Monoamines

1
Monoamines
2
Monoamine Neurotransmitters

• The monoamine transmitters share a common
  structure (catechol) and form a family of
  neurotransmitters
• Catecholamines include dopamine (DA),
  norepinephrine (NE), and epinephrine (EPI)
• Indolamines include serotonin (5-HT)
• The cell bodies of monoamine neurons are located
  in the brainstem and give rise to axon terminals
  that are distributed widely throughout the brain

3
DA-NE-EPI Synthesis
4
Dopamine

• Dopamine is found in a number of neural systems
• Nigrostriatal system projects from the substantia
  nigra to the caudate nucleus and putamen
• Mesolimbic system projects from ventral tegmental
  area to the limbic system (including the nucleus
  accumbens, amygdala, and hippocampus)
• Mesocortical system projects from the ventral
  tegmental area to the cortex
• This implies that manipulation of DA activity may
  have wide-ranging actions (specific as well as
  non-specific)
• Dopamine receptors are metabotropic
• Two families of dopamine receptors
• D1-like receptors are postsynaptic, whereas
  D2-like receptors are pre- and postsynaptic

5
(No Transcript)
6
Dopamine Overview
7
Drug Modulation of DA Synapses

• Synthesis blocked by AMPT
• Reserpine blocks the vesicular transporter
• MAO degrades cytoplasmic DA (located outside
  membrane of mitochondria)
• MAO inhibitors prolong DA activity
• MAO-A present in DA and NE neurons
• MAO-B greater presence in 5-HT neurons
• MAOIs can be reversible/irreversible
• Release can be modulated by amphetamine
• Autoreceptors are negatively coupled to
• Release of DA
• Synthesis of DA
• Synaptic DA is terminated by reuptake (slight
  role for synaptic COMT)

8
DA Receptors
D1-Like D1, D5
D2-Like D2,D3,D4
Metabotropic Action
Post-synaptic
Pre- and Post-synaptic
Synaptic Location
Agonist(s)
SKF 86393
Quinpirole
Antagonist(s)
SCH 23390
Haloperidol
Locations
Accumbens Caudate/Putamen Retina Parathyroid Hypot
halamus
Pituitary Striatum (D2) Autoreceptors (all but
D4) Accumbens (D2,D3) Hippocampus Frontal cortex
(D4)
9
Dopamine receptor agonists
D1 D2 D3 D4 D5 Ergot Bromocriptine -
Cabergoline 0 ? ? ? Lisuride ? ? ? Per
golide Non-Ergot Pramipexole 0
? Ropinirole 0 0 Apomorphine

10
DA Receptor Affinities
11
Norepinephrine
12
Norepinephrine

• Norepinephrine is synthesized from dopamine
  within vesicles
• The locus coeruleus gives rise to NE fiber
  systems
• NE is secreted from varicosities along fibers
• NE interacts with four receptor types in brain
• ?-adrenergic (subtypes 1 and 2)
• ?-adrenergic (subtypes 1 and 2)
• Adrenergic receptors are metabotropic

13
Direct versus Indirect Effects
Source Harvey, RA 1997
14
Adrenergic Receptors
B3 Peripheral receptors Induce thermogenesis
15
Adrenergic Receptor Subtypes
16
Alpha Receptors
17
Presynaptic Manipulations of NE
18
Adrenergic Drugs
Source Feldman et al., 1997
19
Behavioral Roles of NE

• NE and feeding
• Alpha1 versus alpha2 adrenoceptors
• Amphetamine-like psychostimulants may act via NE
• Depression
• Sibutramine as a failed AD medication
• NE and stress (PVN NE controls CRH which induces
  CORT release from the adrenals)
• NE and REM sleep/arousal (vigilance)

20
Locus Coeruleus and Arousal

• NE secretion inhibits sleep (amphetamine) (Peter
  Tripp)
• Lesions of ascending LC fibers increase REM,
  slow wave sleep
• Correlation of LC NE neurons with sleep-waking
  cycle
• LC firing rate declines during REM sleep
• LC firing rates increases on awakening

21
Overview of the Serotonin Synapse
Synthesis of 5-HT
5-HT Transporter
22
5-HT Release and Termination

• Serotonin release
• 8-OHDPAT is an autoreceptor agonist that reduces
  5-HT release
• No selective release blocker
• Fenfluramine is a 5-HT releasing drug
• FEN makes the membrane transporter run in reverse
• Serotonin termination
• Reuptake of serotonin into the axon terminal is
  via a membrane transporter
• Reuptake is blocked by fluoxetine (elevates 5-HT)
• Degradation of serotonin MAO converts serotonin
  to 5-HIAA

23
Serotonin Receptors

• There are at least 9 types of 5-HT receptors
• 5-HT1 1A, 1B, 1D, 1E, and 1F
• 5-HT2 2A, 2B, and 2C
• 5-HT3
• 5-HT3 receptors are ionotropic, the remainder are
  metabotropic
• 5-HT1B and 5-HT1D are presynaptic autoreceptors

24
5-HT Behavioral Actions

• Food intake increased 5-HT reduces FI
  (Fenfluramine)
• Pain sensitivity (reduced 5-HT increased pain
  sensitivity)
• 5-HT is low during sleep
• 5-HT metabolite 5-HIAA is low in suicides
• Loss of 5-HT transporters in MDMA users

25
Loss of 5-HT Transporters in A MDMA User
Control subject 5-HTT Binding
This MDMA user exhibited reduced 5-HTT binding
(darker colors indicate less binding) Suggestive
of axonal damage
Source McCann et al (1998) The Lancet, 352
1433-1437