Chapter 5 Opener

5.1 Structural features of catecholamines

• How enzymes affect the molecule– Hydroxylase adds a hydroxyl group (OH)– Decarboxylase removes a carboxyl group

(COOH)

5.2 Catecholamines are synthesized in a multi-step pathway

Synthesis of the catecholamines

• Begins with the amino acid tyrosine• Obtained from dietary protein• Transported from blood to the brain• Dopamine neurons

– contain only the first two enzymes• Tyrosine hydroxylase (TH)• Aromatic amino acid decarboxylase (AADC)

• Norepinephrine neurons– Also contain

• Dopamine β-hydoroxylase (DBH)

• Conversion of tyrosine to DOPA is the slowest– Thus, tyrosine hydroxylase (TH) is the rate

limiting enzyme.• Lots of DA or NE in a cell inhibits TH• High firing rates increases TH

Drugs that affect synthesis

• Catecholamine formation can be increased by administration of a biochemical precursor– L-DOPA– Treatment for Parkinson’s Disease

• Drugs that reduce catecholamine synthesis– Inhibit a synthesizing enzyme– AMPT (α-methyl-para-tyrosine)

• Blocks TH (tyrosine hydroxylase)• Depletes catecholamines• Causes return of depressive symptoms in patients treated

with antidepressants

Drugs that affect Storage

• Catecholamines are stored in and released from synaptic vesicles– Provides a means of release

• Several thousand molecules per vesicle

– Protects neurotransmitter from degradation by enzymes in the terminal button.

VMAT

• Vesicular monoamine transporter (VMAT)– A protein in the membrane of the vesicle– Pulls catecholamines into the vesicle

• Reserpine blocks VMAT– DA and NE are thus not encased in a vesicle

• Broken down by enzymes• Low levels of DA and NE

– Causes sedation in animals– Depressive symptoms in humans

• Effects can be reversed with DOPA– Led to the catecholamine theory of depression– Depression – too little catecholamine activity

5.3 Catecholaminergic neurons use a vesicular monoamine transporter protein (VMAT2)

5.4 Role of catecholamine depletion in the behavioral depressant effects of reserpine

Drugs that affect release of catecholamines

• Normally nerve impulse reaches the terminal button– Causes exocytosis

• Some drugs cause exocytosis independently of nerve firing– amphetamine and methamphetamine– Causes behavioral activation

• Notice opposite effect of reserpine– Can cause stereotypy at high doses

• Sniffing, licking, biting, repetitive head movement

• In humans– increased alertness– energy– euphoria– insomnia

Drugs that affect autoreceptors

• Work by inhibiting the amount of Ca++ that enters the terminal button in response to an action potential reaching the terminal button– Less DA or NE released when next action potential

arives

• D2 = DA autoreceptor• α2 = NE autoreceptor

– Agonists of these receptors = decrease release– Antagonists of these receptors = increase release

5.5 A typical dopaminergic neuron possesses autoreceptors on the membrane of its terminals

Drugs that affect the transporter

• Transporters cause reuptake from the synapse– The neurotransmitter is then either repackaged in

vesicle, or broken down by enzymes

• Transporter blocking drugs– Tricyclic antidepressants– SSRIs– NSRIs– cocaine

5.5 A typical dopaminergic neuron possesses autoreceptors on the membrane of its terminals

Drugs that affect metabolizing enzymes that break down catecholamines after reuptake

• Catechol-O-methyltransferase (COMT)• Monoamine oxidase (MAO)

• Breakdown of DA – Homovanillic acid (HVA)

• Breakdown of NE– 3-methoxy-4-hydroxy-phenylglycol (MHPG)

• Concentrations of these metabolites in blood and urine play a role in determining the involvement of DA and NE in mental disorders (e.g., depression and schizophrenia).

MAO and COMT inhibitors

• MAO inhibitors– used to treat depression

• COMT inhibitors– Often prescribed with L-DOPA in Parkinson’s

disease to prevent the break down of L-DOPA prior to reaching the brain.

The A system = from the Swedes

• A = cells that stain for NE or DA

• A 1-7 = noradrenergic

• A 8-16 = dopaminergic

Organization of the DA system

• Three main pathways– 1. Nigrostratal tract (movement)

• Starts in A9 – substantia nigra (in mesencephalon)• projects to the striatum (caudate and putamen).

5.7 The ascending DA system can be divided into three pathways (Part 1)

Box 5.1 Parkinson’s Disease—A “Radical” Death of Dopaminergic Neurons? (Part 1)

Box 5.1 Parkinson’s Disease—A “Radical” Death of Dopaminergic Neurons? (Part 2)

• 2. Mesolimbic dopamine pathway (reward)– Starts in A10 – ventral tegmental area (in

mesencephalon.– Projects to limbic system (in particular nucleus

accumbens and olfactory tubercules).

5.7 The ascending DA system can be divided into three pathways (Part 2)

• 3. Mesocortical dopamine pathway (reward)– Starts in A10 – VTA– To cortex (primarily prefrontal cortex)

5.7 The ascending DA system can be divided into three pathways (Part 3)

5 subtypes of dopamine receptors

• D1 like– D1 and D5

• D2 like – D2, D3, and D4

• All are metabotropic receptors

• Both families are largely found in the striatum and nucleus accumbens

D1 and D2 effects on cAMP

• In general, increased postsynaptic DA receptor stimulation decreases nigrostriatal DA activity

– D1 and D2 receptors work together• Synergistic relationship

D1

• D1 activation – Gs protein– increases cAMP synthesis– D1 receptor activation may be necessary for

full expression of D2 effects

D2

• D2 activation – Gi protein– decreases cAMP synthesis– Autoreceptors inhibit DA synthesis and

release– Post synaptic receptors slow firing rate

• Inhibition of Ca++ entry• Opening of K+ channels

5.9 Signaling mechanisms of D1 and D2 receptors

• Agonists– D1

• SKF 38393 – elicits grooming behavior

– D2 • Quinpirole – locomotion and sniffing

• Antagonists– D1

• SCH 23390 – decreased activity

– D2• Haloperidol – decreased activity

5.10 Catalepsy can be produced by DA receptor antagonists

Ascending noradrenergic system

• Starts in the pons and medulla– A6 – locus coeruleus

• Axons extend throughout the forebrain– Also cerebellum and spinal cord

5.11 The locus coeruleus (LC) contains a dense cluster of noradenergic neurons

• Sleeping or inactive rats– Slow firing of cells in LC

• Novel sensory stimuli– Fast firing of cells in LC

• Thus, LC may play a role in vigilance– Being alert to stimuli in the environment

5.12 Role of the locus coeruleus in vigilance

• α and β receptors– β1 and β2 receptors are like D1 – α2 similar to D2– α1 works somewhat differently – phosphoinositide second

messenger

• Adrenergic agonists increase arousal and eating behavior

• Adrenergic antagonists– Treat hypertension = α1 – Impotence = α2

• Increase parasympathetic; decrease sympathetic

– Generalized anxiety disorder = β blockers• Reduce sympathetic response

• α and β receptors– β1 and β2 receptors are like D1 – increase cAMP– α2 similar to D2 – decrease cAMP– α1 works somewhat differently – phosphoinositide second

messenger• Adrenergic agonists increase arousal

– Animals sleep less

• Adrenergic antagonists– Treat hypertension = α1 – Impotence = α2

• Increase parasympathetic; decrease sympathetic – Generalized anxiety disorder = β blockers

• Reduce sympathetic response