The neurobiology of mental disorders: neurotransmitters and circuits

Theory

Mental disorders involve brain chemicals (dopamine, serotonin, glutamate, GABA) and emotion and reward circuits; no single chemical explains them.

Updated Nov 13, 2026

Key points

Monoamine hypothesis of depression: low serotonin, norepinephrine and dopamine signalling; limits: antidepressants act only after a delay, many patients do not respond, and lowering monoamines does not reliably make healthy people depressed.
Dopamine hypothesis of schizophrenia: excess mesolimbic dopamine causes positive symptoms; low mesocortical dopamine contributes to negative and cognitive symptoms.
Antipsychotic D2 blockade: helps positive symptoms through the mesolimbic pathway, causes extrapyramidal symptoms and tardive dyskinesia through the motor (nigrostriatal) pathway, and raises prolactin.
Glutamate is the main excitatory transmitter and acts partly through NMDA receptors, which are dysregulated in depression; ketamine and esketamine can improve depression within hours.
GABA is the main inhibitory transmitter; benzodiazepines and barbiturates act at GABA-A receptors, where alcohol also binds.
HPA axis: chronic stress keeps cortisol high and weakens feedback, leaving the hippocampus and prefrontal cortex vulnerable; HPA overactivity is linked to melancholic depression.

What it is

Biological psychiatry studies how neurotransmitters, stress hormones and brain circuits contribute to mental disorders. The first theories came from medicines: drugs that raise monoamines lift depression, and drugs that block dopamine D2 receptors calm psychosis. These monoamine and dopamine hypotheses remain useful for understanding treatment but are incomplete. Current models add glutamate and the NMDA receptor, GABA, the HPA stress axis, inflammation and neuroplasticity, and they see disorders as problems of circuits linking the prefrontal cortex, limbic system and striatum.

Function

Serotonin: raphe nuclei; linked to depression and anxiety and their treatment; target of SSRIs.
Norepinephrine: locus coeruleus; one of the monoamines linked to depression.
Dopamine: ventral tegmental area and substantia nigra; reward, motivation, movement and hormone (prolactin) control.
Glutamate: main excitatory transmitter; synaptic plasticity, partly through NMDA receptors.
GABA: main inhibitory transmitter; benzodiazepines act at its GABA-A receptors.
Acetylcholine: basal nucleus of Meynert; helps form new memories and is reduced in Alzheimer disease.

The four dopamine pathways: role, symptoms and antipsychotic effects

Pathway	From and to	Normal role	In schizophrenia	Effect of D2 blockade
Mesolimbic	Ventral tegmental area to nucleus accumbens	Reward, motivation, salience	Too much dopamine: hallucinations and delusions	Reduces positive symptoms (the intended effect)
Mesocortical	Ventral tegmental area to prefrontal cortex	Planning, working memory, motivation	Too little dopamine: negative and cognitive symptoms	May worsen apathy and cognition
Nigrostriatal	Substantia nigra to dorsal striatum	Movement control	Not primarily affected	Extrapyramidal symptoms and tardive dyskinesia
Tuberoinfundibular	Hypothalamus to pituitary	Controls prolactin release	Not primarily affected	Raised prolactin

Clinical notes

Second-generation antipsychotics also act on serotonin receptors, which contributes to their low risk of movement side effects; 5-HT2A blockade can raise dopamine in the prefrontal cortex.
Parkinson disease shows the motor role of dopamine: losing dopamine neurons in the substantia nigra causes its movement symptoms.
Cortico-limbic circuits (amygdala, cingulate and prefrontal cortex) carry the fear, mood and reward functions that therapies and medicines change.
No neurotransmitter test diagnoses a mental disorder; biomarkers remain at the research stage.

Test yourself

Think of the answer, then tap the question to see it.

What are two limits of the monoamine hypothesis of depression?

Antidepressants work only after a delay, many patients do not respond, and depleting monoamines does not reliably cause depression in healthy people.

Which dopamine pathway explains antipsychotic-induced high prolactin?

The tuberoinfundibular pathway, from hypothalamus to pituitary, where dopamine normally controls prolactin release; D2 blockade raises prolactin.

Which receptor do benzodiazepines act on?

The GABA-A receptor, part of the brain's main inhibitory system; barbiturates act there too.

Which pathway causes extrapyramidal side effects when D2 receptors are blocked?

The nigrostriatal pathway, from substantia nigra to dorsal striatum.

Add to my cards (4)

Elsewhere in DurgiPedia

Connections

In Pharmacology6

← All of behavioral science

Educational content on behavior and the clinical relationship; not a diagnostic or treatment guide and no substitute for assessment by a health professional. If you or someone near you is at risk, seek help now from an emergency service or a mental-health helpline.

Sources: Dopamine: Functions, Signaling, and Association with Neurological Diseases (Cellular and Molecular Neurobiology (PubMed Central), 2019); The Monoamine–Glutamate Continuum of Depression: A Neurobiological Framework for Precision Psychiatry (Pharmaceuticals (PubMed Central), 2026); Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future (Current Topics in Medicinal Chemistry (PubMed Central), 2016); Neurotransmission (MSD Manual Professional Edition, 2025).

Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake

Representative model, for educational purposes only.