psych336 exam 2 lectures

psychomotor stimulants

stimulate alertness/arousal and motor activity

major classes of psychomotor stimulant drugs

• amphetamines and related compounds

• cocaine

active components of ephedra plant

• ephedrine (most abundant in plant)

• pseudoephedrine

ephedra use

• decongestant (vasodilation → blood vessels widen, easier to breathe)

• Sudafed (pseudoephedrine) used to be OTC

amphetamine history

• synthetic phenylethylamines

• goal was to be substitute for ephedrine

• structurally related to catecholamines

• peak use in early 1970s (10 billion tablets sold)

Benzedrine

• inhaler for asthma and then used for narcolepsy as well

• amph, high abuse potential

amphetamines and related compounds

known as beta-phenylethylamine derivatives and sympathomimetic amines (mimicking activity of sympathetic NS)

four main amphetamine formulations

• racemic (mix of D and L isomers), ex. Benzedrine

• D-amph (dextroamphetamine), Dexedrine

• L-amph (levoamphetamine), less potent than D

• methamphetamine, most potent

amphetamine-type stimulants (ATS)

world’s second most used drug after cannabis, international amph trade (71% of seizures of meth in E and SE Asia)

fenethylline

• amph conjugated with theophylline

• “pro-drug” response

  • amph effect AND caffeine-like effect

  • additive or synergistic effects, potentiation can also happen

methamphetamine epidemic

• can be made in very pure form

  • higher concentration

• easily smoked → upped abuse potential

problems with amph

• often resulted in dose and frequency of use escalations

• high abuse liability

• not treating what they claim to treat

• development of dependency

amph approved medical uses

• narcolepsy and ADHD

• Adderall (DL racemic mixture)

• low-dose and oral medication

• slow release = no “high”

• prescription rates are highest in US

methylphenidate

prototypical ADHD med

limitations of amphs for ADHD

• sleep problems

• agitation and nervousness

• alternatives like Modafinil (promote wakefulness without abuse libability of amph)

• no biomarkers for certain behaviors, set and setting matter

designer drugs

• some are cannabinoid derivatives

• many are amph and cathinone variants

• more being made than can be scheduled in time

• enhance NT transmission (like DA and 5HT)

  • emotional connectedness effect from action on SERT

  • feature of MDMA that you don’t really get with amph and other drugs

cathinone

• used socially in E. African countries

• mild stimulant effects

• route of absorption and dose from leaves

• methcathinone is synthetic variant (“cat”)

major amph effects

• autonomic effects (ex. increased blood pressure, hyperthermia)

  • sympathomimetic effects

    • such as effect on NE

• CNS effects

  • analeptic (waking)

  • anorexia

  • psychomotor stimulant effects

    • decreased fatigue and arousal

    • hyperactivity

    • stereotyped behavior

• psychosis at very high dose

amph effects in animals

• same autonomic effects as humans

• psychomotor stimulant effects

  • low dose = locomotor hyperactivity

  • high dose = stereotypy

• reinforcing effects (self-administration and place preference)

50 kHz ultrasonic vocalizations

interpreted as subjective pleasure (euphoria) in animal models (22 = bad feelings)

effects of repeated psychostimulant administration

• autonomic and anorectic (no appetite) effects show tolerance

• 100-fold greater dose compared to starting dose

• tolerance dissipates in 1-2 weeks

• sensitization

Paul Vesna psychomotor stimulant effects study

• Q: How reinforcing is the drug?

• used Prog ratio

• one group amph (injected, sensitized), one group saline

• animals with history of amph exposure show sensitization to motivational properties

• some effects show sensitization at the same time as others are showing tolerance

factors influencing extent of sensitization

• stress and environmental novelty

• conditioning effects

• route of administration

• genes

• sex (F can be more sensitive to induction of sensitization in terms of locomotor processes)

• magnitude of shift in dose-effect, and duration of effect

development of sensitization vs. tolerance

• depends on pattern of drug administration

• drugs given closely spaced, continuous infusion, slower routes of administration → tolerance

• drugs given widely spaced apart, or very brief → sensitization

• one effect sensitizes while another shows tolerance but also you can get sensitization or tolerance to the same drug effect (do not tend to happen at the exact same time)

why catecholamines are grouped together

their NTs all have a similar chemical structure, each is a precursor for another (ex. DA is the precursor that is converted into NE, NE is the precursor that is converted into epinephrine)

ADHD consensus

• no consensus on neurobiology that produces it

• theories are differences in DA and glutamate systems

• no animal models, wide variation in manifestation in individuals → barriers

ADHD current understanding

• different rates of maturation of brain regions

• difference in neurodevelopmental processes

• difficulty understanding adult onset compared with theory that symptoms can abate with age

• there IS a lot of evidence that psychostimulants are effective treatments, but no idea why they are

  • data mixed on test-taking performance

Do patterns of medical use of psychostimulants produce long-term effects on the brain and behavior?

prescribed use = low dose, oral administration (maintenance of blood levels)

• these conditions are NOT conducive to sensitization (so NO, effects aren’t drastic)

monkey methylphenidate study

• administration of orange solution, methylphenidate, DL-amph (3 groups)

• results found that there was no difference between groups getting psychostimulants vs. controls getting orange solution

meta-analysis of psychostimulant use and drug abuse

• children with ADHD followed from childhood to young adulthood

• neither more or less likely to develop alcohol or other substance use disorders compared to unmedicated children

• no strong relationship between medical drug use and increased risk of developing addiction

sex, drugs, and ADHD study

• probability of contracting STD decreased by 3.6% in those on ADHD meds

• probability of having substance use disorder was lower in ADHD population

• population-based, does not mean direct cause and effect

misuse of prescribed stimulants for ADHD study

• 36% of sample reported overusing prescribed meds

• 19% intentionally used with other substances

• these students are at higher risk for substance abuse

• interaction between intent and use of drug, how it’s used, how often

recreational d-amph study

• lower binding of D2 and D3 receptors in ppl with history of recreational use

• Q: Did ppl have lower D2 receptors to begin with or is it the drug that caused the reduction in D2 receptor expression?

procaine

(1905) cocaine variant, local anesthetic properties without psychomotor effects of cocaine

coquerette

cigarette laced with cocaine, cocaine neutralizes the depressing effects of nicotine

raw coca leaves

• weak base (ppl have with other things to increase saliva of pH)

• not stable in this form, leaf dries out and degrades in about 2 weeks, cannot ship it

coca paste (Paco)

• 20-80% cocaine sulfate

• mix with sulfuric acid kerosene or gasoline, stomping on leaves to release chemicals

• low-grade cocaine that can be smoked (often mixed with tobacco)

• 900 lbs of leaves makes about 1 kg of drug

• bulky, not stable enough to ship

cocaine HCL

• take coca paste and wash it with solvent (like kerosene) to extract into crystalline powder

• snorted or injected

  • 20-30% of total cocaine content gets into bloodstream

• not smoked → burn pt is close to vaporization pt (lose more drug than it’s worth to smoke)

cocaine free base

• take salt off cocaine HCL

  • add water or base like ammonia and flammable solvent

• lower melting pt → can be vaporized and smoked

crack cocaine

• another form of freebase

• Fair Sentencing Act of 2010 reduced sentencing disparity between crack and powder from 100:1 to 18:1

cocaine pharmacokinetics

• smoking gives a bigger peak than IV (lipophilic)

• freebase and crack reach brain in seconds

• metabolized in liver

benzoylecgonine

• INACTIVE metabolite of cocaine

• excreted in urine, detectable for weeks in heavy users

• not FDA-approved, sold as topical analgesic in some countries (mild Na+ channel blocking → numbness)

cocaethylene

• ACTIVE metabolite of cocaine

• formed when ppl ingest cocaine and ethyl alcohol (alc)

• actively as potent as cocaine

• increases duration of action of cocaine

How similar are the effects of amph and cocaine?

• subjective effects basically indistinguishable

• rodent drug discrimination studies report the two being similar even through IV route

mild to moderate effects of amph and cocaine

heightened energy, amplification of mood, insomnia, hyperactivity, increased sexual interest and desire, suppressed appetite, inflated self-esteem, sometimes anger and aggression

severe effects of amph and cocaine

extreme anxiety or fear, extreme exhaustion, compulsive complicated motor behaviors, decreased sexual interest, extreme violence, delusions of grandiosity

differences between amph and cocaine

• cocaine does NOT produce psychosis

• danger of cardiovascular accident is way greater for cocaine: convulsions (and they sensitize while euphoria does NOT)

• amph causes inability to determine what is real or not during psychosis

• cocaine has local anesthetic effects and amph does not (C inhibits Na+ channels)

duration of action for cocaine vs. amph

0.5-1.5 hrs vs. 7-30 hrs

How do amphs and cocaine produce most of their behavioral, physiological and psychological effects?

by acting on monoamine NT systems, especially catecholamines

catecholamines vs. indolamines (names)

dopamine, norepinephrine, epinephrine | vs. serotonin (5-HT)

catecholamine synthesis

• tyrosine (amino acid) created from phenylalanine in diet

• tyrosine converted into DOPA by tyrosine hydroxylate (TH)

  • rate-limiting step in synthesis of DA!

• DOPA rapidly converted into DA by aromatic amino acid decarboxylase (AADC)/AKA dopa decarboxylase

• DA converted into NE by DA beta-hydroxylase (DBH)

• NE is precursor for E and is made by PNMT

rate-limiting step meaning

speed at which chemical reaction occurs

dopamine functions

• translating thoughts into action (decision-making, goal-directed behavior, movement)

• mood (desire vs. dread, negative or positive passion)

• arousal, sleeping/waking

DA pathways

ventral tegmental area, substantia nigra

mesocortical pathway

cognition; organize thoughts and actions with internal goals

nigrostriatal pathway

motor, planning and execution

tuberoinfundibular

tonic inhibition of prolactin release, regulate growth hormone and release (pituitary and hypothalamus)

chemoreceptor trigger zone

medulla, nausea, emesis (vomiting), primal circuit for making sure you don’t ingest toxins

dopamine neurotransmission

• synthesized in pre-synaptic terminals

• stored in vesicles

• released in response to APs

• binds to and activates DA receptors (GPCRs)

• DA transporter removes DA from synapse

DeWitt CPP study

• humans form conditioned place preference for amph

• humans find amph effects rewarding

• mirror expectation that subjects work to experience the reinforcing effects of a drug

NBOMe

• designer drug, synthetic hallucinogen

• variant of phenylethylamines

dopamine synthesis and metabolism pathway

• tyrosine converted to L-DOPA by tyrosine hydroxylase (TH = rate-limiting step!)

• L-DOPA converted to dopamine by dopa decarboxylase

• dopamine broken down by MAO

• main metabolite DOPAC

• DOPAC broken down by COMT into HVA

3 ways DA receptors modulate neural activity

• G proteins can affect membrane potential post-synaptically

• affect gene transcription

• affect other receptors’ trafficking

DA transporter (DAT)

removal of DA molecule; grabs DA from synaptic cleft and brings it inside the presynaptic terminal, where it can then undergo enzymatic degradation or be repackaged into vesicles

How does D2 autoreceptor negative feedback reduce DA transmission?

• inhibit Ca channels → reduce ability of transmitter to be released through vesicles

• indirectly influence by increasing DAT expression and activity (more DA brought back into the presynaptic terminal)

• affect phosphorylation state of TH (reduce it) → less pKa, less phosphorylation of TH, less DA synthesis

Metabolites (HVA and DOPAC) are often measured because

they act as an indicator of how much DA is present

D1-like receptor family

• D1 and D5

• increase cAMP

D2-like receptor family

• D2, 3, 4

• decrease cAMP

haloperidol

• D2R antagonist

• first antipsychotic (potent, causes catatonia)

• good at reducing psychosis symptoms and agitation

DA receptors affecting other receptors’ trafficking

• movement of receptors from inside cell to synapse

• ex. D1R activates pKa, increases amount of AMPA receptors at membrane, enhances likelihood that they’ll end up in a synapse and increase transmission (affects actual movement of AMPA-type glutamate receptor into extra-synaptic space)

D2R autoreceptor

• located on presynaptic terminal

• degree to which any of the 3 negative feedback mechanisms is engaged depends on the strength of signal

• lots of DA = more activity, processes are stronger (hence negative feedback action to bring transmission back down)

striatum importance

key site of DA action

in situ hybridization

• radioactive probe that is complement to mRNA that codes for receptors

• probe binds to mRNA, expose sections to film, radioactive energy can be transduced

• darker color = more radioactive tracer present, more receptors

different receptors have ______ distributions, helpful for?

distinct, helpful for limiting drug action if targeting receptors that each exist in specific brain areas

Parkinson’s disease basic facts

• death of DA neurons

• no/less melanin in substantia nigra = DA neuron death

• can be heritable, can come from toxins

• strong symptoms do not appear until ppl have lost about 80% of their DA cell bodies

• often not bilateral

Parkinson’s pharmacotherapy

• L-DOPA given with another drug (ex. Pramipexole) that prevents it from being converted intp DA in peripheral tissues (so that as much as possible gets to the brain)

• DA receptor agonists

  • on-target SE = compulsive behaviors

Terry Robinson study (paradoxical behavior)

• toxin used to deplete DA from rat brain → rat cannot move

• rat can swim in cold water, however

• human Parkinson’s ex. running during fire alarm (cue jumpstarts action that ordinarily cannot be performed)

• DA acts as bridge between thought of movement and actual movement

The Case of the Frozen Addicts

• 1970s; Berkeley students tried to make synthetic opioid MPPP

• drug contaminated with MPTP compound, which kills DA neurons

• drug users contracted Parkinson’s symptoms

DA neurotoxin rat study

• 6-hydroxydopamine used for rodents since they are resistant to MPTP

• dark color = dense with DA terminals coming from VTA and SN

• lesion both sides of brain = severely akinetic

DA Deficient Mice

• how to get rid of DA but not NE

• TH knockout mouse

  • no DOPA or DA

  • introduce TH gene back into cells that also express DBH (which converts DA into NE)

  • cells make DA and convert it to NE

  • restore NE in neurons that normally make it, but get rid of DA in the DA cells because they don’t have TH

• develop normally until 10-15 days after birth; then develop Parkinson’s symptoms

autonomic effects of psychostimulants and NE

• sympathomimetic effects (increase blood pressure, hyperthermia, bronchodilation

• NE transmission important for sympathetic NS activation (and fight or flight responses)

• NE acts on adrenergic receptors

adrenergic receptors

• alpha and beta-adrenergic

• peripheral sympathetic NS fight or flight response

  • activated to cause it

NE synthesis and storage

• DA comes into vesicle through VMT

• DA converted by DBH into NE

• happens inside vesicles

• NE broken down by MAO

• NE transporters bring NE back into presynaptic terminal

difference between DA vs. NE synthesis

takes place in cell body and presynaptic terminal itself vs. in synaptic vesicle

locus coeruleus relevance

• located centrally in brain, projects broadly to many different regions

• cell bodies that predominantly make NE in the CNS live here and send axons out

• no PMNT (creates epinephrine from NE)

• lots of DBH (enzyme required to make NE)

noradrenergic projections

• dorsal bundle: coordinates and affects different brain regions all at once

• ventral bundle: primarily goes to bed nucleus of the stria terminalis, more specific activity

AMPT

depletes catecholamines by inhibiting TH

reserpine

depletes catecholamines by inhibiting vesicular uptake, binds to VMAT and blocks cocaine effect by making vesicles leaky (no DA to release)

6-OHDA

damages or destroys catecholaminergic neurons

apomorphine

stimulates DA receptors, generally agonists

quinpirole

stimulates D2 and 3 receptors (agonist)

cocaine and methylphenidate action on DA system

inhibit catecholamine reuptake

primary action of psychomotor stimulant drugs

increase concentrations of monoamine NTs in synapse (act at transporters; DAT, NET, SERT)

microdialysis

• probe with semi-permeable membrane

• artificial CSF

• can pick up NTs (measurable molecules)

• dialysate is whatever diffuses across

effects of amph and cocaine on DA in striatum

• microdialysis probe into striatum

• increase in extracellular DA after animal is given drug injection

• different strains of rat show different sensitivity

• DA response is BIGGER in animals with a history of amph than those that got saline

• sensitization of response to amph in DA signal

amph, c, DA (dose-effect functions)

• orders of magnitude are huge for amph compared to c

• even at lower doses, amph axis starts higher than c

amph vs. c (in terms of monoamines)

• both increase DA, NE, 5-HT

• cocaine primarily blocks transporters

• blocks reuptake of DA from synapse by DAT

By blocking ___, high doses of cocaine can produce ____-fold increases in striatal dopamine levels.

DAT, 2-3

DAT KO mice

• white mouse (wild type), brown (heterozygous, missing half of DAT), black (homozygous, no DAT)

• hyperactive mouse = too much DA, DAT KO

• mice lacking DAT are spontaneously hyperactive as if they were on cocaine

• even if half the DATs are gone, the remaining do a good job of regulation (heterozygous activity is close to wild type)

cocaine mechanism of action and requirements

• blocks DAT, NET, SERT

• requires AP, Ca+, exocytosis, DA synthesis and storage