Physio psychomotor stim_new
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Transcript of Physio psychomotor stim_new
Drugs & Behavior 65.2
Psychomotor StimulantsNeurophysiology
Effects on the Behavior and Performance of HumansEffects on the Behavior of non-HumansDissociation & Drug State Discrimination
Tolerance, Withdrawal, Self AdministrationHarmful Effects, Overdose, Treatment
Psychomotor Stimulants
• Neurophysiology– Amphetamines, cathinone, methcathinone
• Affect 5-HT, E, NE, and DA Synapses– spontaneous leaking from vesicles into synaptic cleft– Increase quantity of neurotransmitter released– Block reuptake of neurotransmitter prolonging duration and intensity
of effect
– Cocaine• Blocks reuptake of neurotransmitter prolonging duration and
intensity of effect– PET Studies and DA transporter blockade
» 60-77% blockade; ~47% blockade to exp “high”
Psychomotor Stimulants• Neurophysiology
– Peripheral Nervous System• Drug’s affect is thorough stimulation of synapses that use
epinephrine– Sympathetic nervous system and arousal– Fight or flight response
– Central Nervous System• Psychomotor stimulants affect all monoamine systems• Primarily affecting DA system
– Nigrostriatal System: substantia nigra and basal ganglia» Motor activity
– Mesolimbic DA system: nucleus accumbens; increased release of DA» Reward and motivation
Psychomotor Stimulants
• Neurophysiology
– Central Nervous System• DA control over Pituitary Gland
– Inhibits secretion of prolactin» Hormonal control of milk release » Suppresses male sexual activity
Psychomotor Stimulants
• Neurophysiology
– Central Nervous System
• Cocaine as an Anesthetic (…caine)– Blocks opening of NA channels
» Action potential blocked along nerve axon
– Not related to monoamine effects– Requires much higher concentrations to achieve effect
• Procaine (novocaine) used as synthetic substitute» Positive reinforcement in rats and monkeys but n
oy humans
Psychomotor Stimulants• Effects of Psychomotor Stimulants
– Effects on Body• Increased heart rate, blood pressure• Vasodilation• Bronchodilation (asthma, medically useful)• Other effects: headaches, dry mouth, stomach disturbances,
weight loss• Methamphetamine has fewer peripheral effects than isomers d-
& l-, and stronger CNS effects
– Effects on Sleep• Prevent sleep (reason for use during WW2)• Insomnia
Psychomotor Stimulants• Effects on the Behavior and Performance
of Humans
– Subjective Effects• Cocaine, Amphetamine via IV Route
– Identical Effects
• Amphetamine– Positive Mood Changes
» Well being, exhilarated high spirits, clear and organized mind, desire to get things done
– Profile of Mood State Questionnaire Study via Oral Route» Effects of amphetamine greatest after 3 hrs, lasted up to 6
hrs, and are followed by depression
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans: POMS, 5 mg amphetamine (oral)
Vigor Confusion Elation Friendliness Arousal Positive Mood
Sco
re
Empirical Scales Derived Scales
Dark circles = placebo; open circles = drug
Psychomotor Stimulants
• Effects on the Behavior and Performance of Humans
– Subjective Effects• London et al, 1990: Cocaine-induced euphoria r’d with
reduction in brain glucose metabolism
• PET Study Measuring Glucose Metabolism– Neocortex– Basal ganglia– Thalamus– Midbrain– Hippocampus
• Subjective experience enhanced with expectation of drug
Global Reduction
Psychomotor Stimulants• Effects on the Behavior and Performance
of Humans
– Subjective Effects
• Nora Volkow et al, 1991: Cocaine - Glucose metabolism rebounds to above normal levels during first week of withdrawal
– Global brain metabolism increase and,– Regional brain metabolism increase
» basal ganglia and orbitofrontal cortex
• What do the findings of London and Volkow, taken together, suggest about brain metabolism, cocaine use, and subjective experience?
Psychomotor Stimulants
• Effects on the Behavior and Performance of Humans
– Subjective Effects• Greater when blood levels are rising than when falling
• Higher acute doses produce intense subjective effects
• Tolerance can develop with one administration or with repeat doses in one drug session
– Humans and cocaine self administration via IV» Fixed Interval; 10 minutes for a total of 1 hr» Positive mood increased after 1st administration only, despite
rising blood levels
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans– Subjective Effects
• Amphetamine rush and cocaine freeze– Tachyphylaxis
• Rush: euphoria or intense pleasure that has been described as…“being lifted into the air with feelings of extreme happiness” and “the shot goes straight from the head to the scrotum”
• Freeze: sensation of psychic numbing followed by exhilaration and a sense of well-being
– Rush similar to amphetamine does occur with injection of cocaine
– EEG Study; (Color Palate C p 208)
• Comedown or letdown: mild depression
• Effects on the Behavior and Performance of Humans
– Electroencephalography (EEG) Study & Subjective Effects
– Subjective reports correlated with neurophysiological changes
• Baseline measure of alpha wave activity
• Detection of cocaine: 75 minutes post-injection
• Euphoric feelings: first 10-15 minutes correlated with alpha activity over parietal and occipital lobes
• Dysphoric feelings: 20-30 minutes post-injection and correlated with below-baseline activity in parietal and occipital lobes
Psychomotor Stimulants
Psychomotor Stimulants• Effects on the Behavior and Performance of Humans: EEG Study; Cocaine;
90 mg/kg injection
Baseline Euphoria Dysphoria
Neutral
Detection
Euphoria
Dysphoria
Joys
tick
Psychomotor Stimulants• Effects on the Behavior and Performance of Humans
– Subjective Effects
• Are the euphoric effects induced by amphetamine and cocaine mediated by the mesolimbic DA system?
• D1, D2 receptor blockade does not block the euphoria induced by amphetamine and cocaine-like drugs.
• Other systems involved in mediating the subjective experience.
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans– Stereotyped Behavior & Nigrostriatal DA System
• 1965, Phenmetrazine – amphetamine-like drug for weight control
– Punding: repetitive performance of usually useless act for a period of time
» Annoyance with interruption» Forgo eating and drinking» Taking apart and putting things together
• Human amphetamine induced “punding” behavior is equivalent to stereotyped behavior seen in animals
Psychomotor Stimulants• Effects on the Behavior and Performance of Humans
– Amphetamine-Induced Psychosis• High doses, can last for several days, no residual effects• Indistinguishable from psychosis seen in full-blown, paranoid
schizophrenic– Auditory and visual hallucinations, delusions of persecution, delusions of
grandeur, hostility and violence triggered by paranoid belief that danger is looming
– Cocaine-Induced Psychosis• Dr. von Fleischl-Marxow & White Snakes• Cocaine Bugs & Crank Bugs
– Formication; feeling of bugs
– Common neurochemistry in Schizophrenia?
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans
– Effects on Performance (Improve Deficits)• Military Use
– WWII and as of 2006, “go pills” d-amphetamine– Combats fatigue
» restores reaction time to normal» restores motor coordination and control during more complex
tasks
• Clock Test of Vigilance– Detection of two steps vs. one over 2 hr period– Normal performance declines from 95 to 80% accuracy– 10 mg amphetamine, no deterioration of performance
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans
– Effects on Performance (Normal Performance)
• Simulated Flying Task - 4 hour period (5 mg Amphetamine)– Drug group improved performance over normal levels– Placebo group performance deteriorated– Drug group remained above placebo group levels throughout test
• Does the “improved task performance” benefit occur when a task requires flexible thinking?
– No – it may disrupt this type of performance (i.e., WCST)– suggests effects of amphetamines are limited to over-practiced or
over-learned tasks
Psychomotor Stimulants• Effects on the Behavior and Performance of
Humans
– Effects on Athletic Performance in Swimmers• G.M. Smith and Beecher (1959)
– Amphetamine– 1% improvement in swim times compared to best drug free
swim times– Normally takes many months of training to see 1%
improvement
• Drug testing athletes– Psychomotor stimulants– Ephedrine and other substances found in cold medicines
Psychomotor Stimulants
• Effects on the Behavior of non-Humans
– Unconditioned Behavior• Arousal Level
– Spontaneous Motor Activity (SMA)– Exploratory Behavior
• Stereotyped Behavior– Repetitious behaviors such as bobbing, sniffing, rearing, gnawing, biting
• Automutilation– Formication (i.e., feeling of “bugs”)
• Appetite and thirst– Increases or decreases– Changes in preferences
• Species Differences
Psychomotor Stimulants• Effects on the Behavior of non-Humans
– Unconditioned Behavior• Dosage Differences
– Low Dose: Spontaneous locomotor and exploratory behavior– Higher Dose: Increased locomotion that leads to stereotyped behavior
• Species Differences in Stereotyped Behavior & Locomotor Activity– Monkeys decrease locomotor activity
– Monkeys and Rodents» complex vs. simple stereotypy
– Individual differences within species» Examining hands vs. shifting sideways
• Automutilation in Primates and Rodents– Could be caused by formication (i.e., feeling of bugs)
• Decrease in feeding and drinking observed
Psychomotor Stimulants• Effects on the Behavior of non-Humans
– Conditioned Behavior• Dews (1958) Amphetamine Study
– Pigeons responding for food on varied reinforcement schedules– Rate Dependency Effect
» Increased responding on FI schedule» Low rate of responding could be increased
» Decreased responding on fixed ratio» Fast rate of responding could be decreased
• Showed psychomotor stimulant was not just “stimulant” (i.e., classification issue)!!!!!
• Showed drug interacts dynamically with behavior of organism!!!
• Effects of cocaine are similar; rate increasing not as great
Psychomotor Stimulants• Dissociation
– Testing for recall of learning or transference of learned information– State-dependent learning occurs when material is not transferable
• Under influence of drug• Drug free state• Important to understand for interpretation of experimental results
– performance differences may not be a result of your drug, but rather the state it puts “one” in
• Caffeine, tobacco, alcohol are examples in humans
• Drug State Discrimination– Stimulus Properties
• Can the drug act as a discriminative stimulus• Experimental design tests if animal can discriminate between drug state and
saline state, or between drug-state A and drug-state B • Will he press a lever for food associated with opiates when he is administered
your drug?– Yes: the drug induces the same state; poor discriminative stimulus; response generalizes– No: your drug induces a different state; good discriminative stimulus;
Psychomotor Stimulants
• Dissociation – Amphetamine causes dissociation
• When drug effect has worn off, animals don’t completely remember everything they’ve learned
• Drug State Discrimination• Animals (inc humans) can learn to discriminate between the effects
of cocaine and amphetamine vs. placebo• Amphetamine response is generalizes to…
– cocaine, methylphenidate, cathinone, MAOIs• but not to..
– Caffeine, nicotine, barbiturates, atropine, chlorpromazine or hallucinogens
• D1, D2 receptor blockade interrupts discriminative ability
Psychomotor Stimulants• Tolerance
– Characterization of Acute Tolerance• Coke-out: tolerance to repeated administration over a
period of 10-12 hours
• Rush and improved mood-effects dissipate, but acute tolerance of this type is over in ~24 hours
• Blood pressure and heart rate effects do not develop tolerance
– First time users of amphetamines and cocaine can overdose and die of heart attack because tolerance to subjective effects leads to increasing doses
Psychomotor Stimulants• Tolerance
– Characterization of Chronic Tolerance• Heart and blood pressure effects diminish• Appetite suppressant effects diminish in about 2 weeks• YOWZA! Amphetamine Tolerance
– 15,000 mg dose over 24 hour period– 1,000 times normal therapeutic dose– Well over the estimated LD50 for non-tolerant humans
– Characterization of Sensitization or Reverse Tolerance• After repeated doses we see increases in …
– Psychotic behavior, stereotyped behavior in humans– Lower threshold for convulsions and increased electrical activity in brain
in rats with cocaine– Increased frequency and intensity of SMA & Stereotypy
Psychomotor Stimulants• Characterization of Withdrawal
– Letdown Depression: immediate, 1st administration• Occurs more rapidly with cocaine compared to amphetamines
(1/2 hr vs. several hrs)
– Persistent Depression • after prolonged use, treated with antidepressants• depression does not always remit
– worse in amphetamine abusers
– Rebound • REM sleep with amphetamine withdrawal • Rebound feeding behavior
– Impaired performance on tasks requiring strategy switch; i.e., win-lose strategy
Psychomotor Stimulants• Self-Administration in Humans
– Cocaine & Amphetamine
• South American vs. North American Use– Why did North Americans become addicted and South Americans not so
much…?
• Speed-balling: heroin + cocaine (or amph)– Benzodiazepines, Ketamine, PCP
• Binges and bouts vs. constant prolonged use
• Cocaine and amphetamine use in social setting vs. task specific, respectivley
• Speed-freak: when amphetamine is used for euphoric effects; injections every few hours for a few days
– Punding and paranoia abound!
Psychomotor Stimulants• Self-Administration in non-Humans
– Cocaine
• 1968, Pickens & Thompson– Bar Press on FR Schedule for IV Cocaine– Lead to the establishment of cocaine self administration– Cocaine was reinforcing despite not having apparent withdrawal
symptoms» Secondary Psychological Dependence not a Factor
• Cocaine self administration is learned more quickly than with other drugs and they have higher break points
– Yanagita (1975) demonstrated break point of 6,400 presses on lever– Yanagita (1969) demonstrated an erratic pattern of S-A in monkeys
when cocaine was available for 24 hours (binges)
Self Administration in Nonhumans
• The pattern of cocaine self-administration in the monkey. Top: Daily intake for 21 days. Bottom: Intake in four-hour periods from day 14 to day 21, illustrating the cycles of intake and abstinence.
Psychomotor Stimulants
Psychomotor Stimulants• Harmful Effects
– Direct Effects• Methylphenidate reduces growth velocity• Cocaine and jaundice; liver disease• Cocaine ulceration of mucosal layers of the nose
– Pain is relieved by more sniffing; motivational factor• Depletion of finances in only a few days
– Physiological and psychological • CVA such as stroke due to blood pressure changes• hallucinations, paranoia, focus and attention problems, excessive
talking, restlessness…• Neurotoxicity such as reduced DAT function
Psychomotor Stimulants• Harmful Effects
– Indirect Effects• Injection apparatus and disease associated with sharing needles or
using dirty needles• Compromised immune systems with chronic use due to poor self
care
– Reproduction• Enhance sexual activity with low doses
– Physioogical changes as well as decreased inhibition• Decreased sexual activity and function in males with higher doses
– Physiological effects as well as decreased interest
Psychomotor Stimulants
• Overdose (Caine Reaction)
– Weakness in legs, respiratory depression, inability to stand up
– LD depends on route of administration• Oral Administration
– 150lb LD = 500 mg• Intranasal administration
– LD as low as 30 mg
– Absolute dose may be less important than levels of drug in brain
– Cardiovascular effects
– Cocaine sudden-death syndrome when injected or inhaled• Genetic variations and sensitivity to rewarding effects leading to higher dosage
Psychomotor Stimulants• Overdose
– Caine Reaction
• Two Phases 1. Excitement followed by headache, nausea, vomiting, and severe
convulsion
2. Loss of consciousness, respiratory depression, and cardiac failure
• Death: 2-3 minutes up to ½ hour
• Brain damage from loss of oxygen if you survive severe respiratory depression phase
• Seizure: treated with diazepam
• Chlorpromazine: antagonist in overdose
Psychomotor Stimulants• Treatment
– Detoxification• Acute toxic effects are addressed until patient is out of
danger• Depressant drugs follow for 3-12 days
– Relapse Prevention• Biggest concern• Priming: 1 exposure can lead to intense cravings• Provide Incentives - Positive Reinforcement
– Monetary reward in exchange for clean urine sample» Each test reward increases
– Enjoyed activity with loved one part of reward
Psychomotor Stimulants• Treatment
– Relapse Prevention• CBT in conjunction with…
– Social Support, family education, individual psychotherapy, urine testing
• Antidepressants– Preventative for relapse; depression causes cravings
• Other drugs– Topiramate, prevent seizures– Modafinil, stimulant for narcolepsy