3. Psychomotor Stimulants Flashcards
(26 cards)
cocaine history
freud liked it to treat alcoholism/depression, said it wasnt addictive
coca cola had cocaine, alternative to alcohol
illegal 1914 harrison narcotics acts
basic pharmacology of cocaine
coca leaves, water soluble not heat stable
crack (dissolve with baking soda) is heat soluble, very euphoric
rapid entry to brain (addictive)
lipophilic = cross BBB
Metabolism of cocaine
broken down by blood/liver NON-CYP enzymes
half life 30 mins
metabolites = benzoylecgonine, urine detection for days
cocaine and alc = cocaethylene
how does cocaine work
monoamine reuptake inhibitor (DA/NE/5HT)
binds highest affinity with 5HT transporter, blocks DA reuptake is reinforcing
cocaine at high conc. inhibits voltage gated Na channels = acts as local anesthetic, prevent sensory pain transmission, (procaine/lidocaine), vasoconstrictor)
how know DA reuptake inhibition important for cocaine effects
SSRI/SNRI dont produce psychostimulant effects
DAT KO = no further cocaine increase in activty
SERT/NET KO still show cocaine increase activity
destroy NET nerve fibers = no effect on cocaine action
destory DAT fibers = no cocaine effect anymore
DA concentration time matches cocaine
mild and chronic effects of cocaine
mild - euphoria, talkative, sexual
chronic - irritable, insomnia, decrease sexual
mesolimbic DA and reinforcers of cocaine
mesolimbic does reinforcing, self admin to NAcc
can reinstate cocaine beh’r by inject DA in NAcc
insensitive DAT show reduced cocaine self admin
all species self admin cocaine (high abuse)
when two reinforcers available - chose saccharine more
cocaine has higher breaking point than saccharine
sympathomimemtic cocaine
cocaine is sympathomimemtic
activates sympathetic nervous system - inc. BPM, vasoconstruct, hypothermic,
high doses toxis
DAT baseline levels and cocaine
low cocaine responders have higher DAT numbers (no diff when drug free)
high responders have less DAT so more synaptic DA when taking cocaine
intensity of high depends on DAT occupancy (ROI dependent also, and baseline DA levels (no DA release = cocaine no effect))
capture ratio and factors of abuse cocaine
15% capture ratio
reinforcing early stage of euphoria, tolerance = more drug, social response of positive attention
‘incubation of craving’ = craving inc. over time leading to relapse
abnormal PFC in cocaine = disinhibition, lack self monitor take more cocaine
Cocaine Tolerance in NAcc
and long term access effects
long term cocaine use = less DA released (need more drug to get high)
when rats had more time with cocain (6hrs vs 1hr) they took more cocaine each session, took more cocaine in first hour, and ICSS threshold increased in long-term access group, constant threshold in short-term access
PET imaging of cocaine
baseline D2 receptor binding reduced (no pre-drug control tho, between subj only)
MP (Methylphenidate, cocaine analog DAT blocker) has greater effect in control subjs, cocaine users DA system less responsive = beh’r tolerance, hypodominergic state of lower D2 levels
show PET scans with Raclopride (flourescent binds to D2 Receptor, displaced by released DA, SO control have less bright in MP bc more DA binded)
Systemic effects of cocaine
organ systems - heart/lung/GI
perforated nasal septum
cog abnormalities inf etus
high doses = panic attacks and delusion
elevated body temp = multiple organ failure is major cause OD death
treatment for cocaine
no fda approved meds
ketamine - decreases cocaine use, NMDAR antagonist
GLP-1 agonist - reduces cravings of all kinds, project VTA/NAcc, neuropeptide made in NTS, reduce palatable food intake too
cocaine vaccine - antibodies against cocaine, reduce binge/reward
chemical structure of amphetamines
synthetic derivative of phenylethylamine
compounds related to DA
indirect catelcholamine agonist (dont bind to rec)
natural amphets = cathinone and ephedrine
two modes of action of amphet/meth
indirect agonist of catechlomaniergic NET/DAT systems
1. enter DA/NE terminals, via updtake by DAT/NET, cause vesicles to release DA/NE
2. reverses DAT/NET, mediated by DAT phosphorylation by CaMK2 and PKC (leads to high levels of DA/NE)
meth vs amphet
amphet PO/IV
meth more potent, PO/snort/IV, made from pseudoephedrine, highly addictive, binges/runs take barbs to come down
both metab’d slowly by liver, amphet 6 hr half life, meth 12 hr
therapeutic uses of amphet
nasal/bronchial decongestant
narcolepsy
appetite suppression/weight loss (induces CART)
psychostims calming effect ADHD
stimulant meds ADHD and amphets
stimulant meds (dexedrine, adderall, vyanse, all these are amphets, ritalin is DAT/NET blocker)
non stimulant meds ADHD amphets
non-stimulant meds (dont affect DA) = strattera NET inhibitor which also releases more DA, NET reuptakes DA in PFC
Intuniv - a2 agonist (post syn in PFC, also autorec = less NE in PNS)
ADHD and amphets PFC
Hypothesis = DA/NE acitivty deficient in PFC for ADHD
PFC functioning is U shaped curve
ADHD enhance catecholamingeric PFC activity to restore balance
Amphetamine Psychosis
support for DA hypothesis of schizo (too much DA psychosis)
chronic high does psychotic reactions, visual hallucinations (unlike schizo), formication, anxiety
none these symptoms in schizo tho
Neurotoxicity in amphets and DAT effects
meth damages DA nerves and 5HT nerves
neuroinflammation
loss of tyrosine
Reduced striatal DAT binding with chronic meth, damage similar to Parkinsons but no loss in somas in SN, only projections
meth effects on body
premature aging, cardio problems, meth mouth - sympathomimetic so increase NE and inhibits saliva = tooth decay, grinding/neglect hygeine
