6.2. Cocaine & amphetamines: Catecholamine neurotransmission

Cocaine and amphetamines are indirect agonists of monoamine systems

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

Two actions of amphetamines lead to very high DA in synaptic cleft

- cause vesicles to release transmitter.

- monoamines to be transported out of neuron via reversal of transporter

Catecholamine synthesis

- Tyrosine is an amino acid and the precursor for catecholamines.

- The enzyme tyrosine hydroxylase (TH) is the rate-limiting step in catecholamine synthesis.

- All monoamines are classical neurotransmitters (anterograde signaling)

Catecholamine inactivation

- Inactivated by: Reuptake via transporters and/or enzymatic degradation

- Catecholamine reuptake into the axon terminal is the primary mechanism for inactivation and is much faster than metabolism.

Catecholamine transporters

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

Catecholamine transporters cont

However, each monoamine has its own synaptic (plasma membrane) transporters:

DAT = dopamine transporter

NET = norepinephrine transporter

SERT = serotonin transporter

Each monoamine also has its own receptors.

Catecholamine metabolism

Two types of enzymes are involved in catecholamine metabolism:

1. MAO

2. COMT

Dopamine receptors

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

- D1-like receptors (D1, D5): coupled to Gs

- D2-like receptors (D2, D3, D4): coupled to Gi

- Presynaptic autoreceptors are mostly D2.

Dopamine receptors have distinct distributions

dopamine receptors are concentrated in prefrontal cortex areas

Monoamine ascending neuromodulatory systems

Neurons in brainstem send broad, diffuse projections to large areas of forebrain

Dopamine nuclei (collections of cell bodies / somas)

The majority of dopamine neurons (cell bodies) can be found in the midbrain, in

1) substantia nigra

2) ventral tegmental area (VTA)

Dopamine projections (pathways).

Nigrostriatal pathway

DA neurons in substantia nigra target dorsal striatum.

Dopamine projections (pathways).

Mesolimbic pathway

DA neurons in ventral tegmental area (VTA) target ventral striatum(nucleus accumbens) and amygdala

Dopamine projections (pathways).

Mesocortical pathway

DA neurons in VTA target prefrontal cortex

Striatum is a major target of dopamine in the brain

*There are no DA neurons in striatum, but rather, DA neurons send axon projections to striatum. Therefore, striatum has lots ofDA fibers, DA release at synapses, and DA receptors/transporters.

Dopamine inputs to striatum influence basal ganglia function

- In the striatum, half of neurons express D1 and half express D2 receptor.

- In basal ganglia circuitry, D1 neurons are part of thedirect pathway and D2 neurons projections are part of the indirect pathway.

Direct pathway = “go”

Indirect pathway = “no-go”

Loss of dopamine = Parkinson's disease

Parkinson's disease death of midbrain dopamine neurons and their striatal terminals.

Drug-induced Parkinson's disease

- MPP+, a potent DA neurotoxin developed Parkinson's symptoms

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

Catecholamine neurotoxin

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

Adrenergic receptors

Four primary adrenergic (NE and Epi) receptors found in brain (all GPCRs):

- Alpha-1 (α1) coupled to Gq

- Alpha-2 (α2) coupled to Gi

autoreceptor

- Beta-1 and beta-2 (β1 and β2) coupled to Gs

Norepinephrine nuclei (collections of cell bodies)

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

Norepinephrine projections.

Dorsal noradrenergic bundle (DNAB):

Originates from locus coeruleus major source of NE in brain; involved in cognition, arousal, attention

Norepinephrine projections.

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 and cognition.

Distribution of NE

- NE and Epi are in brain (central nervous system).

- also peripheral sympathetic nervous system “fight or flight” response.

Pharmacodynamics of cocaine

- Cocaine blocks reuptake of dopamine, norepinephrine, and serotonin

- DA is important for stimulating, reinforcing, addictive properties.

- In high concentrations, cocaine also blocks voltage-gated Na+ channels.

Pharmacodynamics of amphetamine (1)

- Amphetamines also block reuptake of monoamines but amphetamine also causes DA release via:

- Entering nerve terminals (via DAT) and causing vesicles to release DA.

- Reversing the transporter (DAT) so that DA is transported out of cell into synapse.

At high doses: also inhibits MAO.

Pharmacodynamics of amphetamine (2)

Amph, meth, and MDMA are agonists of TAAR1, an intracellular GPCR