PBSI 336 Chapter 6: Cocaine and Amphetamines

stimulants, psychomotor stimulants, psychostimulants, or “uppers”

cocaine and amphetamines are a part of a larger class of drugs known as

stimulate alertness and arousal

stimulate motor activity

major behavioral properties of psychomotor stimulants

cocaine, amphetamines, nicotine, and caffeine

stimulants include

cocoa leaves

cocaine is a psychoactive alkaloid found in

weak base

cocaine is a

raw cocoa leaves chewed with lime powder or ash

enhances absorption by decreasing the ionization of cocaine

< 2% of cocaine

absorption from mouth

coca paste

crude extraction from leaves

~80% of cocaine sulfate

coca paste concentration

smoked

coca paste administration

cocaine HCl

crystalline powder extracted and purified from coca paste

very high

cocaine HCl concentration

orally, intranasally, or injected IV

cocaine HCl administration

cocaine free base

made from cocaine HCl + water + base

vaporized and smoked

cocaine free base administration

Crack or Rock cocaine

cruder preparation of free base, made from cocaine HCl

75-90%

crack cocaine concentration

smoked

crack cocaine administration

crack cocaine

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

blocks monoamine transporters, like DAT

primary mechanism of cocaine

high doses of cocaine

inhibits voltage gated Na+ channels (action potential)

extremely rapid absorption

cocaine with smoking or IV

~1-2 minutes

peak subjective effect for crack cocaine

0.5-1.5 hours

half life of cocaine

detectable in urine for several days

inactive major metabolite benzoylecgonine

formed when cocaine and ethanol are ingested simultaneously

active metabolite cocaethylene

amphetamine

chemical family of synthetic and natural psychostimulants

ephedrine

natural, decongestants

cathinone

comes from khat or qat shrub, chewed

methcathinone and mephedrone (bath salts)

synthetic variants of cathinone

1920-30s

medical use of amphetemine developed

1940s

widespread adoption of amphetamine during WWII

early 1970s

peak use of speed

1887

amphetamine synthesized

1919

methamphetamine synthesized

D-amphetamine

L-amphetamine

amphetamine (adderall)

orally or by injection (IV, SC)

amphetamine administration

methamphetamine

most potent of amphetamines

oral, snorted, injected Iv, or smoked

methamphetamine administration

methylphenidate and modafinil

amphetine like stimulants

narcolepsy, mild depression, and as a diet pill

amphetamine was used for

military during WWII and subsequent conflicts

amphetamines used widely by

> 10%

percent of population that used amphetamine in 1970

smoking

faster route of methamphetamine

narcolepsy, ADD/ADHD

current medical uses of amphetamine

slower metabolism and elimination

compared to cocaine, amphetamines have a

7-30 hrs

half life of amphetamines

increased blood pressure, hypothermia, bronchodilation

autonomic effects of amphetamines

shorter duration of action, worse cardiovascular effects, higher convulsive/seizure properties

effects of cocaine compared to amphetimines

go down because rats perform stereotypy behavior instead

locomotor activity appears to what with high AMPH doses

chronic, high dose users of stimulants

withdrawal symptoms are mostly psychological and not fatal

autonomic effects, anorexic effects

tolerance to some effects of psychostimulants

rewarding effects, psychotomimetic effects, locomotor stimulant effects

sensitization to other effects of psychostimulants

psychosis, anorexia, physical damage

negative effects of chronic amphetamine use

MDA

MDE or MDEA

MDMA related drugs

never used clinically

MDMA was

enhance communication and openness

recent evidence shows that MDMA can

club drug during 1980s-90s

MDMA first became popular as

Schedule 1

MDMA classification

mostly orally

MDMA administration

8 hrs

MDMA half life

increased energy/sociability; mild euphoria

increased heart rate and temp

MDMA effects at low doses

mild hallucinogenic

hyperthermia and dehydration; increase HR and BP » stroke

MDMA effects at high doses

cocaine

blocks reuptake of monoamines

very high DA in synaptic cleft

actions of amphetamines lead to

catecholamines and indolamines

monoamines synthesize to

dopamine, norepinephrine, and epinephrine

catecholamines synthesize to

seratonin

indolamines synthesize to

tyrosine hydroxylase

rate limiting step in catecholamine synthesis

tyrosine

amino acid and the precursor for catecholamines

classical neurotransmitters

all monoamines are

reuptake via transporters and/or enzymatic degradation

catecholamines are inactivated by

primary mechanism for inactivation and is much faster than metabolism

catecholamine reuptake into the axon terminal is the

vesicular monoamine transporter VMAT 2

all monoamines packaged into vesicles by

synaptic transporters

each monoamine has its own unique

DAT

dopamine transporter

NET

norepinephrine transporter

SERT

serotonin transporter

MAO and COMT

types of enzymes involved in catecholamine metabolism

D1 D2 D3 D4 D5

dopamine receptors

coupled to Gs

D1 and D5 (D1 like receptors)

coupled to Gi

D2 D3 and D4 (D2 like receptors)

D2

presynaptic auto receptors are mostly

prefrontal cortex area

dopamine receptors are concentrated in

neurons in brainstem

send broad diffuse projections to large areas of forebrain

midbrain, substantia nigra and ventral tegmental area (VTA)

majority of dopamine neurons can be found in

nigrostriatal pathway

DA neurons in substantia nigra target dorsal striatum

mesolimbic pathway

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

mesocortical pathway

DA neurons in VTA target prefrontal cortex

send axon projections to striatum

no DA neurons in striatum but rather DA neurons

DA fibers, DA release at synapses, and DA receptors/transporters

striatum has a lot of

death of midbrain dopamine neurons and their striatal terminals

parkinsons disease

MPP+

a potent DA neurotoxin

MPTP

used in research to produce dopamine lesions in non human primates

6-OHDA is used instead

rats are resistant to MPTP so

α1 α2 β1 β2

primary adrenergic receptors found in brain

coupled to Gq

alpha 1

coupled to Gi and autoreceptor

alpha 2