Cocaine and Amphetamines Flashcards
Amphetamine : Mechanism of Action
Block reuptake of catecholamines and also enhances their release.
- Block cat reuptake and induce their release into the synapse (at high doses can also inhibit cat metabolism by MAO).
- -> Reverse DAT via phosphorylation via activation of PKC and Ca2+ /calmodulin Kinase II.
- –> Also: releases DA from vesicles into cytoplasm in terminal; then transported to synapse via reversed DAT
- —> Therefore final result = BIG DA increase in synapse and transmission.
Cocaine: Mechanism of Action
Block monoamine reuptake - DA is especially important
- leads to increased NT in the cleft and increased transmission at the synapse.
- @ high doses can inhibit Na+ voltage gated channels to block nerve conduction – this is why it works as a local anesthetic (ex: novacaine, lidocaine)
Amphetamines: Behavioral Effects
- Increased alertness, well being, confidence, decreased fatigue, desire to accomplish tasks
- Increased performance on some psychomotor tasks, decreased sleep, increased athletic performance,
- when admin’d IV - undistinguishable from cocaine
- ->In animals: BEHAVIORAL ACTIVATION similar to cocaine and highly reinforcing.
- Stereotypy - repetitive motor behaviors ex) punding - take apart a phone and put it back together.
- Attentional focus problems
-At High levels: Amphetamine Psychosis - transient psychotic behavior - looks like schizo.
Amphetamines - Bio/Neuro Effects
- Increased HR, BP, vasodilation, brochodilation
- increased motor activity (nigrostriatal)
- euphoria and addiction (mesolimbic cortical)
- Inhibits pituitary function (prolactin deficient)
- Attentional focus problems
- @ high doses: neurotoxic (meth) - damage to DA axons and terminals:
- indicated by long lasting decreases in DA, TH, and DAT in the striatum
- -DAT binding decreases with chronic use
- damage to 5HT fibers (neocortex, hippo, striatum)
Cocaine Breakdown
Rapid breakdown once absorbed - half life around 1/2 - 1 1/2 hours; but metabolites last longer:
- — major metabolite = benzoylecgonine (can last for several days)
- — when taken with alcohol - produces different active metabolite: cocaethylene - similar effects to cocaine but longer half life.
Cocaine: Behavioral Effects
‘High’ = reinforcing
- -> Stimulates Mood and Behavior:
- high = euphoric, increased nrg, alertness, decreased fatigue, increased confidence
- increased sexual interest
- increased aggressiveness
- –> Animal Studies: Behavioral Activation:
- ——@ low dose: increased locomotor activity, mild sniffing, rearing
- ——@ high dose: focused stereotypes (often confined to a small area of the cage floor); repetitive, aimless behaviors performed in relatively invariant manner.
Cocaine: Physio effects
- sympathomimetic effects
- @ high doses can cause seizures, heart failure, stroke, hemorrhage
Cocaine: Neuro Effects
DA important for many neuro effects: – especially projections from midbrain (sn/vta) to striatum / NA.
- -> microinjection of cocaine to NAcc increases loco
- -> microinjection of cocaine to striatum increases stereotyped behaviors
- -> 6OHDA lesions to both these areas blunts both these effects
- -> In human study: ‘high’ = likely to occur based on occupancy of DAT receptors, the rate at which DAT occupancy occurs after drug admin, and the baseline level of DA activity of mesolimbic pathway to begin with..
But….. DAT KO mice still self admin!! (just not as much) why?
Also: Gm-DAT mice with DAT transporters that are nonfunctional to cocaine but otherwise viable are insensitive to cocaine and do not self administer.
what gives?
Anywho - NAcc DA implicated in reward tasks that test drug seeking behavior – train animals on an IV and then extinguish their responses – reinstatement of that DSB can be stimulated by a microinjection of a D1 or D2 agonist to the NAcc.
Also: several DA receptor subtypes mediate the functional effects of stimulants:
- D1: loco stimulating, self admin (reinforcement)
- D3 (in NA) - decreases the reward threshold for electrical self stimulation and self administration
Cocaine Use and Abuse
Pattern of Abuse - binges followed by periods of exhaustion
Incubation - cocaine craving and relapse increases over time since last drug admin.
Animal Models of Cocaine Dependence
1) increased drug intake via self admin: LgA vs ShA study – self admin 1 v 6 hours a day and electrical stim threshold measured 3hrs, 20hrs after the end of the session –> ((longer periods of access to cocaine can lied to increased intake, which then down regulated the reward circuit.))
2) Relapse to cocaine seeking behavior after abstinence; cocaine seeking behavior despite aversive consequences, increased BP when working to self admin on progressive ratio scale: HRein vs LRein study – self admin 3 mo’s and a end 5 day abstinence – then primer ,and reinstatement behaviors analyzed. Then took the top 24% vs the bottom 25% responders and reanalyzed based on these groups –> HRein showed increased raps during no drug conditions, increased raps despite footshocks, increased BP and of course increased raps during reinstatement test. –> ((((Addiction is a combination of prolonged exposure and genetic vulnerability )))) – take into account the study that found traits involved in cocaine use = impulsivity and novelty seeking.
Tolerance and Sensitization
Tolerance: usually to euphoric high and mood related effects – can explain increased drug taking behavior
–> methylphenidate and raclopride study and behavioral tolerance in users.
Sensitization: to locomotor activity and behavioral activation; (2 phases: induction - establishment of; and expression)
- -> DA in VTA could be important to locomotor sensitization to stimulants: pretreatment with amphetamine to the VTA can increase release of DA to the NAcc and increase locomotor response when CHALLENGED later with systemic injection of amphetamine.
- -> In humans: decreased DA activity in striatum with response to drug challenge – decreased activity of D2 receptor at baseline in users..
Cocaine Treatments
Medical:
Most target DA: agonists (methylphenidate) and antagonists (D3 receptor antag)
also:
-Modafinil/Provigil
-Antabuse found to curb alcohol use AND cocaine (even if individual doesn’t use alcohol)
-Cocaine Vaccine
Psychosocial:
- Contingency Mgmt programs
- 12 step programs
- CBT
