Unit 6: Cocaine & Amphetamines

Current medical uses for amphetamines

• narcolepsy

• attention deficit disorder (ADD,ADHD)

  • almost all ADHD meds are stimulants

amphetamines metabolism and excretion

• slower metabolism and elimination as compared to cocaine

  • half life is 7-30 hours

behavioral and subjective effects of cocaine and amphetamines in humans

• mood amplification

• heightened energy

• sleep disturbance

• motor excitement

• talkativeness

• hyperactive ideation

• increased sexual interest

• anger

• mild to moderate anorexia

• inflated self esteem

autonomic effects of cocaine and amphetamines in humans

• increased blood pressure

• hypothermia

• bronchodilation

cocaine vs amphetamines

cocaine has

• shorter duration of action

• worse cardiovascular effects (can be lethal)

• higher convulsive/seizure properties of cocaine

effects in animals

• hyperlocomotion: locomotor activity can appear to go down with high AMPH doses because rats perform stereotypy behavior instead

• reinforcing/rewarding effects

withdrawal

• mostly psychological (as opposed to physical) and not fatal

tolerance effects

• autonomic effects

• anorexic effects

sensitization

• rewarding effects

• psychotomimetic effects (psychosis)

• locomotor stimulant effects

negative effects of chronic amphetamine use

• psychosis: such as delusional parasitosis (crawling sensation)

• anorexia

• physical damage

  • meth mouth: tooth decay due to lack of saliva and neglected oral hygiene

  • skin sores: skin dehydration, obsessive picking

MDMA history

• patented as cough syrup but never used clinically

• recent evidence that MDMA can enhance communication and openness (similar to psychedelics)

MDMA use

• club drug during 80s-90s

• schedule I classification

• taken orally

• long half life (8hrs)

MDMA effects

low doses:

• increased energy and socialbility/empathy; mild euphoria

• increased heart rate and temperature

high doses:

• mild hallucinogenic

• hypothermia and dehydration, increased HR and BP→ stroke

catecholamine synthesis

• tyrosine is an amino acid and the precursor for catecholamines

• enzyme tyrosine hydroxylase (TH) is the rate limiting step in catecholamine synthesis

• all monoamines are classical neurotransmitters (anterograde signaling)

catecholamine inactivation

• reuptake (primary mechanism) via transporters and/or enzymatic degradation

catecholamine transporters

• all monoamines are packaged into vesicles by the same transporter VMAT2

• plasma membrane transporters:

  • DAT: dopamine transporter

  • NET: norepinephrine transporter

  • SERT: serotonin transporter

• each monoamine has its own receptors

enzymes in catecholamine metabolism

1. MAO (monoamine oxidases)

2. COMT (catechol-o-methyltransferase)

Dopamine receptors

all GPCR’s: D1, D2, D3, D4, D5

D1 like receptors

D1 and D5

• coupled to Gs

• stimulatory

• increase neuron excitability

concentrated in prefrontal cortex areas

D2 like receptors

D2 D3 and D4

coupled to Gi

inhibitory

decrease neuron excitability

• most autoreceptors are D2

Dopamine nuclei

• majority of dopamine neurons (cell bodies) can be found in the midbrain in the substansia nigra or vental tegmental area (VTA)

nigrostriatal pathway

DA neurons in substantia nigra target dorsal striatum

mesolimbic pathway

DA neurons in ventral tegmental area (VTA) target ventral striatum (nucleus accumbens) and amygdala

mesocortical pathway

DA neurons in VTA target prefrontal cortex

Striatum

• has NO dopamine neurons

• lost of DA fiber, DA release at synapses, and DA receptors/transporters

  • half neurons express D1 receptor and other half D2

D1 receptors

• direct pathway

  • go

D2

• indirect pathway

  • no-go

  • extra stop

parkinsons disease

• caused by progressive death of midbrain dopamine neurons and their striatal terminals

  • symptoms: bradykinesia (slow movement), rigidity, shuffling gait, akinetic (frozen)

MPTP

• converted by MAO-B to MPP+, a potent DA neurotoxin

• Student was trying to make a synthetic opiod, but it was contaminated by MPTP, he developed Parkinsons symptoms in 3 days

  • now MPTP is used in research to produce dopamine lesions in non human primates

6-OHDA

6-hydroxydopamine

• rats are resistant to MPTP so this neurotoxin is used instead to create lesions of catecholamine neurons and/or axon fibers

amphetamine

releases catecholamines

cocaine and methylphenidate

inhibits catecholamine reuptake

adrenergic receptors

four primary receptors (NE and Epi) receptors found in brain (all GPCRs)

• alpha-1 coupled to G excitatory

• alpha-2 coupled G inhibitory (inhibit AC and cAMP)

  • serves as a autoreceptor

• Beta-1 and beta-2 coupled to G stimulatory (stimulate AC and cAMP)

Locus Coeruleus

“blue spot”

• major source of Norepinephrine in the brain

• has TH and DBH but not PNMT

Dorsal noradrenergic bundle (DNAB)

• originates from locus coeruleus in pons, major source of noroepiephrine in brain

• involved in cognition, arousal, and attention

  • increased norepinephrine is responsible for many stress effects on memory and cognition

ventral noradrenergic bundle (VNAB)

• originates from noroepinephrine neurons in medulla

• involved in aversive aspects of stress

Noroepinephrine and epineprine location

in brain; central nervous system

• also major componenet of peripheral sympathetic nervous system “fight or flight” response

Cocaine

• blocks reuptake of dopamine, norepinephrine, and serotonin

• DA is important for the stimulating, reinforcing, addictive properties of a drug

• in high concentrations, cocaine also blocks voltage-gated NA+ channels (blocks pain)

amphetamines

• also block reuptake of monoamines but also increase release of dopamine by:

  • enterning nerve terminals (via DAT) and causing vesicles to release DA

  • reversing the transporter (DAT) so that DA is transported out of the cell into the synapse

    • at high doses also inhibits MAO

• Amphetamines, meth, and MDMA are agonists of TAAR1, an intracellular GPCR

  • causes cAMP production, release of vesicular catecholamines, and phosphorylation of transporters

Cocaine in the human brain

• distribution of cocaine binding matches the distribution of DAT(densest in striatum)

evidence for why dopamine is critical for the reinforcing and locomotor effects of amphetamine and cocaine

• pharmacological studies

• lesion studies

• neurochemical studies

• genetic studies

dopamine: pharmalogical studies

• Dopamine antagonists, but not NE antagonists, disrupt amphetamine reinforcement (self-administration)

  • similar results with locomotor effects

• other drugs that block DAT are also self-administered by animals

• not readily self administered by animals or abused by people:

  • selevctive blockers of NET- Strattera

  • selective blockers of SERT- SSRIs

  • other local anesthetics (NA+ channel blockers ) - lidocaine

• only DAT blockade appears to be the core mechanism by which cocaine and amphetamine are reinforcing

dopamine: lesion studies

• using 6-OHDA to lesion DA, but not NE, disrupts cocaine reinforcement (self-administration)

  • nucleus accumbens lesion (targets DA)

dopamine: neurochemical studies

• similar time course for amphetamine effects on

  • DA release in striatum and

  • locomotor effects

• repeated amphetamine treatment produces sensitization of locomotor and reinforcing effects, as well as sensitization of dopamine levels in striatum

dopamine: genetic studies

DAT knockout mice (DAT-/-) are spontaneously hyperactive, showing increased locomotion

Knockin

DAT Knock-in have a mutation that makes DAT insensitive to cocaine but normal otherwise. They show loss of cocaine reinforcement (self-administration)

• show normal food self-administration despite lack of cocaine self-administration

dopamine pathways: mesolimbic

• stimulant induced DA in nucleus accumbens= locomotion and reinforcement

dopamine pathways: nigrostriatal

stimulant-induced DA in dorsal striatum=stereotypies

conditioned stimuli

once learned, reward-associated cues elicit dopamine release and drive motivation for the reward

cocaine cues

cue-induced dopamine release in dorsal striatum correlates with craving

• addicted individuals show dopamine release related to viewing cocaine cue vs neutral cue

• in rats, cocaine-associated cues also trigger drug seeking

therapeurtics

• no clinically licensed therapeutics for cocaine/amphetamine treatment

best treatments currently available:

• psychosocial treatment

• cognitive behavior therapy

• relapse prevention therapy

neurotoxicity

• amphetamine, meth, and MDMA can cause depletion of monoamines, and degeneration of nerve terminals depending on drug and dose

neurotoxicity: amphetamine/methamphetamine neurotoxicity

• high doses

• high extracellular DA necessary

• damage to DA terminals

neurotoxicity: MDMA

• only seretonin terminals (5-HT)

• acute adverse effects of MDMA reflect dehydration and hyperthermia

• subtle cognitive deficits in regular MDMA users

• humans: long-lasting decrease in SERT availability after chronic MDMA

• squirrel monkeys: loss of serotonin axons after MDMA; fine 5-HT axons destroyed in cortex, hippocampus, and striatum

neurotoxicity: methamphetamine

damage to both DA and 5HT terminals

• humans show long-lasting decrease in DAT availability, in abstinent methamphetamine and methcathinone users (average 3 years)

• baboons: long-lasting decrease in DAT availability after meth

• rats: long-lasting decreases in TH and DAT after meth (higher doses caused longer-lasting damage to DA terminals)

cocaine and amphetamines

are part of a larger class of drugs known as stimulants, psychomotor stimulants, psychostimulats, or uppers

psychomotor stimulats

• stimulate alertness and arousal

• stimulate motor activity

stimulants include

• cocaine

• amphetamines

• nicotine

• caffeine

cocaine

psychoactive alkoid found in coca leaves (natural)

• is a weak base

1800s and early 1900s: widely used; doctors and scientists lauded its properties

cocaine: raw leaves

• chewed with lime powder or ash to increase saliva pH which enhances absorbtion by decreasing the ionization of cocaine (weak base)

• absorbtion in mouth

• <2% cocaine

cocaine: coca paste

• crude extraction from leaves

• ~80% cocaine sulfate

• can only be smoked

• Paco or Basuco is very cheap and low grade

cocaine: HCl

• crystalline powder extracted and purified from coca paste

• cocaine concentration: very high

• water soluble can be taken orally(coca-cola), intranasally, or injected IV

• CANNOT be smoked

cocaine free base

Cocaine HCl+ water+ base → extraction with ether (flammable solvent)

• vaporized and smoked (free basing) but, residual ether can be dangerous and explode with flame

crack cocaine

• cruder preparation made from cocaine HCl. safer to make because baking soda is used instead of solvent

• cocaine concentration: 75-90%

• smoked

• crack led to new epidemic of cocaine use in the 80s-90s

cocaine history

• widely used in many products by late 1800s; until 1903 coca cola had ~60mg cocaine per 8oz serving

current cocaine medical use

• local anestethic effects (schedule II)

  • primary mechanism of cocaine: blocks monoamine transporters (like DAT)

  • high doses: also inhibits VG Na+ channels (involved in action potentials

cocaine absorption and distribution

• extremely rapid absorption of cocaine with smoking or IV

• peak subjective effect for crack cocaine is ~1-2 min

cocaine metabolism and elimination

• half life is 0.5-1.5 hrs

• inactive major metabolite bezoylecgonine is detectable in urine for several days

• active metabolite cocaethylene is formed when cocaine and ethanol are injected simultaneously; longer half-life than cocaine

amphetamines

chemical family of synthetic and natural psychostimulants

amphetamines: ephedrine

• natural

• active components: decongestants

amphetamines: cathinone

• comes from “khat” or “qat” shrub leaves (natural)

• commonly chewed

amphetamines: bath salts

• methcathinone (cat) and mephedrone (meow meow) are synthetic variants of cathinone

• designer drugs

• schedule I

amphetamine history

amphetamine 1887

methamphetamine 1919

• 1920-30: medical use developed

  • benzedrine inhaler (for conjection)

  • narcolepsy

  • used for mild depression and as a diet pill (NOT a current medical use though)

• 1940s: widespread adoption during WWII

• early 1970s: peak use of ““speed”

  • >10% of population were regular users

forms of amphetamine

• D-amphetamine

• L-amphetamine

• Amphetamine (adderall)

• methamphetamine: most potent of the amphetamines

methamphetamines

most potent

• oral, snorted, injected IV, or smoked

amphetamine related synthetics

stimulants that differ in chemical structure

• methylphenidate

• modafinil

current methamphetamine use

• meth epidemic

  • can be smoked, faster route of administration= more abuse potential

  • easily prepared from common household ingredients