Synaptic Basics
Neurotransmitters are released at synapses, bind postsynaptic receptors, and are cleared by reuptake, enzymatic degradation, or diffusion. Psychiatric medications target these steps β they rarely "fix chemistry"; they modulate it.
| Class | Examples | Signaling |
|---|---|---|
| Monoamines | Serotonin, NE, DA, histamine | Slow, modulatory (G-protein coupled) |
| Amino acids | Glutamate (excitatory), GABA & glycine (inhibitory) | Fast (ligand-gated ion channels) + slow metabotropic |
| Acetylcholine | ACh | Fast (nicotinic) + slow (muscarinic) |
| Neuropeptides | Endorphins, substance P, CRH, oxytocin | Slow, modulatory |
Serotonin (5-HT)
Produced by the raphe nuclei in the brainstem; projects diffusely throughout the brain. Synthesized from tryptophan. ~90% of body's serotonin is actually in the gut (enterochromaffin cells).
Functions
- Mood regulation, well-being
- Sleep (precursor to melatonin)
- Appetite / satiety
- Sexual function
- GI motility, platelet aggregation
Receptors Relevant to Psychiatry
| Receptor | Effect | Clinical Relevance |
|---|---|---|
| 5-HT1A | Inhibitory autoreceptor; postsynaptic anxiolytic | Buspirone (partial agonist) β anxiolytic without sedation or dependence |
| 5-HT2A | Excitatory; mediates hallucinations | Blocked by atypical antipsychotics; target of psychedelics (psilocybin, LSD) |
| 5-HT2C | Satiety, mood | Blocked by mirtazapine β appetite β |
| 5-HT3 | Ligand-gated ion channel; nausea | Blocked by ondansetron; SSRI activation causes N/V early |
Clinical Correlations
- β in depression, anxiety, OCD, PTSD, bulimia, premenstrual dysphoria
- SSRIs block SERT (reuptake transporter) β β synaptic 5-HT
- Serotonin syndrome: hyperthermia, clonus, hyperreflexia, agitation (combining SSRIs + MAOIs, tramadol, linezolid, triptans, St. John's wort, etc.)
π₯ Serotonin Syndrome TriadAutonomic instability (hyperthermia, tachycardia, diaphoresis) + neuromuscular excitability (clonus, hyperreflexia, rigidity β worse in lower extremities) + altered mental status (agitation, confusion). Tx: stop offending agents, supportive care, cyproheptadine in severe cases.
Norepinephrine (NE)
Produced by the locus coeruleus (pons). Mediates arousal, attention, and fight-or-flight.
Functions
- Arousal, vigilance, alertness
- Stress response (panic attacks = locus coeruleus firing)
- Attention and working memory
- Mood
Receptors
- Ξ±1 β vasoconstriction (prazosin for PTSD nightmares, antipsychotic orthostasis)
- Ξ±2 β presynaptic autoreceptor (clonidine, guanfacine β β NE; used for ADHD, anxiety, withdrawal)
- Ξ² β HR/BP, anxiety tremor (propranolol for performance anxiety)
Clinical Correlations
- β in anxiety, panic, PTSD, mania
- β in depression, ADHD
- SNRIs (venlafaxine, duloxetine) block NET + SERT
- Atomoxetine (ADHD) is a selective NE reuptake inhibitor
Dopamine (DA)
Synthesized from tyrosine. Four major pathways (see Neuroanatomy page). The rate-limiting enzyme is tyrosine hydroxylase.
Receptors
- D1-like (D1, D5) β excitatory (Gs)
- D2-like (D2, D3, D4) β inhibitory (Gi). Antipsychotics act here.
Clinical Correlations
| State | Dopamine | Clinical |
|---|---|---|
| β mesolimbic | High | Positive psychotic sx (delusions, hallucinations), addiction, mania |
| β mesocortical | Low | Negative sx (flat affect, avolition), cognitive deficits |
| β nigrostriatal | Low | Parkinsonism β either disease or drug-induced (EPS) |
| β tuberoinfundibular | Low | Prolactin β β galactorrhea, amenorrhea, gynecomastia |
π― Board PearlThe "dopamine hypothesis" of schizophrenia: too much DA in mesolimbic pathway β positive symptoms; too little in mesocortical pathway β negative symptoms. That's why typical D2 blockers help positive sx but can worsen negative sx, while atypicals (with 5-HT2A blockade) address both.
GABA β The Inhibitor
The main inhibitory neurotransmitter in the CNS. Synthesized from glutamate by glutamic acid decarboxylase (GAD), a B6-dependent enzyme.
Receptors
- GABA-A β ligand-gated Clβ» channel. Modulated by benzodiazepines, barbiturates, alcohol, z-drugs, propofol. Benzos β frequency of channel opening; barbs β duration.
- GABA-B β GPCR (KβΊ efflux). Target of baclofen.
Clinical Correlations
- β GABA β anxiety, seizures, insomnia, alcohol withdrawal
- Benzodiazepine withdrawal β seizures, delirium (like alcohol withdrawal)
- Vitamin B6 deficiency β β GAD β seizures (classic: INH toxicity)
π§ Mnemonic"Barbs duration, Benzos frequency" β Barbiturates increase duration of GABA-A Clβ» channel opening; Benzodiazepines increase frequency. That's why barbs are more dangerous (they can open the channel without GABA bound); benzos cannot.
Glutamate β The Excitator
The main excitatory neurotransmitter. Essential for learning, memory, and synaptic plasticity (LTP).
Receptors
- AMPA β fast NaβΊ influx
- NMDA β CaΒ²βΊ influx, requires glycine co-agonist + membrane depolarization; central to LTP
- Kainate β NaβΊ influx
- mGluR β metabotropic
Clinical Correlations
- Excitotoxicity β excess glutamate β CaΒ²βΊ influx β neuronal death (stroke, TBI, ALS)
- NMDA hypofunction hypothesis of schizophrenia (PCP and ketamine β NMDA antagonists β produce schizophrenia-like symptoms)
- Ketamine / esketamine (NMDA antagonist) β rapid antidepressant for treatment-resistant depression (within hours vs. weeks for SSRIs)
- Memantine β NMDA antagonist for Alzheimer's
Acetylcholine (ACh)
Two main CNS sources: basal nucleus of Meynert (cortex, memory) and pedunculopontine nucleus (arousal, REM sleep).
- β in Alzheimer's β cholinesterase inhibitors (donepezil, rivastigmine, galantamine)
- Anticholinergic toxicity: "Hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter" β elderly especially sensitive
- Many psych meds have anticholinergic side effects: TCAs, low-potency antipsychotics, diphenhydramine, benztropine (used to treat EPS)
Histamine
Hypothalamic nuclei project widely. H1 receptor β wakefulness. H1 blockade = sedation + weight gain.
- Many psych meds are potent H1 antagonists β sedation + weight gain: mirtazapine, quetiapine, olanzapine, low-potency typicals
- Used therapeutically: hydroxyzine for anxiety, diphenhydramine for insomnia
Neuropeptides
| Peptide | Psych Relevance |
|---|---|
| CRH | Drives HPA axis; β in depression, PTSD |
| Oxytocin | Social bonding, trust; studied in autism & social anxiety |
| Endogenous opioids | Pleasure, analgesia; naltrexone blocks to reduce alcohol/opioid cravings |
| Substance P | Pain, mood; NK1 antagonists studied for depression |
| Orexin / hypocretin | Wakefulness; deficient in narcolepsy; suvorexant (dual orexin antagonist) for insomnia |
Sleep Architecture
Sleep disturbance is both a symptom and a driver of psychiatric illness.
Stages (per 90-min cycle)
- N1 (~5%) β light sleep, theta waves
- N2 (~45%) β sleep spindles & K-complexes
- N3 (~25%) β slow-wave / delta; restorative, parasomnias occur here (sleepwalking, night terrors, bedwetting)
- REM (~25%) β dreams, muscle atonia, β sympathetic, β ACh. Erections/vaginal engorgement. Nightmares occur here.
Psychiatric Sleep Findings
- Depression: β REM latency, β REM density, early morning awakening, β N3
- Mania: β total sleep need without fatigue
- PTSD: nightmares (REM) β prazosin reduces them
- Narcolepsy: sleep-onset REM, cataplexy (loss of atonia regulation)
π― Board PearlREM sleep behavior disorder (RBD) β loss of REM atonia, patient acts out dreams β is a strong prodrome of Parkinson's / Lewy body dementia. Refer to neurology; screen for synucleinopathy.