4.3.2 Mechanisms of action of major psychotropic/psychoactive drug classes

Putative Mechanisms of Action of Major Psychotropic/Psychoactive Classes (‘Target’ Actions) at Molecular and Systems Levels

The mechanisms of action of major psychotropic/psychoactive classes are complex and involve multiple levels of regulation. At the molecular level, the effects of these drugs are mediated by interactions with specific receptors, enzymes, and intracellular signalling pathways. At the systems level, these drugs alter the functioning of neural circuits that regulate mood, perception, and behaviour.

Antipsychotics:

Antipsychotics are a class of drugs that work by modulating the activity of neurotransmitters in the brain, particularly dopamine.

At the molecular level, antipsychotics interact with dopamine receptors in the brain to reduce the overactivity of dopaminergic pathways. Dopamine is a neurotransmitter that plays a role in the regulation of mood, perception, and behaviour. Antipsychotics are thought to alleviate symptoms of psychosis by blocking dopamine receptors in the brain, reducing the overactivity of dopaminergic pathways.

Some antipsychotics also have an affinity for other receptors, such as serotonin receptors, which further modulate their effects on the brain. The exact mechanism of action of antipsychotics is still not fully understood and is the subject of ongoing research.

At the systems level, antipsychotics alter the functioning of neural circuits in the brain. These drugs modulate the activity of neurotransmitters and their receptors, which in turn modulate the activity of brain regions involved in mood regulation, perception, and behaviour.

In summary, antipsychotics modulate the activity of neurotransmitters in the brain, particularly dopamine, to reduce the overactivity of dopaminergic pathways and alleviate symptoms of psychosis. The exact mechanisms of action of antipsychotics are complex and the subject of ongoing research. Understanding these mechanisms is critical for the development of new and more effective treatments for mental health disorders (Seeman, 2002).

Antidepressants:

At the molecular level, antidepressants target specific receptors and enzymes, such as the serotonin transporter (SERT) and monoamine oxidase (MAO), involved in the regulation of neurotransmitter levels. These target actions result in changes in neurotransmitter levels in the synaptic cleft, leading to changes in neuronal signalling and ultimately affecting mood and behaviour.

At the systems level, antidepressants can impact the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response, which are involved in the regulation of stress and emotional responses. Antidepressants also affect brain plasticity, including neurogenesis, dendritic branching, and synaptic connectivity, which may contribute to their therapeutic effects.

The putative mechanisms of action of antidepressants are complex and involve a number of molecular and systems-level processes. Antidepressants are believed to modulate the levels of neurotransmitters, such as serotonin and norepinephrine, in the brain, which in turn leads to changes in mood, energy, and overall well-being (Samuels, 2001).

There are several classes of antidepressants, each with a distinct mechanism of action.

1. Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs are the most commonly prescribed class of antidepressants. They work by selectively inhibiting the reuptake of serotonin, leading to an increase in the level of the neurotransmitter in the synaptic cleft.
2. Tricyclic Antidepressants (TCAs): TCAs are an older class of antidepressants that work by blocking the reuptake of both serotonin and norepinephrine, leading to increased levels of the neurotransmitters in the synaptic cleft.
3. Monoamine Oxidase Inhibitors (MAOIs): MAOIs are a class of antidepressants that work by inhibiting the metabolism of neurotransmitters, leading to increased levels in the synaptic cleft.
4. Atypical Antidepressants: This class of antidepressants includes drugs that do not fit into the above categories, such as mirtazapine, venlafaxine, and duloxetine, among others. These drugs have a range of mechanisms of action, including serotonergic, noradrenergic, and dopaminergic effects.
5. Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): NaSSAs are a class of antidepressants that work by blocking the alpha-2 adrenergic receptors, leading to increased norepinephrine release and improved mood.
6. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): SNRIs are a class of antidepressants that work by blocking the reuptake of both serotonin and norepinephrine, leading to increased levels of the neurotransmitters in the synaptic cleft.

Mood stabilisers:

The putative mechanisms of action of mood stabilizers involve the regulation of neurotransmitters and signalling pathways in the brain. At the molecular level, mood stabilizers target specific receptors and enzymes, such as the sodium-potassium ATPase pump and the voltage-gated ion channels, involved in the regulation of neurotransmitter levels and neuronal excitability.

At the systems level, mood stabilizers can impact the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response, which are involved in the regulation of stress and emotional responses. Mood stabilizers can also affect brain plasticity, including neurogenesis, dendritic branching, and synaptic connectivity, which may contribute to their therapeutic effects in mood disorders.

Mood stabilizers can also act on specific neurotransmitter systems, such as the glutamate and GABA systems, to regulate neuronal excitability and prevent excessive neurotransmitter release. Some mood stabilizers, such as lithium, can also impact intracellular signalling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, which play a role in mood regulation.

It is important to note that the exact mechanisms of action of mood stabilizers are still not fully understood and may vary depending on the class of mood stabilizer and the individual patient. However, the target actions described above represent the current understanding of the putative mechanisms of action of mood stabilizers at the molecular and systems levels (Berk, 2011).

Sedative hypnotics:

The putative mechanisms of action of sedative-hypnotics involve the modulation of neurotransmitter systems in the brain that regulate arousal, sleep, and consciousness. At the molecular level, sedative-hypnotics target specific receptors, such as the GABA-A receptor, to increase the affinity for GABA and enhance its inhibitory effects on neurotransmitter release.

At the systems level, sedative-hypnotics can impact the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response, which are involved in the regulation of stress and emotional responses. Sedative hypnotics can also affect the activity of the circadian rhythm, including the suprachiasmatic nucleus (SCN) and the pineal gland, to regulate the sleep-wake cycle.

Sedative hypnotics can also impact the activity of other neurotransmitter systems, such as the dopamine and noradrenergic systems, to regulate arousal and consciousness. Some sedative hypnotics, such as benzodiazepines, can also act on specific intracellular signalling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, to enhance their therapeutic effects.

It is important to note that the exact mechanisms of action of sedative-hypnotics are still not fully understood and may vary depending on the class of sedative-hypnotic and the individual patient. However, the target actions described above represent the current understanding of the putative mechanisms of action of sedative-hypnotics at the molecular and systems levels (Rattenborg, 2000).

Cognitive enhancers:

The putative mechanisms of action of cognitive enhancers, also known as nootropics, are diverse and complex. These drugs aim to improve cognitive functions, such as memory, attention, and executive function. The putative mechanisms of action of cognitive enhancers can be broadly classified into three categories: (1) neurotransmitter-based, (2) neuroplasticity-based, and (3) neuroprotective-based.

1. Neurotransmitter-based mechanisms involve the regulation of neurotransmitter levels, such as acetylcholine, dopamine, and norepinephrine, and their respective receptors. These drugs enhance the release and/or inhibit the reuptake of these neurotransmitters, leading to increased availability and improved synaptic transmission.
2. Neuroplasticity-based mechanisms focus on improving the capacity of the brain to change and adapt in response to environmental stimuli. This includes enhancing the formation of new synapses, promoting neurogenesis, and improving synaptic plasticity.
3. Neuroprotective-based mechanisms aim to protect neurons from damage and promote their survival. This includes reducing oxidative stress and inflammation and promoting the removal of neurotoxins.

These putative mechanisms of action at the molecular and systems levels are still being studied and are not fully understood. Nevertheless, the evidence suggests that cognitive enhancers have the potential to improve cognitive function in various ways (Sinha, 2017).

Opioids:

The mechanism of action of opioids at molecular and systems levels is complex and involves several neurotransmitter systems in the brain and spinal cord. Opioids bind to specific receptors, known as mu (μ), delta (δ), and kappa (κ) opioid receptors, located in the central nervous system (CNS). Activation of these receptors leads to changes in the release of neurotransmitters, such as dopamine and noradrenaline, which result in pain relief, sedation, and feelings of pleasure and euphoria.

At the molecular level, opioid binding to specific receptors results in the activation of intracellular signalling pathways that lead to changes in gene expression and protein synthesis. This can result in the inhibition of neurotransmitter release, or the activation of inhibitory neurotransmitter systems, such as the descending pain pathways.

At the systems level, opioids produce their effects through changes in the activity of various brain regions involved in pain processing, emotional regulation, and reward. For example, activation of the μ opioid receptor results in decreased activity in the pain-processing regions of the brain, as well as increased activity in the regions responsible for reward and reinforcement (Woolf, 2011).

Psychostimulants:

Psychostimulants are drugs that enhance the function of the central nervous system (CNS) leading to increased alertness, wakefulness, attention, and performance. They achieve this by modulating the release of various neurotransmitters and their actions in the brain.

At the molecular level, the mechanism of action of psychostimulants involves the blocking of the reuptake of monoamines such as dopamine, norepinephrine, and serotonin. This leads to an increase in the concentration of these neurotransmitters in the synaptic cleft, leading to greater stimulation of their respective receptors. For example, amphetamines increase the release of dopamine and norepinephrine, while cocaine blocks the reuptake of dopamine, leading to an increase in its concentration.

At the systems level, psychostimulants have been shown to activate the mesolimbic dopamine system, which is responsible for the regulation of motivation and reward. This activation leads to an increase in the release of dopamine in the nucleus accumbens, which is the primary reward centre in the brain. This release of dopamine is thought to be responsible for the euphoric effects of psychostimulants, as well as their reinforcing properties, which can lead to dependence and addiction.

The mechanisms of action of psychostimulants involve the modulation of neurotransmitter release and reuptake, leading to an increased concentration of neurotransmitters in the synaptic cleft and subsequent stimulation of their respective receptors. These actions lead to changes in brain function, including increased alertness, wakefulness, attention, and performance, as well as the regulation of motivation and reward (Volkow, 2003).

Cannabinoids:

The putative mechanisms of action of cannabinoids at the molecular and systems levels are largely due to the interaction of cannabinoids with specific receptors in the body, primarily the cannabinoid receptors CB1 and CB2. CB1 receptors are primarily expressed in the central nervous system, and activation of these receptors leads to effects such as pain relief, anxiety reduction, and euphoria. CB2 receptors are primarily expressed in immune cells and activation of these receptors results in anti-inflammatory effects.

The endocannabinoid system also plays a role in regulating the release of neurotransmitters such as dopamine, serotonin, and glutamate, which are involved in processes such as pain, mood, and appetite. Additionally, cannabinoids have been shown to modulate the activity of other receptor systems such as the opioid receptors, suggesting that their effects may be due to a complex interplay between multiple receptor systems. The putative mechanisms of action of cannabinoids at the molecular and systems levels are complex and not fully understood (Pertwee, 2008).

Hallucinogenics:

Hallucinogenics, also known as psychedelics, are a class of psychoactive substances that produce profound changes in perception, thought, and mood. These changes are thought to be due to the actions of these compounds on specific receptor systems in the brain, such as the serotonin 5-HT2A receptor. The exact mechanisms of action of hallucinogenics are still not well understood, but it is believed that they primarily affect the serotonergic system, which is involved in the regulation of mood, cognition, and perception.

Activation of 5-HT2A receptors by hallucinogenics is thought to cause changes in the way that neurons communicate with each other, leading to alterations in perception, thought, and mood. Additionally, some studies suggest that hallucinogenics may also affect other neurotransmitter systems, including dopamine and glutamate.

Despite significant advances in our understanding of the molecular and systems-level actions of hallucinogenics, much is still unknown about these compounds and how they produce their effects. Further research is needed to fully understand the mechanisms of action of hallucinogenics, and to determine their therapeutic potential for treating a range of psychiatric disorders (Schmidt, 2017).

Novel (new) psychoactive substances:

Novel psychoactive substances (NPS) refer to a diverse group of substances that have been synthesized or modified to produce mind-altering effects. These substances are often sold in the market as designer drugs, legal highs or research chemicals, and are used for their stimulant, hallucinogenic, or sedative properties. The putative mechanisms of action of NPS at the molecular and systems levels are not well understood, as they are frequently novel compounds that have not been thoroughly studied. However, they are thought to interact with various neurotransmitter systems such as the dopamine, serotonin, and glutamate systems, leading to changes in neurotransmitter release, reuptake, and signalling. This can result in changes in mood, perception, and behaviour. Further research is needed to understand the exact molecular and systems-level mechanisms of action of these substances (Harmon, 2017).

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