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


• Neurophysiology

– Central Nervous System• DA control over Pituitary Gland

– Inhibits secretion of prolactin» Hormonal control of milk release » Suppresses male sexual activity


• 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


• 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?



– 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


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


– 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• 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.


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?


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


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


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


• 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;


• 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• 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


• 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

Physio psychomotor stim_new

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