Neurochemistry
Introduction:
- In the resting state: intracellular = negative; during the action potential = positive
- Inhibitory NT’s make interior more negative (hyperpolarize)
- Excitatory depolarize
- Act on ligand-gated or votage-gated channels
- 3 types of ligand-gated channels: direct coupled, G PRO coupled, and 2nd messenger coupled
- G PRO neurotransmitter acts on it receptor protein, which then activates the G protein which activates the ion channel
- Second messenger activated by a 2nd messenger product of some physically removed NT receptor
Neurotransmitters
- Neurotransmitters
- Biogenic amines- Dopamine, NE, Epi, Ach Histamine, Serotonin
- Amino acids- GABA and glutamate
- Peptide NT’s
- Second messengers- cAMP, Ca, Inositol triphosphate
- Dopamine
- Cell bodies are located in the substantia nigra
- Pathways include nigrostriatal pathway, mesolimbic/mesocortical pathway and the tuberinfundibular tract
- Synthesized in the axon terminals
- Tyrosine is synthesized into 3,4 DOPA by tyrosine hydroxylase (rate limiting step)
- Either taken back into the axon by reuptake or catabolized by MAO-B and COMT (catechol-o-methytransferase)
- Norepinephrine
- Produced in the locus ceruleus in the pons
- Dopamine is synthesized into NE by Dopa β-hydroxylase
- NE is synthesized into Epi by phenyethanolamine N-methyltransferase
- Several different subtypes of alpha & beta receptors
- NE and Epi ↑ in mania, ↓ in depression
- Serotonin
- Produced in the median and dorsal raphe nuclei
- Projections are the most widely divergent of all NT’s
- Synthesized from tryptophan by the action of tryptophan hydroxylase
- Catabolized by MAO-A into 5-hydroxyindolacetic acid (5-HIAA)
- Up to 7 different serotonin receptors
- Buspar- anti-anxiety agent 5HT1A agonist
- Atypical antipsychotics are 5HT2 antagonists
- 5-HT3 antagonists are used to decrease nausea/vomiting during chemotherapy
- Involved in MOA of LSD & ecstasy (MDMA)
- °Permissive Hypothesis- low levels of serotonin permit abnormal levels of NE to cause depression/mania
- Acetylcholine
- Produced in the nucleus basalis of Meynert
- Formed from Acetyl Co-A and choline by the action of choline acetytransferase
- Catabolized by acetylcholinesterase
- Muscarinic & nicotinic receptors
- ↓ dementia
- Mismatch in movement d/o
- Side effects of TCA’s and low potency neuroleptics
- Histamine- produced in the hypothalamus
- Glutamate
- Formed from glucose and glutamine
- Action terminated by reuptake mechanism
- Most notable receptor is NMDA
2 glutamate, 1 glycine, and an action potential of > 65 mV is required for the magnesium pore to fall off and be stimulated
- Blocked by Mg and PCP
- Involved in memory
- Has exotoxicity:
Excessive stimulation of glutamate receptors leads to prolonged concentrations of Ca and NO which causes increased activity of proteases which destroys neurons
Possibly ↓ NMDA in psychosis
- GABA
- (G-aminobutyric acid)
- Synthesized from glutamate by glutamic acid decarboxylase – (rate limiting step)
- Requires vitamin B6 (pridoxone) for the rxn
- Receptors include GABA-B (G protein) & GABA-A & C (ligand gated chloride channels)
- Inhibitory
- Effective in suppressing
Seizures
Anxiety
Mania
- Benzodiazepines and barbituates work thru GABA-A
- Glycine
- Synthesized from serine by serine transhydroxymethylase and beta glycerate dehydrogenase, which are both rate limiting
- Mandatory for glutamate activity
- Inhibitory NT; chloride channel
- May play a role in decreasing the negative symptoms of schizophrenia
Peptide Neurotransmitters
- Short proteins; < 100 a.a.
- Activity is terminated by enzymes = peptidases
- Receptors are G proteins
- Endogenous opiods- involved in regulation of pain, stress, and mood
Tags: Amino acids, barbituates, Benzodiazepines, Biogenic amines, Dynorphins, Endomorphins, Endorphins, glutamate, Histamine, mania, Neurotransmitters, norepinephrine
