Chapter 12: Psychomotor Stimulants Flashcards
(46 cards)
Cocaine- HCl
- Oral, intranasal, IV
- Vulnerable to heat
Free base:
- dissolve in H2O, NaHCO3 - heat and dry= “crack”
Lipophilic
- easily crosses BBB
Metabolites:
- benzoylecgonine
- coc + EtOH —> cocaethylene
Ephedrine
- Decreased appetite; increased energy
- Bronchodilator
Amph:
- oral, IV
Meth:
- from pseudo- ephedrine - smoked, intranasal
Metabolism:
- about 50% excreted unchanged - half life 7-30 hrs
Primary drug actions of cocaine are:
Inhibition of neurotransmitter transporters
- low affinity for DAT - higher affinity for NET and SERT
Increased DA release independent of DAT
- inhibition of NET in PFC drives excitation of VTA (increased frequency of DA release)
Inhibition of VGNaC in nerve axons (local anesthetic)
- procaine (Novocain) and lidocaine (Xylocaine)
Cocaine increased DA release independent of actions on DAT
- LC fibers project to the PFC, where they release NE onto excitatory a1-AR on glutamatergic pyramidal neurons
- NET inhibition by COC augments (increases) NE effects and actions of a1-AR in PFC
Increased excitation in PFC stimulates DA neurons in the VTA and elevates release of DA in NAcc
The primary drug actions of AMPH/mAMPH are
- inhibition of neurotransmitter transporters
- DAT, NET, and SERT (similar to COC) - increased DA release by reversal of DAT
- AMPH and mAMPH are substrates for VMAT and DAT (takes up AMPH and gets into neuron)
- m/AMPH are taken into vesicles, disrupt H+ gradient, reduce transport of DA into vesicles by VMAT; increases intracellular DA levels, because we can’t pump them into vesicles
- DAT runs in reverse, releasing DA into synapse
AMPH and mAMPH disrupt the monoamine transport cycle
- m/AMPH enters DA nerve terminals in part through uptake by DAT
- m/AMPH provoke DA release from the synaptic vesicles into the cytoplasm
- DAT functions in reverse, releasing DA into the extracellular fluid
- The combined effect of these processes is a massive increase in synaptic DA levels
The behavioral effects of COC include
Euphoric “high”
-exhilaration, more energy, less fatigue, reinforcing, self-administered
Behavioral Activation
- repetitive, stereotypes behaviors - locomotion, rearing, sniffing
Sympathetic Arousal
- tachycardia, vasoconstriction, hypertension, hyperthermia
AMPH produces other effects
Other behavioral effects:
- increased alertness, decreased sleep and improvised performance
- sustained physical effort without need for sleep
Therapeutic uses:
- Weight loss
- ADHD
- Narcolepsy
Psychostimulant microinjection: Nucleus accumbens
Increased locomotor behavior
Psychostimulant microinjection: Striatum
Increased stereotyped behaviors
6-OHDA lesion: Nucleus accumbens
- decreased locomotor response following systematic administration of a low-dose psychostimulant
- decreased reinforcing effectiveness of systemically administered psychostimulants
Cocaine and Amphetamine microinjection
Nucleus accumbens
Reinforcing to animal
- NAcc DA (either D1 or D2 receptors) has been implicated in COC reward as model of relapse
COC-insensitive DAT-ki mice do not self-administer COC
DAT “knock-in”
- transport DA - but not blocked COC
WT and HET mice
- show dose-dependent SA of COC
DAT-ki mice do not
Variations in DAT expression underlie behavioral response to COC
2 mechs:
1. Differing DAT levels
2. Differing levels of baseline DA release
LCR: increased DAT, less sensitive to COC
HCR: decreased DAT, more sensitive to COC
DA receptors in COC
D1 KO:
- required for COC-induced behavioral activation
- do not self-administer COC
- drug’s ability to promote conditioned associations with environmental cues are dependent on activating D1 receptors
D2 or D3 KO:
- not required for behavioral effects of COC
- persist in COC self-administration
Chronic COC use alters brain function
- occasional COC use may escalate to abuse and dependence
- chronic COC use leads to tolerance and sensitization
- hypofunction of the PFC caused by chronic COC
As COC dose increases
Locomotion, rearing, sniffing —> focus stereotypies
[…]% of COC users eventually abuse COC
- rewarding properties
- binge use
- switch to smoking, IV administration
Binge use
Episodic bouts of repeated uses lasting hours/days with little or no sleep
Abstinence Syndrome
- Crash- exhausted, depressed
- Withdrawal- anhedonia, anergia, anxiety, growing craving
- Extinction- symptoms subside
CS (or US) exposure induces craving
- incubation of craving
- mesolimbic DA release in NAcc(US,CS) —> increases craving
Incubation of craving
Cravings and relapse increase over time following withdrawal
Mesolimbic DA release —> increases craving
Increased in dorsal and ventral striatum, hippocampus, amygdala, and PFC
Cue-induced cocaine craving is associated with heightened […]
Cue-induced cocaine craving is associated with heightened striatal DA release
