Psychology 411 lecture notes chapter 4, Psychopharmacology, Part 2'

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Psychology 411 lecture notes chapter 4,
Psychopharmacology, Part 2.
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Monoamine Neurotransmitters

• The monoamine transmitters share a common
  structure 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

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Catecholamine Synthesis
All of the catecholamines have the amino
acid tyrosine as their common precursor
substance. Norepinephrine and epinephrine are
very similar chemically.
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Dopamine

• Dopamine is used by several 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
• Dopamine receptors are metabotropic
• D1 receptors are postsynaptic, whereas D2
  receptors are pre- and postsynaptic

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Dopamine

• Dopamine (DA) is used by several 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
• At least 5 types of DA receptors have been
  identified, all metabotropic. The two most common
  are the D1 and D2.
• D1 receptors are postsynaptic, whereas D2
  receptors are pre- and postsynaptic

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Dopamine
? The nigrostriatal system is a DA pathway that
degenerates in Parkinsons disease and is
involved in the motoric function of the basal
ganglia and these symptoms of Parkinsons. ? The
mesolimbic system is a DA neural circuit involved
in the effects of positive reinforcement
mechanisms of environmental stimuli and drugs
with abuse potential. This system is also
implicated in the euphoric effects of the
positive symptoms of schizophrenia. ? The
mesocortical system is a DA neural circuit
involved in the behaviors of planning,
remembering and problem solving. Abnormal
activity in this system has been implicated in
the deficits in these behaviors seen in
schizophrenia.
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Drug-Dopamine Interactions

• AMPT blocks tyrosine hydroxylase, preventing the
  conversion of tyrosine to l-DOPA.
• L-DOPA is a precursor substance for DA,
  facilitates DA synthesis.
• Reserpine prevents the storage of dopamine within
  vesicles
• Cocaine blocks the reuptake of dopamine, as do
  amphetamines, along with causing the release of
  DA and NE from axon terminals.
• Monoamine oxidase (MAO) within the axon terminal
  degrades dopamine
• Deprenyl blocks MAO-B to increase dopamine, an
  agonist for treating Parkinsons. Deprenyl also
  serves to retard the loss of DA neurons.

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Drug-Dopamine Interactions

• Chlorpromazine, an anti-psychotic, blocks D2 DA
  receptors as a treatment for symptoms of
  behavioral excess in schizophrenia
  (hallucinations, delusional thought and speech,
  etc.).
• A newer anti-psychotic, clozapine also remediates
  these behaviors but by blocking the D4 DA
  receptors.

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Norepinephrine

• Norepinephrine (NE) is synthesized from dopamine
  within vesicles.
• The locus coeruleus, a nucleus in the pons, gives
  rise to the major NE fiber systems. NE is also in
  the autonomic nervous system.
• NE is secreted from varicosities along axons and
  is degraded by MAO.
• Drugs that act as MAO-inhibitors or as NE
  reuptake inhibitors are used as anti-depressants.
  Amphetamines also retard NE reuptake and
  facilitate NE release.
• NE interacts with four receptor types in brain
• ?-adrenergic (subtypes 1 and 2)
• ?-adrenergic (subtypes 1 and 2)
• Adrenergic receptors are metabotropic

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Norepinephrine
? As much as it is possible to summarize the
effects of NE in a few sentences, NE is generally
involved in the behaviors of vigilance, in
discriminating important environmental stimuli.
NE also has a role in emotional behavior or
mood, sexual behavior and appetite.
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Serotonin

• Serotonin (5-HT) cells are mostly located in the
  GI tract (98) with only 2 of serotonin cells
  are in the brain. Serotonin is synthesized from
  the amino acid l-tryptophan.
• Serotonin cell bodies are located in the
  brainstem in the raphe nuclei and project to
  widespread areas of the cortex
• Serotonin systems
• D system originates in the dorsal raphe nucleus
  but with varicosities that do not form synapses
  (5-HT as a neuromodulator)
• M system originates from the median raphe nucleus
  and these varicosities form synapses

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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
• Serotonin termination
• Reuptake is blocked by fluoxetine (elevates
  5-HT), a Serotonin Selective Reuptake Inhibitor
  (SSRI) antidepressant
• Degradation the enzyme MAO converts serotonin to
  5-HIAA

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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

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Serotonin
?As much as it is possible to summarize the roles
of serotonin in a few words, serotonin has
complex effects. It is involved in moods, food
intake and appetite, the regulation of pain, and
in states of arousal and sleep, in particular
REM sleep.
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Serotonin Agonists and Antagonists
?Serotonin Selective Reuptake Inhibitors, the
most famous of which is fluoxetine (prozac) are
widely prescribed as anti- depressants but their
efficacy relative to placebo is still
debated. The herbal product St. Johns Wort also
acts to inhibit the reuptake of 5-HT.
Fluoxetine is also used to treat OCD
(obsessive-compulsive disorder) but behavior
therapy for OCD has very high success rates
without side effects. ?Fenfluramine is a drug
which facilitates the release of 5-HT as well as
acts to retard reuptake and is used to suppress
appetite to treat obesity. ?LSD is an infamous
hallucinogen that acts as a 5-HT antagonist on
autoreceptors as well as a direct agonist for the
5-HT2A receptor. This latter action is now
thought to be responsible for LSDs behavioral
effects as other hallucinogens also affect the
5-HT2 receptor.
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Glutamate

• Glutamate (glutamic acid) is an excitatory
  neurotransmitter, an amino acid. Glutamate is
  the primary excitatory NT in the brain and spinal
  cord.
• Glutamate interacts with four receptor types
• NMDA receptor controls a CA channel
• Activation by glutamate requires glycine binding
  and displacement of magnesium ions. The NMDA
  receptor is involved in the effects of the
  environment on changes in the brain commonly
  called memory formation.
• AMPA receptor the most common glutamate
  receptor, controls sodium channels
• Kainate receptor controls sodium channels
• Metabotropic glutamate receptor

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Glutamate
?Besides producing EPSPs by activating receptors,
glutamate also has a direct excitatory effect on
axons themselves by lowering the threshold of
excitation. Another amino acid NT, GABA (gamma
amino butyric acid) also has an effect on axons
but an inhibitory effect by raising the
threshold of excitation. ?Following a stroke,
glutamate neurons can produce a state
of overexcitation upon neurons (excitotoxicity),
killing neurons. Treating this excitotoxicity
is one of the emerging treatments for stroke
victims. ?The hallucinogen PCP occupies a binding
site on the NMDA receptor.
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GABA

• GABA (gamma amino butyric acid) is synthesized
  from glutamate another amino acid NT
• GABA induces IPSPs
• GABA acts via 2 receptors
• GABAA ionotropic receptor (controls a Cl-
  channel)
• GABAA receptors contain 5 distinct binding sites
• GABA Site
• Benzodiazepene site site for ETOH (alcohol) (?)
• Barbiturate Site
• Steroid binding site
• Picrotoxin binding site
• GABAB metabotropic receptor (controls a K
  channel)

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GABA
?Benzodiazepenes act via the GABAA receptor to
treat anxiety disorders, as well as produce
sedation. Behavior therapy is more successful,
without side effects or dependence.
The barbiturates are also anti-anxiety agents and
sedatives but due to a greater risk of overdose,
rarely used. The benzodiazepenes and the
barbiturates can additively interact with alcohol
to an overdose. Benzodiazepenes are also used
as anti-seizure medications as a GABA-ergic
defect may be one cause of some epilepsy.
Picrotoxin, an indirect GABAA antagonist is a
convulsant at sufficient doses. ?The brains own
anti-anxiety ligand at GABAA has not been
identified but a GABA indirect antagonist has
been isolated which induces behaviors of anxiety.
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Glycine

• Glycine, another amino acid NT
• Glycine induces IPSPs
• Glycine acts via an ionotropic receptor
  controlling a Cl- channel)
• Glycine receptors are found in the spinal cord
  and several brain structures, substantia nigra,
  and brain stem structures.
• The bacteria that causes tetanus produces a
  substance that blocks the release of glycine and
  GABA resulting in uncontrolled persistent muscle
  contraction (lockjaw).
• The poison strychnine is a glycine antagonist and
  a powerful convulsant.

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Peptides

• Peptides consist of 2 or more amino acids (linked
  by peptide bonds)
• Peptides are synthesized in the soma and
  transported to axon terminal in vesicles
• Peptides are released from all parts of the
  terminal button and after release are
  enzymatically degraded (no reuptake)
• Peptides can be co-released with other NTs
• Peptides can serve as neuromodulators
• One of the most important peptide families are
  the endogenous opioids involved in analgesia,
  species-typical defensive responses, positive
  reinforcement mechanisms and addiction

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Peptides
?A placebo can cause pain relief via the release
of the endogeneous opioid peptides. Naloxone
serves as a receptor blocker for the endogenous
opioids which can block placebo analgesia or
treat heroin overdose. ?The peptides serve as
neuromodulators via co-release with an NT and
modifying the sensitivity or affinity of pre-and
postsynaptic receptors to the NT ligand. ?Other
peptides Substance P, involved in pain
transmission ?Angiotensin, involved in
thirst ?CCK (cholecystokinin) possibly involved
in hunger and satiation, along with neuropeptide Y
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Lipids

• THC, marijuanas active ingredient interacts with
  cannabinoid (CB) receptors in brain to produce
  analgesia and sedation. The function of these
  receptors is unclear but they are found in
  widespread brain areas, cortically and
  subcortically.
• There are two endogenous ligands for the CB
  receptors, each is derived from lipid precursors
• Anandamide
• 2-arachidonyl glycerol (2-AG)
• Anandamide interferes with 5-HT3 receptors to
  reduce vomiting and nausea

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Nucleosides

• Nucleosides consist of sugar molecule bound with
  a purine (ATP, ADP) or pyrimidine base.
• Adenosine is a typical nucleoside, a vasodilator
  and a neuromodulator, acting to produce IPSPs via
  K channels possibly involved in sleep
• Caffeine blocks adenosine receptors, producing
  excitation behaviorally, and is a widely used
  stimulant. Caffeine withdrawal can produce pain
  from vasodilation.

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Soluble Gases

• Soluble gases can diffuse widely to exert actions
  on distant cells
• Nitric oxide (NO) is created within cells from
  the amino acid arginine
• NO exerts effects within intestinal muscles,
  dilates brain blood vessels, and contributes to
  the changes in blood vessels that produce penile
  erections. NO may also be involved in learning.
• NO is also utilized by immune system cells
  (macrophages) to kill infectious agents.
• NO activates an enzyme that produces cyclic GMP
  (a second messenger) within adjoining cells