Transcript Psychopharmacology

Chapter 6 Opener
Synthesis and metabolism of ACh
• Synthesis
– Precursors
• choline – from dietary fat
• acetyl coenzyme A (acetyl CoA) – from fats and sugars
– Enzyme
• choline acetyltransferase
• Metabolism
– Enzyme
• acetylcholinesterase
– Metabolites
• choline
• acetic acid
Drugs that affect ACh storage and release
• ACh is stored in vesicles
– Put there by vesicular ACh transporter (VAChT)
– Vesamicol
• Blocks VACHT
– Less ACh in vesicles
– Thus, less available for release
• Suppresses REM sleep
– Cholinergic system interacts with Thalamus to influence sleep
» Increased cholinergic activity = awake and REM
» Decreased cholinergic activity = nREM sleep
6.2 A cholinergic synapse
Acetylcholinesterase (AChE)
• One form is in the presynaptic cell to break down
excess intracellular ACh
• Another form is present on the postsynaptic
membrane.
– Breaks down ACh in synapse
• Another form is neuromuscular junction
– Muscle cells secrete the enzyme to breakdown the
ACh released by the corresponding neuron
• Immediately after ACh causes muscle contraction AChE
removes it.
Choline transporter
• Choline is reuptaken by choline
transporter
• Hemicholine-3 (HC-3)
– Blocks choline transporter
– Reduces ACh production
– Impairs attention in rats
Block metabolism
• Drugs that block AChE (reversible effects)
– Physostigmine
– Increases levels of ACh
• Slurred speech
• Hallucinations
• convulsions
Neostigmine and pyridostigmine
• Synthetic analogs of physostigmine
– Do not cross blood-brain barrier
– Also reversible
– Used to treat myasthenia gravis
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Autoimmune disorder
Antibodies attach to ACh receptors in muscle
Eventually the receptors are broken down
Lack of receptors leads to insensitivity to ACH
– Severe weakness
– Fatigue
– Blocking AChE prolongs ACh activity which
stimulates the remaining receptors.
6.4 Myasthenia gravis, an autoimmune disorder
Irreversible AChE inhibitors
• Insecticides
– Weak versions
• Nerve Gas
– Sarin and Soman
• Strong irreversible AChE inhibitors
– over-activates cholinergic synapses
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Sweating
Salivating
Vomiting
Convulsions
Death by asphyxiation due to paralysis of diaphram muscles
Antidote for nerve gas
• Pyridostigmine bromide (PB)
– Reversible AChE inhibitor protects against nerve gas
– Apparently the reversible inhibition protects from the irreversible
inhibition.
– Must be administered ahead of time
• During first gulf war soldiers were instructed to take 3
tablets daily when at risk for nerve gas
• Animal studies had shown low risk for crossing blood
brain barrier (BBB).
• Unfortunately it appears that stress can increase the
level at which this drug crosses the BBB
– Forced swim test in rats.
– Gulf war syndrome?
Forced Swim Test
6.5 Stress increases pyridostigmine entry into the brain
Botulinum Toxin
• Blocks release of ACh at neuromuscular junction
– Stops the vesicles from cleaving to the presynaptic
membrane
– Very potent poison
– Muscle weakness
– Paralysis
– Can lead to death by asphyxiation
• Rarely
• Now drugs have been created to treat muscle
spasms
– Purified botulinum toxin A (Botox)
– Also used as a cosmetic treatment to treat wrinkles
Box 6.1 Botulinum Toxin—Deadly Poison, Therapeutic Remedy, and Cosmetic Aid
Cell bodies of cholinergic neurons in brain
• Interneurons in striatum (caudate and
putamen)
– Balance between ACh and DA affects
movement
• If ACh activity in the striatum outweighs DA activity
that can lead to the symptoms of Parkinson’s
disease
– Thus, anticholinergic drugs are sometimes
used to treat Parkinson’s in the early stages
of the disease.
6.7 Anatomy of cholinergic pathways in the brain
Basal forebrain cholinergic system (BFCS)
• These are cholinergic brain regions that send
their axons to the forebrain, particularly frontal
cortex regions.
– Also hippocampus and Amygdala.
• All of these areas of the brain are involved in
learning and memory
• Atropine and Scopolamine (anticholinergic
drugs; muscarinic receptors)
– Interfere with learning and memory in many types of
learning tasks
Lesions of BFCS disrupt cognitive functioning
• 192 IgG-saporin
– 192 IgG is an antibody that binds specifically
to basal forebrain cholinergic neurons.
– Saporin is a neurotoxin
• When injected into the ventricular system
the BFCS neurons take in this substance.
• Those neurons are selectively destroyed
• Affects learning and memory
– i.e., Berger-Sweeney et al. (1994)
4.20 The Morris water maze
6.8 Cholinergic lesions
• Note in the previous study that ventricular
exposure was more disruptive
– This exposure would affect the entire BFCS,
rather than just one part (as in injection only in
the nucleus basalis).
Alzheimer’s disease
• It has been proposed that a portion of the cognitive
decline that is seen in aging may be due to dysfunction
of the BFCS
• Perhaps Alzheimer’s disease as well.
– There is severe damage to the BFCS in Alzheimer’s disease.
• As well as other cortical regions and the hippocampus
• Early medications for Alzheimer’s disease were
Cholinergic agonists
– Tacrine (Cognex)
– Donepezil (Aricept)
– Rivastigmine (Exelon)
• These are all AChE inhibitors
– Only somewhat effective
Acetylcholine receptor subtypes
• Nicotinic receptors
– Respond to nicotine (ACh agonist)
• Concentrated at neuromuscular junction
• Also in the sympathetic and parasympathetic nervous
system and parts of the brain
• Ionotropic receptors
– ACh binding opens Na+ and Ca++ channels
– Depolarizing effects
– Thus, excitatory
• Muscles = contract
• Neuron = increase in firing rate
Nicotinic receptors
• They have two binding sites for ACh
– Both must be activated for the channel to
open.
• The affinity of nicotinic receptors in the
brain and autonomic nervous system are
greater than the affinity of nicotinic
receptors on muscle cells.
– Smokers
• Enjoy a smoke without having muscle spasms.
6.9 Structure of the nicotinic ACh receptor
Curare
• D-tubocurarine = active ingredient
• Nicotinic receptor antagonist
– High affinity for receptors in muscles
• Used by south American Indians in poison
darts.
– Paralyzes animal and causes death because
of respiration failure
• Good for horror stories and movies
– Person would be paralyzed, but still aware.
• Muscarinic receptors
– Respond to muscarine (derived from a
particular mushroom; Amanita muscaria).
• Metabotropic
• 5 subtypes (m1-m5)
– Different subtypes activate different second
messengers
– Often cause K+ channels to open
• Widespread throughout the brain.
M5 muscarinic receptor and opiate reward
• M5 may be related to the rewarding
properties of morphine
– Mutant mice that lack M5 receptors show
lowered place conditioning effects to
morphine
• Could lead to pharmacological treatment of opiate
conditioning
4.22 Place-conditioning apparatus
6.11 Genetic deletion of the M5 muscarinic receptor reduces the rewarding effects of morphine
Many drugs used to treat psychological disorders produce muscarinic side effects
• Muscarinic receptors common in autonomic nervous
system
– Particularly parasympathetic
– Agonists = parasympathomimetic – mimic parasympathetic
action
• Slows heart rate
• Controls secretory responses
– Salivation
– Sweating
– Tearing
– Antagonists = parasympatholytic – prevent parasympathetic
action
• Muscarinic blockade
– Lack of salivation
» Tooth decay
• Many drugs used to treat psychological
disorders produce muscarinic side effects
– Pharmacologists are working to make drugs that are
less likely to activate muscarinic receptors
• Atropine is a muscarinic antagonist commonly
used to dilate pupils – as we discussed last time.
– Causes blurred vision
• Derived from Atropa Belladona – deadly
nightshade
– Very poisonous plant
– Women placed juice of the berries in their eyes
• Cosmetic – dilated pupils
6.12 The deadly nightshade (Atropa belladonna)
Serotonin
• Serotonin = 5-hydroxytryptamine (5-HT)
• Synthesis
– Trytophan (precursor)
• Converted by tryptophan hydroxylase
– To 5-hydroxytryptophan (5-HTP)
• Converted by aromatic amino acid decarboxylase
(AADC)
– To 5-hydroxytryptamine (5-HT)
6.13 Synthesis of serotonin
• The first step is the rate limiting step.
– Takes the longest
• Like we talked about with dopamine
– Thus, tryptophan hydroxylase is the rate limiting
enzyme
• Only serotonergic neurons contain this enzyme.
• Thus, labeling for tryptophan hydroxylase is one way to
identify serotonergic neurons
• Also notice that the enzyme in the second step
is the same for catecholamines and indolamines
– Aromatic amino acid decarboxylase (AADC)
Turkey Dinner Effect?
• Although many people believe that increasing tryptophan in
the diet can increase serotonin levels, it is more complicated
than that.
– Turkey dinner effect – not true
• The ratio of tryptophan to other large amino acids determines
the rate that tryptophan enters the brain
– Competition for crossing the blood brain barrier.
• Consequently it is high carbohydrate and low protein diets
that increases brain tryptophan levels
– Insulin release is stimulated by high carb diet.
– Insulin causes most amino acids to be removed from the blood
stream.
• But not tryptophan
– Less competition for tryptophan, means that more crosses the
BBB
6.14 Tryptophan entry into the brain and 5-HT synthesis
• Tryptophan depletion can cause the return
of depressive symptoms in patients that
have recovered from depression.
– Indication of serotonin’s role in mood
regulation.
• Amino acid cocktails
– Without tryptophan
• Competition for crossing the BBB depletes brain
tryptophan levels
– With tryptophan
• Brain levels remain normal
6.15 Rapid tryptophan depletion leads to symptom relapse in recovered depressed patients
Storage and Autoreceptors
• VMAT2 controls storage in vesicles
– Just like for the catecholamines
– Thus, the drug reserpine disrupts storage of
serotonin in the same way it disrupts storage
of catecholamines
• Remember the knocked out rabbits
• 5-HT1a, 5-HT1b or 5-HT1d receptor are the
serotonin autoreceptors
– Agonists of these receptors decrease
serotonin release
Some drugs can cause release independent of action potentials
• Amphetamine like drugs
– Para-choloroamphetamine
• Drug for experimentation
– Fenfluramine
• One time a prescribed appetite depressant
– 3,4-methylenedioxymethamphetamine
(MDMA) – Ecstasy
Serotonin and eating behavior = Fen-Phen
• Fen – Fenfluramine
– Causes release of serotonin
• Phen – phentermine
– Thought to increase catecholamine activity
• The drug combination was an effective
weight loss drug.
• Unfortunately causes heart problems
Box 6.3 Fen–Phen and the Fight against Fat
5-HT transporter
• Reuptake is performed by
– 5-HT transporter
• Cocaine – not selective
• Fluoxetine – Prozac – selective = SSRI
6.16 Features of a serotonergic neuron
Serotonergic system
• The Swedish system
– 5-HT represented by the letter B
• Raphe nuclei – medulla, pons, midbrain
– B7 – Dorsal Raphe
– B8 – Median Raphe
• Give rise to most of the serotonergic fibers in the forebrain
• Lesioning the raphe nuclei disrupts things like
food intake, reproductive behavior, pain
sensitivity, anxiety, and learning and memory
6.17 Anatomy of the serotonergic system
Receptors
• 15 different receptors so far
– 5-HT1 family
• 5-HT1a……5-HT1f
– 5-HT2 family
• 5-HT2a, 5-HT2b, and 5-HT2c
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5-HT3
5-HT4
5-HT5a and 5-HT5b
5-HT6
5-HT7
5-HT1a and 5-HT2a – best known
• 5-HT1a
– Found in hippocampus, septum, amygdala,
and dorsal raphe
– Also serve as autoreceptors
• Reduce synthesis of cAMP
• Increase opening of K+ channels
6.19 5-HT1A and 5-HT2A receptors operate through different signaling mechanisms (Part 1)
5-HT2a
• 5-HT2a
– Numerous in cerebral cortex, striatum, and nucleus
accumbens
– Activates protein Kinase C (second messenger)
– Increases Ca++ levels in the cell (also can serve as a
second messenger system)
• Agonists are hallucinogenic
– LSD thought to produce hallucinations via this
receptor
• Antagonists used as a treatment for
schizophrenia
6.19 5-HT1A and 5-HT2A receptors operate through different signaling mechanisms (Part 2)