Title: Psychopharmacology
1Psychopharmacology
- The study of the effects of drugs on the nervous
system and behavior
2Neurochemistry and psychopharmacology
- Ligand any substance that will act on a
receptor - Exogenous ligand originating outside the body
- Endogenous ligand originating within the body
- Exogenous drugs work on endogenous
neurotransmitter/modulator systems
3Psychopharmacology
- Drug effects
- The changes a drug produces in an animals
physiological processes and behavior. - Drugs must reach sites of action, where they can
exert an effect - Effectiveness depends on
- Site of action
- Affinity
- Expectations
- Pharmacokinetics
- The entry, distribution, metabolisation and
excretion of drugs through the body.
4Sites of drug actions
- Different drugs work at different sites in the
brain - Not ALWAYS as ligands at the post-synaptic
receptors! - All drugs affect synaptic transmission in one of
two ways - Agonists __________ synaptic transmission
- Antagonists ________ synaptic transmission
5Effects on production of neurotransmitters
- In the soma or axon terminal, precursors are
synthesized into NT
- Some drugs act as precursors
- Increase NT production
- AGONISTS
- Some drugs inactivate the enzymes required for NT
synthesis - Decrease NT production
- ANTAGONISTS
6Effects on storage of neurotransmitters
- NTs are packaged into vesicles by transporter
molecules on the vesicles membranes - Some drugs inactivate these transporter
molecules, preventing storage - Vesicles are empty no NT is released into the
synapse - ANTAGONISTS
X
7Effects on release of neurotransmitters
- Drugs may deactivate the ions that allow the
vesicle to fuse with the presynaptic membrane - Inhibits NT release
- ANTAGONISTS
- Other drugs may cause the vesicles to fuse and
rupture - Increases NT release
- AGONISTS
X
8Effects on receptors
- Direct agonists
- Bind with the postsynaptic receptors and mimic
the actions of NTs - Open ion channels
- Results in a PSP
- Direct antagonists
- Bind with the postsynaptic receptor and block it
- Do NOT open ion channels
- Prevent NTs from binding with the receptor
X
9Effects on receptors
- Noncompetitive binding drug ligands may bind at
sites on the receptor that are different from the
binding sites for NTs - Indirect agonists use noncompetitive binding to
open ion channels - Indirect antagonists use noncompetitive binding
to prevent the opening of ion channels
10Effect on autoreceptors
- Autoreceptors on the presynaptic membrane limit
the amount of NT released - Some drugs act on the autoreceptors
- Drugs that activate the autoreceptor decrease the
NT released - ANTAGONISTS
- Drugs that block the autoreceptor increase the NT
released - AGONISTS
11Effects on reuptake or enzymatic deactivation
- Some drugs work by inactivating the transporter
molecules responsible for reuptake or by
deactivating the enzymes that break down NT - Keeps the NT in the synapse longer
- AGONISTS
12Neurotransmitters Neuromodulators
13Acetylcholine
- Excitatory neurotransmitter responsible for
muscle contractions - Neuromuscular junctions
- Target organs of the parasympathetic nervous
system
14Acetylcholine
- Originates in cell bodies located in
- Motor neurons
- Ach originating here controls ______________
- Pons
- ACh originating here controls ______________
- Basal forebrain
- ACh originating here facilitates ______________
- Medial septum
- ACh originating here modulates ______________
- ACh axons distribute widely throughout the brain
15Acetylcholine
- Two types of ACh receptors
- Nicotinic receptors ionotropic
- Fast acting
- Located on muscle fibers and in the CNS
- Muscarinic receptors metabotropic
- Slow, prolonged action
- Located in the CNS and PNS
16Drug effects on ACh system
- Botulinum toxin (Botox) - prevents the release of
Ach - Causes paralysis
- Black widow spider venom - stimulates the release
of ACh - Causes severe muscle contractions
- Nicotine (tobacco) - stimulates nicotinic
receptors - Increases CNS function
- Curare (extracted from plants) - blocks nicotinic
receptors - Causes paralysis
17Drug effects on ACh system
- Muscarine (found in many mushrooms) - stimulates
muscarinic receptors - Causes convulsions
- Atropine - blocks muscarinic receptors
- Nerve block, used to dilate pupils, increase
heart - rate, and decrease lung secretions
- Neostigmine deactivates AChE, blocking the
breakdown of ACh in the synapse - Results in more ACh remaining in the synapse
- Used to treat myasthenia gravis
18Monoamines
- Major class of compounds
- Each derived from a single amino acid
- Two subclasses
- Catecholamines (derived from tyrosine)
- Dopamine
- Norepinephrine
- Epinephrine (hormone)
- Indolamines (derived from trytophan)
- Serotonin
- Melatonin (hormone)
19Catecholamines
- Catecholamies are all synthesized in the same
process
20Dopamine
- DA neurons comprise 3 major
- systems in the brain
- Mesostriatal (or nigrostriatal)
- system originates in the substantia nigra
- Axons project to the _______________________
- Mesolimbic system originates in the ventral
tegmental area - Axons project to the _______________________
- Mesocortical system originates in the ventral
tegmental area - Axons project to the _______________________
21Dopamine
- DA is both excitatory and inhibitory, depending
on the receptors activated - All DA receptors are metabotropic
- There are several types of DA receptors found
throughout the brain - D1 receptors are located only on postsynaptic
membranes - D2 receptors are located on both pre- and
postsynaptic membranes
22Drug effects on the DA system
- Levodopa (L-Dopa) increases DA production
- Parkinsons treatment
- Improves motor function
- Reserpine prevents storage of all monoamines in
synaptic vesicles - Formerly used as an antipsychotic, to decrease DA
availability
23Drug effects on the DA system
- Amphetamine Cocaine
- Stimulates DA release
- Blocks reuptake of DA by reversing (amphetamine)
or inactivating (cocaine) - the DA transporter molecule
- Effects
- Highly addictive
- Can cause psychosis, loss of DA neurons
throughout the brain
24Drug effects on the DA system
- Monoamine oxidase-inhibitors (MAO-I) destroy
monoamine oxidase - MAO limits DA
- MAO-I increase DA that may be released
- Many antipsychotic drugs block DA receptors
- Chlorpromazine
- Clozapine
- Methylphenidate - blocks reuptake of DA
- Inactivates transporter molecule
- Increases DA in the synapse
- Increases attention
25Norepinephrine
- Also called noradrenaline
- Cells originate in the medulla, pons and thalamus
- Locus coeruleus dorsal pons nucleus
- Responsible for ________________
- Axons project widely throughout the brain
26Norepinephrine
- NE is released from axonal varicosities
- Adrenergic receptors are sensitive to both
norepinephrine and epinephrine - Entirely metabotropic
27Drug effects on the NE system
- Methamphetamine - releases/prevents reuptake of
both DA and NE by reversing the transporter
molecules - Highly addictive
- Effects
- Chronic use results in
- Bupropion (Wellbutrin/Zyban) blocks reuptake of
both NE and DA by inactivating the transporter
molecule and blocks the nicotinic ACh receptors. - Anti-depressant
- Anti-smoking drug
28Epinephrine
- Also known as adrenaline
- Hormone, produced by the adrenal glands
- Acts as a ligand in the brain
- At adrenergic receptors
29Serotonin (5-HT)
- Involved in regulation of mood, control of
appetite, sleep, dreaming, arousal and pain
regulation. - Synthesized from ___________
- Neurons in the _________ nuclei of the midbrain
- 5-HT neurons project to the cortex, basal ganglia
and hippocampus - Nine types of 5-HT receptors found throughout
the brain
30Drug effects on the serotonin system
- LSD stimulates 5-HT2A receptors in the
forebrain - Powerful agonist causes hallucinations
- MDMA (Ecstasy) reverses the 5-HT and NE
transporter molecules, releasing serotonin and
norepinephrine and inhibiting reuptake - Effects
- Causes permanent damage to 5-HT neurons
cognitive impairment
31Drug effects on the serotonin system
- Fluoxetine (Prozac), Paroxetine (Paxil),
Sertraline (Zoloft) inhibit 5-HT reuptake by
the transporter molecule - Used to treat
- Fenfluramine stimulates 5-HT release and
inhibits reuptake - Used as
32Amino acid neurotransmitters
- Amino acids produced by cell metabolisation may
also act as neurotransmitters - 3 major amino acid neurotransmitters
- Glutamate
- GABA
- Glycine
33Glutamate
- Major excitatory NT in the brain
- Acts on postsynaptic receptors and directly
affects other axons - ________ the threshold of excitation, so that
________ depolarization is needed to produce an
action potential
34Glutamate
- Four types of glutamate receptors
- AMPA receptor ionotropic
- Opens a ______ channel produces EPSPs
- Kainate receptor ionotropic
- Opens a ______ channel produces EPSPs
- NMDA receptor ionotropic
- Contains 6 binding sites (4 outside, 2 inside)
- Controls an ion channel specific for both
____________ - Only opens in the presence of both glutamate and
glycine molecules at binding sites - Metabotropic glutamate receptor metabotropic
- Controls both ____________ channels
35Drug effects on Glutamate
- Alcohol blocks glutamate at the NMDA receptor
- Phencyclidine (PCP) acts at the PCP receptor
- Blocks the Ca2 channel of the NMDA receptor
- Hallucinations
- Ketamine acts at the PCP receptor
- Blocks the Na channel on the NMDA receptor
- Dissociative interrupts memory and thought
36GABA (gamma-aminobutyric acid)
- Major inhibitory neurotransmitter in the brain
- Produced throughout the CNS
- Inhibitory influence throughout the brain
- Acts on receptors as well as directly on axons
- __________ the threshold of excitation -
__________ depolarization is needed to produce an
action potential.
37GABA
- Two known GABA receptors
- GABAA receptor ionotropic
- Controls _____ channel
- Contains 5 binding sites
- GABAB receptor metabotropic
- Controls _____ channel
- Both postsynaptic receptors and autoreceptors
38Drug effects on the GABA system
- Benzodiazepines, alcohol, barbiturates and
steroid hormones - Indirect agonists on GABAA receptor
- Baclofen, alcohol, gamma-hydroxy butyric acid
(GHB) - Stimulate the GABAB receptor
- All GABA agonists are CNS depressants
- Produce sleep, anxiety relief, muscle relaxation,
seizure alleviation
39Glycine
- Inhibitory neurotransmitter found in the
brainstem and spinal cord - Involved in the inhibition of muscle contractions
in the periphery - Glycine receptor ionotropic
- Drug effects
- Tetanus bacteria prevents glycine release
- Strychnine blocks the glycine receptor
40Neuropeptides
- Composed of two or more amino acids
- Released from vesicles from the entire terminal
button - Diffuse widely, affecting other neurons in the
vicinity - Some are neurotransmitters, some are
neuromodulators
41Endogenous opioids
- Well-known neuropeptides
- Endogenous ligands for the opiate receptors
- Ligands Enkephalins, Dynorphin
- Receptors mu, delta, kappa
- Major effects of endogenous opiates
- Analgesia (pain relief)
- Reinforcement
- Inhibition of species-specific defensive responses
42Drug effects on the endogenous opioid system
- Opium, morphine and its derivatives
- (heroin, oxycodone, other narcotics) stimulate
opiate receptors - Effects ___________________________
- Rapidly lead to tolerance and intense withdrawal
symptoms - Naloxone, Naltrexone block the opiate receptors
- Used to treat opiate addiction
43Endocannabinoids
- Lipid-based molecules that transmit messages
between cells - Act on cannabinoid receptors (named for their
affinity for tetrahydrocannabinol) - Anandamide first natural ligand for the
cannabinoid receptor - Receptors
- CB1 receptors found throughout the brain
- Role in modulating most brain functions
- CB2 receptors found outside of the brain
44Endocannabinoids
- Produced and released on demand, not stored in
vesicles - Retrograde transport - endocannabinoids are
released by the postsynaptic cell, travel
backward, act on the axon membrane of the
presynaptic cell
45Drug effects on the endocannabinoid system
- THC stimulates the cannabinoid receptors
- Produces analgesia and sedation, stimulates
appetite, reduces nausea and vomiting, relieves
asthma attacks, decreases symptoms of glaucoma,
certain motor disorders, wasting syndrome,
depression, decreases anxiety, insomnia,
arthritis pain - Prevents excitotoxicity
- Interferes with concentration, memory, perception
of time, visual and auditory perception. - Effects depend on ____________________,
_______________, and _________________ - Rimonabant blocks the CB1 receptor
- Used as
- Results in depression
46Dependence
47Addiction
- Dependence on a particular substance or activity
- Takes two forms
- Physical dependence
- Psychological dependence
48Repeated drug administration
- Repeat administration of a drug will change the
effect of the drug - Tolerance _________ behavioral effectiveness
- Metabolic tolerance
- Functional tolerance
- Greater amounts of the drug are needed
- Withdrawal symptoms occur in response to
_________ - Specific effects
49Repeated drug administration
- Sensitization __________ behavioral
effectiveness - Smaller amounts of the drug will produce the same
initial effects - Results from long-term structural changes in the
brain - Many drugs result in both tolerance and
sensitization
50Physical dependence
- Withdrawal symptoms opposite from the drugs
effects - Due to the body and brain adjusting to the
presence of the drug - The drug becomes necessary to function at normal
levels - Reduction of physical withdrawal symptoms becomes
the reason for continued use of the drug
51Psychological dependence
- Why do drug users reach the point of withdrawal
symptoms? - Drugs are ______________
- Drugs that are abused act __________
- Reinforcement (of ALL drugs) comes via increased
dopamine in the mesolimbic system - DA acting at the nucleus accumbens produces
positive, reinforcing feelings - Results in the desire to take the drug again
- Removal of withdrawal symptoms is also
psychologically reinforcing
52Psychological dependence
- Exists when a person needs to use a drug to gain
the psychological effects that it produces - Results in craving
- MUCH harder to overcome than physical dependence
- Cravings persist after long periods of abstinence
- Not all drugs are physically addictive, but all
addiction has a psychological component.
53Genetics and addiction
- Research on alcoholism and other drugs suggests
genetic components to addiction - Common genetic factors
- Specific genetic factors
- Every body responds to drugs differently, based
on genetically determined traits