Today: Drugs, depression, schizophrenia
In humans about 50% OF THE RISK FOR DRUG ADDITION IS GENETIC.
Substance abuse
Use leading to impairment or distress i.e. Does it interfere with your life?
How drugs have their effect
a. blocking (antagonist) i. block the receptor ii. make vesicles weak iii. keep vesicles from migrating iv. inhibit reuptake b. facilitating (agonist) i. aid in reuptake ii. eat up the enzyme or block the enzyme that break down the neurotransmitters
Up-regulation- Makes more of neurotransmitter itself Down- Makes less and less neurotransmitter
All with respect to presynaptic not postsynaptic neuron.
LIFE TIME AND 12 MONTHS PREVALENCE OF DISORDERS MALE FEMALE TOT. LIF. Y LIF Y LIF Y
AFFECTIVE
ANXIETY
ADDICTION
ANTISOCIAL SCHIZOPHREN.
ANY %
49
28
47
31
48
30
Drugs of importance to mental health professionals
Depression: severe depression may be linked to
monoamine transmitters (serotonin, noradrenaline, (less often dopamine).
insomnia: serotonin. A dose of tryptophan=insomniac
person will go to sleep. Our bodies make serotonin from tryptophane.
loss of memory: a depression in excitatory
transmission.
Antipsychotic drugs= tranquilizers.
Schizophrenia seems to be related to an excess of
BIOCHEMICAL CORRELATES: THE DOPAMINE HYPOTHESIS. DRUG BEHAVIOR
?
NEUROCHEMISTRY
THE DOPAMINE HYPOTHESIS:
AGONISTS FOR CATECHOLAMINES, E.G., COCAINE, AMPHETAMINES, CAN INDUCE SOME SYMPTOMS OF SCHIZOPHRENIA.
DOPAMINE RECEPTOR BLOCKERS ALLEVIATE SYMPTOMS
ANTIPSYCHOTIC DRUGS DRAMATICALLY DECREASED HOSPITALIZATION OF SCHIZOPHRENICS AND PUT AN END TO FRONTAL LOBOTOMY
1956
450,000
CHLORPROMAZINE
100,000 1900
SMOCK, 441
HALDOL 1975 CLOZAPINE
“ATYPICAL ANTIPSY.
Cocaine- a strong reuptake inhibitor of dopamine
1. chronic use=lose receptors in the postsynaptic membrane 2. block reuptake of dopamine= down regulation occurs and less receptors are available. 3. mood elevation is due to dopamine effects.
Marijuana Tax Act
1937 Congress against the advice of the AMA passed the Marijuana Tax Act effectively banning use of the drug. It is federally classified as a Schedule 1 drug along with heroin and LSD.
5% US population are current users of marijuana.
30% of US population older than 12 have tried it.
marijuana
Benefits Alleviates pain, anxiety, fear Prevent death of injured neurons Suppresses vomiting Enhances appetite
Side effects Impairts short-term memory and cognition Impairs motor coordination Health risks similar to tobacco
2 main cannabinoid receptors
CB1= In CNS in all vertebrate species.
Suggests it has been in existence for 500 million years.
CB2=involved with immune system
Some receptors have waterfilled pores that permit ions to pass. Work by changing relative voltage inside the cell Stored in vesicles Release when neuron fires once
Receptors coupled to G-proteins. These set in motion a biochemical signaling cascade within a cell Can result in changes in ion channels Fats, not stored but rapidly synthesized from components of the cell membrane. Released from places all over the cells (with rise of calcium inside neuron or
when G-protein-coupled receptors are activated).
Neuron must fire 5-10 times for release to occur Eg. CB1
Endogenous cannabinoids do retrograde signaling
(DSI: depolarization-induced suppression of
inhibition).
The postsynaptic cell releases 2-AG which causes the presynaptic cell to decrease its secretions of GABA (-) onto the postsynaptic cell. Result is excitation (+) of postsynaptic cell
Addictive drugs
Nicotine, morphine, etc. Produce their effect by causing dopamine to be released. And dopamine can cause release of endocannabinoids. Glutamate and acetylcholine also initiate endocannabinoid synthesis and release.
Naturally occurring in brain
Morphine (from poppy) binds to opiate receptors in brain.
Natural opioids =enkephalins and endorphins
THC (delta-9-tetrahydrocannabinol) from marijuana
Natural THC= anadamide, and 2-AG (2-arachidonoyl glycerol)
The retrograde signaling (DSI) enhances LTP (learning)
Since fat-soluble do not diffuse. A short-loved local effect Enables individual neurons to disconnect briefly from their neighbors and encode information
Endocannabinoids
located on excitatory nerve terminals aid in regulation of coordinated motor control and sensory integration. extinguish bad feelings and pain triggered by memories of past experiences.
Mice bred to not have CB1 don’t lose conditioned fear response.
Therapy
THC analogues = nabilone and dronabinol Problems =go everywhere. Adverse reactions such as
dizziness, sleepiness, problems with concentration and thinking abnormalities
Major depressive disorder
A feeling of sadness that lasts for weeks. Little energy Feel worthless Contemplate suicide Trouble sleeping Can’t imagine being happy
Bipolar-over 3 days,
normal in middle
Depression
Has a genetic basis (tends to run in families) Twice as common in females Often triggered by an event Some cases linked to viral infection
CLINICAL OR ENDOGENOUS DEPRESSION LACKS AN IDENTIFYABLE ENVIRONMENTAL CAUSE. GENETICS: CONCORDANCE MZT 75% DZT 10% SIBS 9% BIPOLAR DEPRESSION SEEMS TO HAVE THE STRONGEST GENETIC COMPONENT. AMISH: SINGLE DOMINANT GENE? SUICIDE IS MORE PREVALENT IN HOMOZYGOTES FOR AN ALELLE OF THE SEROTONIN TRANSPORTER
Left Prefrontal cortex
Increased activity = happy Decreased activity = depressed
Help with depression
Not just one neurotransmitter
(Serotonin, catecholamines, dopamine etc. Most limit excitation of the postsynaptic cell
Each person different Severe cases are given ECT Bipolars are given lithium
Antidepressants
Antidepressants limit excitation of postsynaptic cell. Autoreceptors is on presynaptic terminal. Depending on how much transmitter is in the cleft it gives feedback to the neuron to produce more or less neurotransmitter.
Schizophrenia is characterized by:
Poor functioning in everyday life Hallucinations or delusions Thought disorders (more dreamlike) Movement disorders Inappropriate emotional expression
What is lacking in schizophrenics
Social interactions, emotional expression Speech memory
Hypothesis for schizophrenia
Poor nutrition during pregnancy, premature birth etc. Some brain structures are smaller (prefrontal, temporal, hippocampus and amygdala). Too much dopamine Too little glutamate
THE BEST DIRECT EVIDENCE FOR DOPAMINE INVOLVEMENT IS AN ELEVATION OF D2 AND D3 RECEPTORS SHOWN BY PETT SCANS.
CONTROL
SCHIZO.
TREATED SCHIZO.
CARLSON, 471
ANATOMICAL CORRELATES OF SCHIZOPHRENIA
ENLARGED VENTRICLES INDICATE DEGENERATION BUT IS NOT UNIQUE TO SCHIZOPHRENIA. MORE COMMON IN CHRONIC TYPES WITH NEGATIVE SYMPTOMS. DISCORDANT MONOZYGOTIC TWINS
CONTROLS SCHIZO. CARLSON, 518, 521
JOURNAL OF NEUROSCIENCE, 2003, 23, 6315-6326.
GENE EXPRESSION IN PREFRONTAL CORTEX OF SCHIZOPHRENICS. SEVERE REDUCTION IN mRNA for GAD (GLUTAMIC ACID DECARBOXYLASE-ENZYME FOR GABA SYNTHESIS
POOR EYE TRACKING (SMOOTH PURSUIT MOVEMENTS) IS FREQUENTLY OBSERVED IN SCHIZOPHRENICS AND SOME FIRST DEGREE RELATIVES
Brain activity Schizo during hallucination= widespread
Hippo normal (L) ,
Schizo (R)
IN SOME CHRONIC SCHIZOPHRENICS THE CYTOARCHITECTURE OF THE HIPPOCAMPUS IS DISORGANIZED CONTROL SCHIZOPHRENIC
Schizophrenia appears to have some genetic basis but not conclusive
Monozygotic twins=50% concordance for schizophrenia 20% for dizygotic 1% general population But a decline since 1950 which genetics doesn’t explain.
USING MICROARRAYS (GENE CHIPS) LOOKING AT 7,700 GENES FROM FRONTAL LOBES OF 16 DECEASED SCHIZOPHRENICS,
IT WAS FOUND THAT 70 GENES SHOWED SIGNS OF ABNORMAL FUNCTION. ONE OF THESE, RGS4, WAS ABNORMAL IN ALL BRAINS. THIS GENE IS INVOLVED IN G-PROTEIN SIGNAL TRANSDUCTION (METABOTROBIC RECEPTORS)
WILL THERE STILL BE A NEED FOR PSYCHOLOGICALLY BASED THERAPIES? YES. IN THE NEAR FUTURE, YOU MIGHT COLLECT A CHEEK SWAB AND SEND IT TO A DNA LAB BEFORE YOU DECIDE ON A TREATMENT STRATEGY. THE LEAST SATISFYING DIAGNOSOIS IS: “THERE IS NOTHING PHYSICALLY WRONG WITH YOU”. THE EXPERIENCES ACQUIRED WHILE COGNITIVE FUNCTIONS OR MOOD STATES ARE IMPAIRED WILL NOT SIMPLY GO AWAY BUT MOST LIKELY WILL BE EASIER TO DEAL WITH AFTER COGNITIVE, BEHAVIORAL, EMOTIONAL THERAPY.
THE PSYCHOLOGIST’S JOB MAY BE MADE EASIER AFTER BIOLOGICAL INTERVENTIONS.
Marijuana Tax Act
1937 Congress against the advice of the AMA passed the Marijuana Tax Act effectively banning use of the drug. It is federally classified as a Schedule 1 drug along with heroin and LSD.
marijuana
Benefits Alleviates pain, anxiety, fear Prevent death of injured neurons Suppresses vomiting Enhances appetite
Side effects Impairts short-term memory and cognition Impairs motor coordination Health risks similar to tobacco
2 main cannabinoid receptors
CB1= In CNS in all vertebrate species.
Suggests it has been in existence for 500 million years.
CB2=involved with immune system
Some receptors have waterfilled pores that permit ions to pass. Work by changing relative voltage inside the cell Stored in vesicles Release when neuron fires once
Receptors coupled to G-proteins. These set in motion a biochemical signaling cascade within a cell Can result in changes in ion channels Fats, not stored but rapidly synthesized from components of the cell membrane. Released from places all over the cells (with rise of calcium inside neuron or
when G-protein-coupled receptors are activated).
Neuron must fire 5-10 times for release to occur Eg. CB1
Endogenous cannabinoids do retrograde signaling
(DSI: depolarization-induced suppression of
inhibition).
The postsynaptic cell releases 2-AG which causes the presynaptic cell to decrease its secretions of GABA (-) onto the postsynaptic cell. Result is excitation (+) of postsynaptic cell
Addictive drugs
Nicotine, morphine, etc. Produce their effect by causing dopamine to be released. And dopamine can cause release of endocannabinoids. Glutamate and acetylcholine also initiate endocannabinoid synthesis and release.
Naturally occurring in brain
Morphine (from poppy) binds to opiate receptors in brain.
Natural opioids =enkephalins and endorphins
THC (delta-9-tetrahydrocannabinol) from marijuana
Natural THC= anadamide, and 2-AG (2-arachidonoyl glycerol)
The retrograde signaling (DSI) enhances LTP (learning)
Since fat-soluble do not diffuse. A short-loved local effect Enables individual neurons to disconnect briefly from their neighbors and encode information
Endocannabinoids
located on excitatory nerve terminals aid in regulation of coordinated motor control and sensory integration. extinguish bad feelings and pain triggered by memories of past experiences.
Mice bred to not have CB1 don’t lose conditioned fear response.
Therapy
THC analogues = nabilone and dronabinol Problems =go everywhere. Adverse reactions such as
dizziness, sleepiness, problems with concentration and thinking abnormalities