Cocaine and Amphetamines

Psychostimulant drugs

Stimulate alertness and arousal as well as stimulate motor activity

ex. cocaine, amphetamines, nicotine, caffeine

Cocaine definition

A psychoactive alkaloid found in coca leaves

Natural in south america

a weak base

1800 -1900: widely used, drs and scientists lauded its properties

Forms of cocaine: raw leaves

Route of Administration: chewed with lime powder or ash to increase saliva pH, enhances absorption by decreasing the ionization of cocaine

concentration: <2%

Forms of cocaine: Coca Paste

A crude extraction from leaves

concentration: 80% cocaine sulfate

route of administration: only smoked

“Paco or “basuco”

Forms of cocaine: Cocaine HCl

A crystalline powder extracted and purified from coca pasts

concentration: very high but cut with other powders

Route of administration: water soluble and can be taken orally, intranasally, or iv. CANT be smoked

Forms of cocaine: cocaine free base

made from cocaine HCL+water+base -→ extraction with ether (flammable solvent)

route of administration: vaporized and smoked but residual ether can be dangerous and explode with flame

Forms of cocaine: crack cocaine

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

concentration: 75-90

route of administration: smoked

crack led to new epidemic of cocaine use in 1980-90s

Current medical use of cocaine

Local anesthetic effects (DEA schedule II)

primary mechanism: blocks monoamine transporters (DAT)

high doses: inhibits voltage gated Na channels

Cocaine metabolism and elimination

Half life: 0.5-1.5 hrs

inactive: major metabolite benzoylecgonine is detectable in urine for several days

active: cocaethylene is formed when cocaine and ethanol are ingested simultaneously; longer half life than cocaine

Amphetamines definition

Chemical family of synthetic and natural psychostimulants

Forms of amphetamines: ehpedrine

natural chinese medicine for astma

ephedrine and pseudoephedrine

decongestants

Forms of amphetamines: cathinone

shrub leaves

natural

commonly chewed in east africa and yemen

Forms of amphetamines: bath salts

methcathinone and mephedrone are synthetic variants of cathinone

designer drugs disguised as household products

DEA schedule I

Forms of amphetamines: methamphetamine

meth: 1919

1930: medical use developed (benzedrine inhaler, use for narcolepsy)

1940: widespread adoption during WWII

1970: peak use of speed (controlled substances act)

most potent, oral, snort, IV, smoked

Forms of amphetamines: amphetamines

amphetamine: 1887

D-amphetamine, L-amphetamine, amphetamine

route of administration: taken orally or by IV

History of amphetamine use

• narcolepsy

• mild depression

• diet pill

• military during WWII (long flights)

• fatigue

Current medical use for amphetamines

Narcolepsy, ADD, ADHD

Slower metabolism and elimination when compared to cocaine

Cocaine vs. Amphetamines

1, shorter duration of action

2. worse cardiovascular effects

3. higher convulsive/seizure properties of coaine

Animals: hyperlocomotion

Locomotor activity can appear to go down with high AMPH doses because rats perfor stereotypy behavior instead

reinforcing/rewarding effects: self administration, CPP

Withdrawal factors

Chronic, high dose users of stimulants withdrawal symptoms are mostly psychological as opposed to physical but not fatal

drug cravings will last the longest

Tolerance effects of psychostimulants

1. autonomic effects

2. anorexic effects

Sensitization to other effects of psychostimulants

1. rewarding effects

2. psychotomimetic effects

3. locomotor stimulant effects

Negative effects of chronic amphetamine use

psychosis, anorexia, physical damage

MDMA

Never used clinically

recent evidence that MDMA can enhance communication and openness

Club drug during 1980-1990

Schedule I

taken orally, half life of 8 hrs

MDMDA low dose

behavioral: increased energy and sociability/empathy; mild euphoria

autonomic: increased heart rate and temperature; decreased appetite, jaw clenching

MDMA high dose

behavioral: mild hallucinogenic effects, more amphetamine-like effects “hangover”

autonomic: hyperthermia& dehydration, increased HR and BP —> stroke

Cocaine and amphetamines agonist of monoamine system

cocaine blocks reuptake of monoamines (Da, NE, 5-HT)

two actions of amphetamines lead to high DA in synaptic cleft

• causes vesicles to release transmitter

• monoamines to be transported out of neuron via reversal of transporter

Monoamines taxonomy

catecholamines: DA, NE, Epi

Indolamines: 5-HT

Catecholamine synthesis

Tyrosine is amino acid and the precursor for catecholamines

TH: rate limiting step in catecholamine synthesis

all monoamines are classical neurotransmitters

Catecholamine inactivation

Reuptake via transporters and enzymatic degradation

reuptake into the axon terminal is the primary mechanism for inactivation and is much faster than metabolism

Cathecholamine transporters

all monoamines are packaged into vesicles by the same vesicular transporter: VMAT2

each monoamines has its own synaptic plasma membrane transporter

DAT: dopamine

NET: norepinephrine transporter

SERT: serotonin transporter

each monoamine also has its own receptor

Cathecolamine metabolism enzymes

MAO and COMT

Dopamine receptors

D1,D5: coupled to Gs, stimulate

D2-D4: coupled to Gi, inhibit

all DA receptors can be postsynaptic, but presynaptic auto receptors are mostly D2

dopamine receptors are concentrated in prefrontal cortex areas (D5)

Dopamine Nuclei

1. Substantia Nigra

2. VTA

Nigrostriatal pathway

DA in neurons in substantia nigra target dorsal striatum

Mesolimbic pathway

DA neurons in VTA target ventral striatum and amygdala

Mesocortical pathway

DA neurons in VTA target prefrontal cortex

DA inputs to striatum

half of neurons express D1 and half express D2 receptor

in BG circuitry, DA neurons are part of the direct pathway and D2 neurons projections are part of indirect pathway

Parkinsons Disease

death of midbrain DA neurons and their striatal terminals

Drug induced parkinsons disease

MPTP converted by MAO-B to MPP+, potent neurotoxin developed parkinsons symptoms

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

Catecholamine neurotoxin

6-OHDA used instead to create lesions of catecholamine neurons and axon fibers in rats

Drugs that affect DA system

DOPA - converted to Da in brain

6 - ODHA- damages or destroys catecholaminergic neurons

Amphetamine- releases catecholamines

Cocaine and meth- inhibits catecholamine reuptake

Adrenergic receptors

4 primary adrenergic (NE and Epi) receptors found in brain (All GPCR)

Alpha 1: Gq

Alpha 2: Gi (serves as an autoreceptor)

Beta 1 and Beta 2: Gs

NE nuclei

Locus Coeruleus is the major source of NE in the brain

LC neurons have TH abd DBH, not PNMT

Dorsal noradrenergic bundle

Originates from LC in pons, broad forebrain innervation, major source of NE in brain

involved in cognition, arousal, attention

Ventral noradrenergic bundle

originates from NE neurons in medulla, innervates limbic areas such as extended amygdala

involved in aversive aspects of stress

NE and stress

Increased NE is responsible for many effects on memory and cognition

Distribution of NE

NE and Epi are in brain (CNS)

major components of peripheral sympathetic nervous system

Pharmacodynamics of cocaine

Cocaine blocks reuptake of DA, NE, 5-HT

DA is important for stimulating, reinforcing, addictive properties

in high concentrations, cocaine also blocks voltage gated Na channels

Pharmacodynamics of amphetamines

Blocks reuptake of monoamines

Causes DA release via

• entering nerve terminals (Via DAT) and causing vesicles to release DA

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

• high doses: inhibits MAO

Amoh, meth, MDMA are agonist of TAAR1 an intracellular GPCR

Cocaine in the human brain

Distribution of cocaine binding matches the distribution of DAT (denset in striatum)

Pharmacological studies: transporter blockers

Other drugs that block DAT are also self administered by animals

not readily self administered by animals or abused by people

• selecting blockers for NEt

• selective blockers for SERT

• other local anesthetics (Na channel blockers)

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

Lesion studies

Using 6-OHDA to lesion Da, but not NE, disrupts cocaine reinforcement (self administration)

Neurochemical studies

Similar time course for amphetamine effects on DA release in striatum and locomotor effects

Sensitization of locomotor and reinforcing effects, as well as sensitization of DA levels in striatum

Genetic studies: knockout

Spontaneously hyperactive, showing increased locomotion

Genetic studies: knockin

mutation that makes DAT insensitive to cocaine but normal otherwise. they show loss of cocaine reinforcement

completely blocks locomotor effects