DBM - Chapter 5

adrenal medulla (kidney)

secretes EPI and NE into the bloodstream

act as hormones

vesicular monoamine transporter (VMAT)

packages monoamines into vesicles

VMAT1 - adrenal medulla; VMAT2 - brain

DA, NE, 5-HT

independent release

some drugs of abuse cause DA and NE release independent of cell firing (Ca²⁺ - independent release)

somatodendritic autoreceptors

on cell bodies or dendrites

slows rate of neuron firing

reduces rate of NT release

“impulse modulating”

terminal autoreceptors

on presynaptic nerve terminal

inhibit further NT release

“release or synthesis modulating”

somatodendritic DA autoreceptors

midbrain in VTA and SN

enhances opening of K+ channels

slows firing rate

terminal DA autoreceptors

enhances opening of voltage-gated K+ channels

inhibits Ca²⁺ entry to VGCCs

enhancing DA uptake via DAT

inhibiting TH

somatodendritic NE autoreceptors

enhance opening of K+ channels

terminal NE autoreceptors

inhibit VGCCs

clonidine

treats high blood pressure and opioid withdrawal

NE autoreceptor agonist

reduces NT release

yohimbine

antagonizes NE autoreceptors

increases NE release

exacerbates opioid withdrawal

membrane transporters

DAT and NET

non-selective, each can take up the other NT

SNRI

inhibits reuptake of both NE and 5-HT

cocaine

inhibits reuptake of all monoamine NTs: DA, NE, 5-HT

catchecol-O-methyltransferase (COMT) and monoamine oxidase (MAO)

metabolize catecholamines

DA → HVA

NE → MHPG in the brain

NE → VMA in the PNS

ascending DA pathways

innervate forbrain regions and release DA

• nigrostriatal

• mesolimbic

• mesocortial

nigrostriatal dopamine tract

substantia nigra → caudate-putamen (striatum)

facilitates voluntary movement

Parkinson’s Disease

massive loss of DA neurons in SN

denervation of the striatum

mesolimbic dopamine pathway

ventral tegmental area → nucleus accumbens

motivated behaviors

positive symptoms in schizophrenia

mesocortical dopamine pathway

ventral tegmental area → prefrontal cortex

working memory

negative and cognitive symptoms in schizophrenia

dopamine receptor subtypes (metabotropic)

D1 and D5 (D1-like)

• stimulates AC via G_s

D2, D3, D4 (D2-like)

• inhibits AC via G_i

• enhances K+ channel opening

• inhibits VGCCs

D2 are autoreceptors and postsynaptic receptors

dopamine hypothesis of schizophrenia (1967)

excess DA function results in symptoms of schizophrenia

high doses of amphetamine can produce psychotic reaction in health individuals » can be reversed by DA antagonists

psychotic behavior driven by excess post-synaptic D2 receptor activation

“typical” antipsychotic drugs: D2 receptor antagonists

D2 receptor antagonists: acute administration

increased firing rate after antipsychotic administration

increased DA turnover (synthesis, release, metabolism)

enhanced release accompanied by post-synaptic blockade

no worsening of symptoms

D2 receptor antagonist: chronic administration

decreased DA turnover

two theories:

1. initial increase in synaptic DA followed by gradual decrease

   • chronic blockade leads to up regulation of autoreceptors

   • regulation of DA turnover

2. after initial increase in DA turnover, DA neurons temporarily inactivate (depolarization block)

   • resulting decrease in turnover

D2 receptor antagonist: side effects

extrapyramidal symptoms (EPS)

• dystonia (continuous spasms + muscle contractions)

• akathisia (motor restlessness)

• Parkinsonism (rigidity, bradykinesia, and tremor)

tardive dyskinesia » permanent

• irregular, jerky movements

dopamine system stabilizers

partial DA agonists: compete with DA for receptors, reduces DA effect » reduces positive symptoms

stimulates DA receptors in brain regions with too little DA » reduces negative symptoms

noradrenergic system

CNS: brainstem » locus ceruleus (LC)

• ascending fibers project to many forebrain structures

PNS: post-ganglionic NT in sympathetic division of ANS

noradrenergic receptors (metabotropic)

α1: operates via Gq, increase in Ca2+ ions in post-synaptic cell, PKC activation

α2: inhibits AC via Gi, increase K+ channel opening, inhibit VGCCs (like D2)

ß1 and ß2: stimulates AC via Gs (like D1)

postsynaptic receptors throughout cortex, thalamus, hypothalamus, cerebellum, limbic system

α2 receptors function as autoreceptors in LC and nerve terminals

α1 and α2 receptors in PFC

NE has higher affinity for α2 than α1 in PFC

activation of post-synaptic α2 in PFC enhances working memory

stress stimulates NE release in the PFC

• activation of α1 receptors » negative effect on cognitive functions of the PFC

ß-antagonists (beta blockers)

hypertension, cardiac arrythmias

generalized anxiety disorder (GAD): propranolol

• reduce physical component associated with excess NE activity

• psychological component still present