Neurochemistry examines the molecular mechanisms of neuronal function, neurotransmitter synthesis and signaling, and the biochemical basis of neurological and psychiatric disorders.

Neurotransmitter Synthesis

Acetylcholine is synthesized from choline and acetyl-CoA by choline acetyltransferase. It is released at the neuromuscular junction and in the central nervous system, where it regulates attention, memory, and arousal. Acetylcholinesterase rapidly hydrolyzes acetylcholine in the synaptic cleft. Organophosphate insecticides and nerve agents inhibit acetylcholinesterase, causing excessive cholinergic stimulation.

The catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine are synthesized from tyrosine. Tyrosine hydroxylase is the rate-limiting enzyme. Dopamine is involved in motor control, reward, and motivation. Dopamine neuron loss in the substantia nigra causes Parkinson disease. Antipsychotic drugs block dopamine D2 receptors. Norepinephrine regulates arousal, attention, and stress responses.

Serotonin is synthesized from tryptophan and regulates mood, appetite, sleep, and pain. Selective serotonin reuptake inhibitors are first-line antidepressants. Gamma-aminobutyric acid is the major inhibitory neurotransmitter, synthesized from glutamate. Glutamate is the major excitatory neurotransmitter, and excessive glutamatergic signaling causes excitotoxicity.

Synaptic Transmission

An action potential arriving at the presynaptic terminal opens voltage-gated calcium channels. Calcium influx triggers fusion of synaptic vesicles with the presynaptic membrane, releasing neurotransmitters into the synaptic cleft. SNARE proteins including synaptobrevin, SNAP-25, and syntaxin mediate vesicle fusion. Botulinum and tetanus toxins cleave SNARE proteins, blocking neurotransmitter release.

Released neurotransmitters bind to postsynaptic receptors. Ionotropic receptors such as AMPA glutamate receptors and nicotinic acetylcholine receptors are ligand-gated ion channels that directly alter membrane potential. Metabotropic receptors are GPCRs that activate second messenger systems. Neurotransmitter signaling is terminated by reuptake transporters or enzymatic degradation.

Parkinson Disease

Parkinson disease is characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein in Lewy bodies. The dopamine deficiency in the striatum causes the classic motor symptoms of bradykinesia, rigidity, rest tremor, and postural instability.

L-DOPA, the precursor of dopamine, remains the most effective symptomatic treatment. It crosses the blood-brain barrier, unlike dopamine itself, and is converted to dopamine by aromatic amino acid decarboxylase. Coadministration with carbidopa prevents peripheral conversion and reduces side effects. Deep brain stimulation of the subthalamic nucleus improves motor function in advanced disease.

Alzheimer Disease

Alzheimer disease is the most common cause of dementia, characterized by extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. The amyloid hypothesis proposes that A-beta accumulation initiates the disease process. A-beta is produced by cleavage of amyloid precursor protein by beta-secretase and gamma-secretase. Mutations in APP and presenilin genes cause early-onset familial Alzheimer disease.

Tau pathology correlates better with cognitive decline than amyloid burden. Hyperphosphorylated tau dissociates from microtubules and aggregates into paired helical filaments that form neurofibrillary tangles. Oxidative stress, neuroinflammation, and mitochondrial dysfunction contribute to neuronal loss. Current treatments provide symptomatic benefit but do not slow disease progression. Anti-amyloid antibodies such as lecanemab modestly slow cognitive decline.

Schizophrenia

Schizophrenia is a severe psychiatric disorder with positive symptoms, negative symptoms, and cognitive impairment. The dopamine hypothesis suggests that hyperactive mesolimbic dopamine transmission causes positive symptoms, while hypofrontal dopamine transmission contributes to negative and cognitive symptoms. Antipsychotics block D2 receptors, with efficacy related to D2 receptor occupancy.

Glutamate dysfunction also contributes to schizophrenia pathophysiology. NMDA receptor antagonists such as phencyclidine and ketamine produce schizophrenia-like symptoms. Abnormal NMDA receptor function on GABAergic interneurons may disinhibit cortical glutamate neurons, causing excitotoxicity and synaptic dysfunction.

Depression

Major depressive disorder is associated with alterations in monoamine neurotransmitter systems. The monoamine hypothesis proposes that serotonin, norepinephrine, and dopamine deficiencies cause depressive symptoms. Most antidepressants enhance monoamine signaling by inhibiting reuptake or degradation.

The neurotrophic hypothesis proposes that reduced brain-derived neurotrophic factor contributes to depression. Stress reduces BDNF expression in the hippocampus, while antidepressant treatment increases BDNF. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects through enhanced AMPA receptor signaling and BDNF release.

Stroke and Excitotoxicity

Ischemic stroke deprives neurons of oxygen and glucose, causing energy failure, loss of ion homeostasis, and membrane depolarization. Glutamate is released in excessive amounts, and impaired reuptake prolongs its presence in the synapse. Overactivation of NMDA receptors allows massive calcium influx.

Calcium overload activates proteases, lipases, and endonucleases that damage cellular structures. Reactive oxygen species are generated, and mitochondria undergo permeability transition. The combination of excitotoxicity, oxidative stress, and inflammation causes delayed neuronal death in the penumbra, the salvageable tissue surrounding the infarct core.