Neurochemistry

Drug Distribution in the CNS

Primary mechanism: passive diffusion across the Blood Brain Barrier (BBB)

BBB is capillary with tight junctions - separated by glial cell lipid barrier - from neuron
in order for a drug to reach the neuron, it must be lipid soluble and have MW less than 2000
although the goal of neuropharmacotherapy is to alter neurotransmitter systems, neurotransmitters themselves are extremely ineffective drugs; although they do meet the low MW criterion, they are polar and do not cross BBB
some areas of CNS have no BBB:

(1) area postrema (chemoreceptor trigger zone)
(2) median eminence in the hypothalamus
(3) choriod plexus
(4) pineal gland

Secondary mechanism: transport through CNS

facilitated transport: i.e., glucose (with Na⁺ ) or amino acids (Trp, Tyr, Phe = neurotransmitters precursors) - no ATP

active transport - ATP required

Neurotransmitters

(1) Biogenic amines: involved in Psychosis and mood changes, Schizophrenia, Depression

Catecholamines: dopamine and norepinephrine

Indolamines: serotonin

(2) Amino acids: GABA and glutamate- (learning and memory, cytotoxic in high concentrations)

(3) Peptides: endorphins and enkephalins (involved in pain and perception)

The Synapse - provides a method for understanding drug design

Presynaptic Terminal Mechanisms

Neurotransmitter (NT) precursors are taken up into brain by facilitated transport, get into neuron where enzymes act on them to synthesize neurotransmitter which is stored in acidic vesicles. Low pH means neurotransmitters are charged and thus trapped in lipid membrane.

Upon Ca⁺⁺ signal, vesicle fuses with presynaptic membrane to release neurotransmitter which then acts on Post and Presynaptic receptors

Autoreceptor-presynaptic receptor that Ý or ß subsequent neurotransmitter release

NT can be metabolized in the cleft but primary mechanism is reuptake.

This is particularly true for biogenic amines and amino acid NTs.

Receptor site is actually upstream of cleft, meaning neurotransmitter spreads (via volume transmission) throughout brain.

Heteroreceptor (R3)-receptor for a different neurotransmitter that binds neurotransmitter being released. Allows interaction between neurotransmitters (i.e. serotonin can affect norepinephrine release).

Postsynaptic Terminal Mechanisms

There may be multiple subreceptor types (dopamine has 5; serotonin has 12) Þ allows for a diversity of function with limited # of NTs.

Mechanisms of Drug Action

(1) Inhibit neurotransmitter synthesis Þ ß neurotransmitter function

(2) Prevent neurotransmitter storage or cause neurotransmitter vesicle leakage into intracellular space where neurotransmitter can be metabolized (e.g., by Monoamine Oxidase (MAO) - breaks down Dopamine)

(3) Alter Ca⁺⁺ influx to modulate neurotransmitter release (Ca⁺⁺ uptake blockers)

(4) Enhance neurotransmitter release specifically

(5) Upregulate or downregulate receptor. Most drugs fall into this category.

there are autoreceptor agonists that mimic neurotransmitter only at the autoreceptor sites, thus ß the release of the NT)

(6) Block neurotransmitter reuptake, thus increasing neurotransmitter concentration in the synaptic cleft. (Prozac blocks serotonin reuptake)

Cocaine blocks reuptake of all biogenic amines: dopamine, norepinephrine and serotonin

Active releasing drugs reverse the presynaptic reuptake transporter (psycho-stimulants: i.e. amphetamine Ý biogenic amines).

(7) Block degradation of neurotransmitter (i.e. MAO inhibitors: dopamine is substrate for A and B; norepinephrine and serotonin is substrate for A)

(8) Activate heteroreceptors, likely inhibitory on neurotransmitter release (agonist Þ ß release of different neurotransmitter system)

Receptor Families - multiple subtypes

Ligand gated ion channels - no transduction - Benzodiazepam, GABA, Glutamate-NMDA-PCP blocks its channel; ACH (nicotinic)

Distinct neurotransmitters have distinct binding sites

G-protein super family - do have transduction via GTP binding protein interaction (Catecholamines- 5HT, glutamate and ACH (muscarinic)

Adenylatecyclase family utilizes Protein Kinase A
Phospholipase C protein system utilizes Protein Kinase C

Tyrosine Kinase System: neurotropin receptor

Dopamine - disturbance is associated with schizophrenia, drug abuse, and Parkinson’s disease

Distribution:

Nigrostriatal pathway: cell bodies in substantia niagra and nerve terminals in the striatum
Mesocorticolimbic pathway: cell bodies - ventral tegmental area; terminals - limbic and cortical areas

control of cognition and behavior

Tuberoinfundibular pathway: cell bodies and terminals in basal hypothalamus- inhibit pituitary prolactin

Synthesis: TyrosineÞ [Tyr hydroxylase]Þ DOPAÞ [DOPA decarboxylase]Þ Dopamine

Metabolism:DopamineÞ [MAO]Þ DOPAC Þ [Catechol-O-methyltransferase]Þ Homovanillic Acid(marker of dopamine synth)

Receptors: D1 stimulates adenylate cyclase; D2 inhibits

Regulation: autoreceptors, feedback

Drugs target: synthesis, release, metabolism, reuptake, receptor agonist and antagonists (pre and postsynaptic)