Cocaine & Amphetamines 6.2

Indirect Agonists of Monoamine Systems

Don’t act on the receptors

Cocaine blocks reuptake of monoamines (DA, NE, 5-HT)

2 actions of amphetamines lead to very high DA in synaptic cleft:

• drugs enter monoamine terminals & cause vesicles to release transmitter

• drugs cause monoamines to be transported out of neuron via reversal of transporter

Monoamine Taxonomy

Monoamines → Catecholamines → Dopamine (DA), Norepinephrine (NE), Epinephrine (Epi)

Monoamines → Indolamines → Serotonin (5-HT)

Catecholamine Synthesis

Tyrosine is an amino acid & precursor for catecholamines

Enzyme tyrosine hydroxylase (TH) is rate-limiting step in catecholamine synthesis

All monoamines are classical NTs (anterograde signaling)

Catecholamine Inactivation

Catecholamines are inactivated by:

Reuptake via transporters (on presynaptic terminal/glia) and/or enzymatic degradation (metabolism)

Within cleft:

Catecholamine reuptake into axon terminal is primary mechanism for inactivation and is faster than metabolism

Catecholamine Transporters

All monoamines are packaged into vesicles by same vesicular transporter: VMAT2

Each monoamine has it own synaptic (plasma membrane) transporters:

• DAT= dopamine transporter

• NET = norepinephrine transporter

• SERT = serotonin transporter

Each monoamine also has its own receptor

Catecholamine Metabolism

2 types of enzymes involved in catecholamine metabolism:

• MAO (monoamine oxidases)

• COMT (catechol-O-methyltransferase)

  • Act on all 3 monoamines: D, N, E

Dopamine Receptors

Five dopamine receptors (all GPCRs): D1, D2, D3, D4, D5

D1-like receptors (D1, D5): coupled to G_s - stimulate AC & cAMP, increase neuron excitability

D2-like receptors (D2, D3, D4): coupled G_i - inhibit AC & cAMP, decrease neuron excitability

All DA receptors can be postsynaptic, but presynaptic autoreceptors (tend to be inhibitory) mostly D2

Distinct Distributions

Cortical dopamine receptors are concentrated in prefrontal cortex areas

Striatum has both dopamine D1 & D2 receptors

Dopamine Nuclei

Majority of dopamine neurons (cell bodied) can be found in midbrain in

• Substantia nigra (“black substance”)

• Ventral tegmental area (VTA)

Dopamine Projections (pathways)

Nigrostriatal pathway: DA neurons in substantia nigra target dorsal striatum

Mesolimbic pathway: DA neurons in ventral tegmental area (VTA) target ventral striatum (nucleus accumbens (NA)) and amygdala

Mesocortical pathway: DA neurons in ventral tegmental area (VTA) target prefrontal cortex

“limbic” areas = moods, emotions, rewards

No DA neurons in striatum

Parkinson’s Disease

Caused by progressive death of midbrain dopamine neurons & their striatal terminals

Symptoms can be relived by giving L-DOPA (eventually, drug-induced dyskinesia & other issues lead to neurosurgery instead)

Drug-induced Parkinson’s Disease

Trying to make MPPP (synthetic opioid), result was contaminated with MPTP

MPTP is converted by MAO-B to MPP+, a potent DA neurotoxin. Student developed Parkinson’s symptoms within 3 days

MPTP is now used in research to produce dopamine lesions in non-human primates

Catecholamine Neurotoxin

Rats are resistant to MPTP, so 6-OHDA (6-hydroxydopamine) is used instead to create lesions of catecholamine neurons and/or axon fibers

Complete 6-OHDA lesions lead to severe akinetic (die because they won’t eat or drink on own)

Drugs that Affect DA System

DOPA: converted to DA in the brain

6-Hydroxydopamine (6-OHDA): damages or destroys catecholaminergic neurons

Amphetamine: releases catecholamine

Cocaine & Methylphenidate: Inhibit catecholamine reuptake

Adrenergic Receptors

4 primary adrenergic (NE & Epi) receptors in brain (all GPCRs):

• Alpha-1 coupled to G_q

• Alpha-2 coupled to G_i (inhibit AC & cAMP)

  • pre & postsynaptic (serves as autoreceptor)

• Beta-1 & Beta-2 coupled to G_s (stimulate AC & cAMP)

Norepinephrine Nuclei

Locus coeruleus (“blue spot”) is the major source of NE in the brain

Have tyrosine hydroylxase (TH) & dopamine beta-hydroxylase (DBH)

Norepinephrine Projections

Dorsal noradrenergic bundle (DNAB):

Originates from locus coeruleus in pons, major source of NE in brain

• involved in cognition, arousal, attention

Ventral noradrenergic bundle (VNAB):

Originates from NE neurons in medulla

• involved in aversive aspects of stress

Norepinephrine: Role in stress/arousal

Increased norepinephrine is responsible for many stress effects on memory & cognition

Distributions of NE

NE and Epi are in brain (central nervous system)

Also major components of peripheral sympathetic nervous system “fight or flight” response

Pharmacodynamics of Cocaine

Cocaine blocks reuptake of dopamine, norepinephrine, & serotonin

DA important for stimulating, reinforcing, addictive properties

In high concentrations, cocaine also blocks voltage-gated Na⁺ channels (important for pain signals)

Pharmacodynamics of Amphetamine

Blocks reuptake of monoamines, also causes DA release via:

• entering nerve terminals (via DAT) & causing vesicles to release DA

• Reversing transporter (DAT) so DA is transported out of cell into synapse

At high doses, also inhibits MAO

Amph, meth, & MDMA are agonists of TAAR1 (an irregular GPCR)