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Chapter 12: Psychomotor stimulants - Cocaine and Amphetamines - Coggle…
Chapter 12: Psychomotor stimulants - Cocaine and Amphetamines
Cocaine Background and History
Freud recommended it for many ailments and declared it was NON-ADDICTIVE (PO)
Coca-Cola contained caffeine AND cocaine
marketed as alternative to alcohol during temperance movement
COCAINE: Basic pharmacology and mechanisms of action
Basic Pharmacology
Cocaine alkaloid
extracted from coca leaves (.6%-1.8% cocaine)
converted to a hydrochloride (HCl) salt and crystallized
water-soluble: can be taken orally, intranasally, or by IV (NOT HEAT SOLUBLE SO IT CAN'T BE SMOKED)
to make SMOKABLE cocaine (crack "rock" cocaine)
mix dissolved cocaine HCl with baking soda, heat the mixture, dry it
freebase crystals "crackle" when heated
produces profound euphoria and is LESS EXPENSIVE than cocaine powder
Lipophilic
readily passes BBB
broken down by enzymes in the blood and liver (non-CYP)
rapidly eliminated
half-life: .5 - 1.5 hours
"high" lasts ~30 minutes
metabolites: benzoylecgonine (detected in urine for several days)
Mechanisms of Action
Monoamine reuptake inhibitor: blocks DA, NE, 5HT reuptake
binds with highest affinity to 5HT transporter
blocking DA reuptake is the most important factor for cocaine's stimulating, reinforcing, addictive properties
How do we know that DA reuptake inhibition --> psychoactive effects?
SSRIs and SNRIs (block SERT and NET) DO NOT produce psychostimulant effects
SERT KO and NET KO mice DO SHOW cocaine-induced increase activity (because you're not affecting DA)
DAT KO mice display no FURTHER cocaine-induced increase in activity
destruction of NE nerve fibers --> LITTLE EFFECT on psychostimulant effects of cocaine
destruction of DA nerve fibers LACKS psychostimulant effects of cocaine
At high concentrations: also inhibits V-gated Na+ channels
acts as a local anesthetic
bc it prevents transmission of signals along sensory nerves
schedule II drug
ex. procaine, lidocaine
also a potent vasoconstrictor
COCAINE Acute Behavioral and physiological effects
Cocaine "high"
low doses --> increased locomotion
as dose is increased: behaviors are replaced by focused stereotypes (picking and scratching in humans AND agression
Mesolimbic DA pathway (key role in reinforcing effects)
Rats self-admin cocaine directly into NAcc
Re-instatement of cocaine-seeking behavior in previously extinguished animals --> stimulated by microinjection of DA receptor agonists directly into the Nacc
mutant mice expressing a cocaine-insensitive DAT --> reduced cocaine self-admin
Continuous self-admin of cocaine
will not eat or drink
reinforcing properties and high abuse potential
in self-admin studies, there is often NO ALTERNATIVE reinforcer available
What happens when 2 reinforcers ARE available
animals trained to press either lever for saccharin or cocaine
cocaine had a higher breaking point than saccharine
animals preferred saccharine
shows that in the presence of alternative reinforcer, animal won't pick cocaine so readily
Psychomotor stimulants are sympathomimetic: activates sympathetic NS by blocking NET
increased heart rate, vasoconstriction --> hypertension, hyperthermia
Low cocaine responder vs. high cocaine responder
LCRs have higher basal numbers of striatal DAT than HCR rats
didn't influence extracellular DA levels, DA signaling, or locomotion under DRUG-FREE conditions
Acute cocaine challenge
lower number of reuptake sites in HCR group --> more synaptic DA
in LCR group, there is spare "free" DAT
COCAINE Effects of chronic exposure
capture ratio: 15% of initial intranasal users become abusers
Reinforcers in the early stages: stimulating, euphoric, confidence
euphoric effects of cocaine shows TOLERANCE over time
increased drug taking
social responses may. play a role in abuse - positive attention from friends
Other facors of abuse
comorbidity with other psychiatric disorders
environmental cues
"incubation" of cocaine craving (craving increases over time following termination of use)
abnormal PFC function - disinhibition, lack of self-monitoring
Tolerance and sensitization in NAcc
long-access cocaine self-admin --> reduced intracellular DA levels and reduced release
Transition from recreational --> compulsive use
ShA-1hr access sessions vs. LgA-6hr access sessions
Total intake
ShA: stable intake across sessions
LgA: escalating intake across sessions (shows tolerance)
Compare intake during 1st hour of each session
LgA escalates across sessions
ICSS after each session
Thresholds INCREASED in LgA group
thresholds CONSTANT in ShA group
PET imaging of cocaine-dependent individuals
baseline D2 receptor binding is REDUCED
MP (has similar action to cocaine) has GREATER EFFECT in the control subjects
DA system in addicts are LESS RESPONSIVE to DA reuptake blocking --> behavioral tolerance
hypodomaninergic state --> lower levels of D2 receptors
Systemic effects of chronic cocaine use
Perforation of nasal septum (frequent snorting) --> constricted nasal blood vessels --> reduced blood flow to nasal septum
High dose --> panic attacks, delusions, hallucinations
elevated body temp --> multiple organ failure --> death
Treatment Options for Cocaine abusers
Ketamine: significant decrease in cocaine use
GLP-1: satiety hormone
neuropeptide: produced inNTS
GLP-1 neurons in NTS send direct projections to VTA and NAcc
GLP-1 receptors regulate intake of highly palatable food (lowers)
GLP-signaling in mesolimbic DA system influence non-feeding motivated behaviors
GLP-agonist (Exendin-4) into VTA and NAcc REDUCES cocaine seeking behaviors during relapse
Gene transfer therapy
natural gene produces BChE enzyme: splits cocaine molecule into 2 harmless compounds
modified gene produces a variant of BChE (cocaine hydrolase CocH) that destroys cocaine 1000s times more effectively than BChE
Amphetamines
Background/history
synthetic derivative of phenylethylamine
parent compound of a family of synthetic psychostimulants that are structurally related to DA
Natural amphetamines
cathinone
ephedrine
pseudoephedrine (for congestion)
Basic pharmacology
AMPHETAMINES: PO or IV
METHAMPHETAMINES: PO, snorted, IV, smoked
stronger effects on CNS than Amphetamines
methamphetamine hydrochloride in crystalline form --> smoking
IV amphetamine/methamphetamine + heroin = speedball
amph and meth are metabolized SLOWLY by the liver --> long half-lives
Amph: 6hrs
Meth: 12hrs
Mechanisms of action
Amph and meth are INDRECT AGONISTS of NET and DAT systems
2 modes of action
1) enter DA/NE nerve terminals via uptake by DAT/NET and cause vesicles to release DA/NE into cytoplasm
2) Reversal of DAT/NET --> very high levels of DA/NE in synaptic cleft
Behavioral/neural effects of amph
stimulant meds for ADHD
hypothesis: DA and NE activity in the PFC is deficient in ADHD patients
ADHD meds enhance catecholaminergic activity in PFC to restore balance (optimal a2 and D1 activation)
ADH is in fatigued state
NE and DA work together to increase signal/noise ratio
NE activation of a2a receptors --> enhances strenth of RELEVANT sensory input (increases signal)
DA activation of D1 receptor --> weakens irrelevant sensory input (decreases noise)
cAMP signaling opens K+ channels --> WEAKENS network connectivity
a2A INHIBITS cAMP. --> INCREASES signal
D1 INCREASES cAMP --> WEAKENS inappropriate responses
Amph-induced psychosis: not relevant to schizophrenia
chronic, high-dose abuse --> psychotic reactions
VISUAL, olfactory, auditory hallucinations
paranoia with delusions of persecution --> SOME INSIGHT remains
FORMIFICATION: feeling bugs crawling on them
EXTREME ANXIETY AND FEAR
Neurotoxicity
meth --> damage to DA axons and terminals
damages 5HT fibers in several brain areas (neocortex, hippocampus, striatum)
mechanisms of neurotoxicity: oxidative stress, excitotoxicity, neuroinflammation (microglial activation), mitochondrial dysfunction
Brain imaging
reduction in striatal DAT bidning with chronic meth use
damage is similar to PD PATIENT
Loss of cell bodies in substantia nigra is not seen - neurochemical response, not physical damage?
Systemic effects
chronic meth use --> cardiovascular problems and premature aging
meth mouth: broken, discolored, rotting teeth
salivary glands dry out --> mouth acids eat away at tooth enamel
grinding teeth, binging on sugary foods, don't brush teeth
Psychomotor stimulants and withdrawal
withdrawal has no visible physical symptoms
withdrawal from cocaine occurs rapidly after last dose (bc of short half life)