early studies on the structural precursor of Semax – the ACTH(4-7)-Pro-Gly-Pro analogue – showed that its administration lowered noradrenaline content in the cerebral cortex and other brain areas. It also normalised the usually asymmetrical distribution of noradrenaline between the right and left hemispheres, without significantly affecting serotonin distribution [9]. In studies following resuscitation from haemorrhagic shock – a life-threatening condition caused by severe blood loss – intravenous Semax affected the dynamics of biogenic amines in the brainstem and spleen during the recovery period. In these studies, the effects on the serotonin system were more pronounced than on the catecholaminergic systems, which include both norepinephrine and dopamine [10].

Research into prenatal hypoxia has shown that a lack of oxygen before birth disrupts the development of the noradrenergic and dopaminergic systems in the brains of newborns. Nasal administration of Semax to pregnant females prevented these disruptions in postnatal offspring catecholamine levels in the central nervous system [11].

The available data suggest that Semax affects noradrenergic system activity – particularly under conditions of stress, hypoxia, or other pathological challenges. However, these effects are less direct and less consistently documented than its serotonergic or GABAergic actions. To date, no studies have directly measured extracellular norepinephrine concentrations in response to Semax using microdialysis or similar real-time measurement techniques, representing a significant gap in the current evidence base. All available data come from animal studies.

Does Semax affect cortisol and the HPA axis?

Semax does not stimulate cortisol production and is classified as a non-hormonal peptide – it does not exhibit steroidogenic activity of its parent hormone, ACTH. Early pharmacological studies confirmed that, unlike ACTH(5-10), the ACTH(4-7)-PGP analogue did not exhibit steroidogenic or melanocyte-stimulating activity, which formed the basis for its non-hormonal classification from the outset of its development [12].

Instead of activating the HPA axis – the central stress hormone system, running from the hypothalamus via the pituitary gland to the adrenal glands – Semax appears to suppress its excessive activity under conditions of chronic stress. In a model of chronic unpredictable stress in male rats, Semax treatment reversed stress-induced adrenal hypertrophy – an abnormal enlargement of these glands, which is a reliable physical indicator of chronic HPA axis overactivity [13]. At the same time, Semax also reversed anhedonia, i.e. the loss of the ability to feel pleasure, inhibited body weight gain, and reduced hippocampal BDNF levels – all induced by chronic stress [13].

At the hypothalamic level – the area of the brain that initiates the cascade of stress hormones – administration of Semax prior to stress exposure reduced c-Fos expression in the paraventricular nucleus of the hypothalamus in stress-susceptible rats [14]. C-Fos is a protein used as a biological marker of cell activation. Lower levels of c-Fos in this area indicate a weaker activation of the hypothalamus in response to stress stimuli.

In the social stress model, Semax also demonstrated anti-inflammatory effects on the immune system: it lowered the concentrations of pro-inflammatory signalling proteins IL-1β and IL-6, restored IL-4 levels, and inhibited the activity of TGF-β1 and TNF-α [15]. This profile is consistent with the substance reducing, rather than exacerbating, stress-induced activation of the HPA axis and immune system.

Studies support this, where rats subjected to immobilisation stress and administered Semax at doses of 50 and 150 micrograms per kilogram of body weight showed lower serum corticosterone levels – corticosterone is the rodent equivalent of human cortisol – and reduced stress-induced structural damage to the colon wall [16]. Data from human studies regarding these effects on the HPA axis remains limited to indirect clinical observations.

How does Semax modulate multiple neurotransmitter systems simultaneously?

Semax affects multiple neurotransmitter systems simultaneously through three interconnected mechanisms: direct interactions with receptors, indirect effects via BDNF and neurotrophin signalling, and broad regulation of neurotransmission-related gene expression. One of the most intriguing questions about this peptide is how one small molecule can act on so many systems at once.

At the gene expression level, RNA sequencing analysis in a rat stroke model revealed that Semax reactivated genes associated with neurotransmission, which were downregulated by ischemia-reperfusion – damage occurring after blood flow to brain tissue is cut off and then restored. Semax effectively restored the expression patterns of these genes to a level comparable to healthy tissue [17].

Under conditions of acute stress, the administration of Semax induced changes in the activity of over 1500 genes in the hippocampus. Both Semax and the related peptide ACTH(6-9)PGP elevated the activity of stress-downregulated genes and reduced the activity of stress-upregulated genes [18]. This represents a broad, systemic correction of neurotransmission patterns disrupted by stress.

The concept of a synthon helps to explain this multisystemic reach. A synthon is Semax along with its active breakdown products - HFPGP and PGP - acting as an integrated regulatory complex. Each of the components interacts with distinct, yet partially overlapping, binding sites on nerve cell membranes [19]. Together, they exert a broader pharmacological effect than what any one of the fragments could achieve on its own. This multi-target action is characteristic of natural brain regulatory peptides and distinguishes Semax from conventional drugs with a single therapeutic target.

Understanding how all these effects integrate and interact in humans remains an important priority for future clinical research.

Disclaimer

This article is for educational and informational-scientific purposes only and should not be interpreted as medical advice, diagnosis, therapeutic recommendation, or a claim regarding the efficacy of Semax in treating any condition. Semax remains an investigational compound in most countries, including the United States and most European countries, and is not approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of any medical condition. It is approved and used clinically in Russia and some Eastern European countries. Most of the evidence presented in this article is derived from preclinical animal studies and a limited number of human clinical trials, many of which originate from Russian-language scientific literature. Additional, well-designed clinical trials are necessary to more accurately establish the safety, efficacy, mechanisms of action, and long-term effects of Semax in humans.