cocaine and amphetamines

psychomotor stimulants

stimulate alertness and arousal

stimulate motor activity

include cocaine, amphetamines, nicotine, and caffeine

cocaine

psychoactive alkaloid found in coca leaves in south america

weak base

raw leaves

chewed with lime powder or ash to increase saliva pH which enhances absorption by decreasing the ionization of cocaine

absorption in mouth

<2% cocaine

coca paste

a crude extraction from leaves by mixing with sulfuric acid, can only be smoked

~80% cocaine sulfate

“paco” or “basuco”

cocaine HCl

crystalline powder extracted and purified from coca paste

very high concentration but usually cut with other powders

water soluble and can be taken orally, intranasally, or injected IV (cannot be smoked)

cocaine free base

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

can be vaporized and smoked but residual ether can be dangerous and explode with flame

crack cocaine

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

75-90% concentration

smoked, led to new epidemic in 1980s - 90s 

benzoylecgonine

inactive major metabolite of cocaine

detectable in urine for several days

cocaethylene

active metabolite formed when cocaine and ethanol are ingested simultaneously

longer half life than cocaine

~1-2 minutes

peak subjective effect for crack cocaine

0.5-1.5 hours

half life of cocaine

amphetamines

chemical family of synthetic and natural psychostimulants that act as sympathomimetic amines (mimic catecholamines like DA) 

ephedrine

form of amphetamine that comes from mormon tea plant, traditional chinese medicine for asthma, colds

used as decongestant

cathinone

form of amphetamine that comes from “khat” or “qat” shrub leaves (natural) 

commonly chewed in east africa and yemen

increases heart rate, excitement, euphoria, more talkative

oral route produces slow onset, relatively mild effects

bath salts

methcathinone and mephedrone are synthetic variants of cathinone

designer drugs designed as household products

placed on DEA schedule I

methamphetamine

synthesized 1919

most potent of amphetamines

oral, snorted, injected IV, or smoked

easily prepared from common household ingredients

7-30 hours

half life of amphetamines

autonomic effects

increased blood pressure, hyperthermia, bronchodilation

hyperlocomotion

effect of stimulants in animals

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

psychosis

delusional parasitosis (crawling sensation on skin causes hallucination of bugs, crank bugs, meth mites) 

anorexia

decreased eating, weight loss

physical damage

“faces of meth”

tooth decay due to neglected oral hygiene and reduced saliva

skin sores due to skin dehydration, delusional parasitosis, and obsessive picking

MDMA

first became popular as a club drug during 1980s-90s 

mostly taken orally

never used clinically but recent evidence suggests that it can enhance communication and openness (similar to psychedelics) 

8 hours

half life of MDMA

tyrosine

amino acid and the precursor for catecholamines

tyrosine hydroxylase (TH)

the rate-limiting step in catecholamine synthesis

reuptake

primary mechanism for inactivation of catecholamines and is much faster than metabolism

vesicular monoamine transporter (VMAT2)

what packages all monoamines into vesicles

DAT

dopamine plasma membrane transporter

NET

norepinephrine plasma membrane transporter

SERT

serotonin plasma membrane transporter

MAO and COMT

two types of enzymes involved in catecholamine metabolism

D1 like receptors (D1, D5)

coupled to Gs

stimulate AC and cAMP, increase neuron excitability

D2 like receptors (D2, D3, D4) 

coupled to Gi

inhibit AC and cAMP, decrease neuron excitability

midbrain

where a majority of dopamine neuron cell bodies can be found

nigrostriatal pathway

DA neurons in substantia nigra target dorsal striatum

mesolimbic pathway

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

mesocortical pathway

DA neurons in VTA target prefrontal cortex

striatum

no DA neurons but has lots of DA fibers, DA release at synapses, and DA receptors / transporters

half the neurons express D1 and half express D2

direct pathway

D1 neurons, “go”

indirect pathway

D2 neurons, “no go” 

parkinson’s disease

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

MPP+

a potent DA neurotoxin that induced parkinson’s disease

caused by MPTP being converted by MAO-B

MPTP

used in research to produce dopamine lesions in non-human primates

6-OHDA

neurotoxin used to create lesions of catecholamine neurons and/or axon fibers in rats because they are resistant to MPTP

alpha 1

adrenergic receptor coupled to Gq

alpha 2

adrenergic receptor coupled to Gi 

post synaptic and pre synaptic (serves as autoreceptor), inhibit AC and cAMP

beta 1 and beta 2

coupled to Gs

stimulate AC and cAMP, tamp down autonomic nervous system

locus coeruleus

major source of NE in the brain

neurons have TH and DBH, but not PNMT

dorsal noradrenergic bundle (DNAB)

originates from locus coeruleus in pons, broad forebrain innervation, major source of NE in brain, involved in cognition, arousal, attention

ventral noradrenergic bundle (VNAB)

originates from NE neurons in medulla, innervates limbic areas such as extended amygdala, involved in aversive aspects of stress

TAAR1

an intracellular GPCR that Amph, meth, and MDMA are agonists of

DAT knockout

genetically modified mice that are spontaneously hyperactive, showing increased locomotion

DAT knockin

genetically modified mice that have a mutation that makes DAT insensitive to cocaine but normal otherwise

show a loss of cocaine reinforcement