DBM - Chapter 12 - Cocaine and Amphetamines (Psychomotor Stimulants)

cocaine metabolism

lipophilic » readily passes through BBB

broken down by enzymes in the blood and liver (non-CYP)

• rapidly eliminated » half-life 0.5-1.5 hrs

• “high” lasts ~30 minutes

cocaine metabolites

benzoylecgonine » detected in urine for several days

when taken together, cocaine and alcohol produce cocaethylene

• similar biological activity to cocaine, longer half-life

monoamine reuptake inhibitor

cocaine blocks uptake of DA, NE, 5-HT

• highest affinity to 5-HT transporter

blocking DA reuptake appears to be most important for stimulating, reinforcing, and addictive properties

evidence for DA reuptake effects

SSRIS and SNRIS do not produce psychostimulant effects

DAT KO mice display no cocaine-induced activity increase

• SERT KO and NET KO show activity increase

destruction of NET nerve fiber » little effect on psychostimulant effects of cocaine

• destruction of DAT nerve fibers » does not produce psychostimulant effects

high dosage of cocaine

also inhibits voltage-gated Na⁺ channels

• acts as local anesthetic

• prevents transmission of signals along sensory nerves

• potent vasoconstrictor

schedule II drug

mesolimbic DA pathway and cocaine

plays key role in reinforcing effects

rats will self-admin cocaine directly into the NAcc

mutant mice with cocaine-insensitive DAT show reduced cocaine self-admin

sympathomimetic effects of cocaine

activates sympathetic NS

• increased heart rate, vasoconstriction » hypertension, hypothermia

low doses: usually not harmful

high doses: can be toxic/fatal

low and high cocaine responders

baseline: LCRs have higher basal # of stratal DAT than HCR

• did not influence extracellular DA levels, DA signaling, or locomotor behavior under drug-free conditions

acute cocaine:

• lower # of reuptake sites in striatum in HCR » more synaptic DA in HCR group

DAT occupancy and cocaine

intensity of “high” depends on the amount of DAT occupancy (needs to be > 50%)

also depends on:

• rate at which DA occupancy occurs » ROI-dependent

• baseline level of DA release in mesolimbic pathway

  • individual differences

“incubation” of cocaine craving

craving increases over time following termination of use » relapse

abnormal PFC function and addiction

leads to disinhibition, lack of self-monitoring (“car without brakes”)

seen in studies of primates repeatedly exposed to cocaine

PET imaging of cocaine dependency

baseline D2 receptor binding reduced in cocaine-dependent subjects

MP (methylphenidate) has greater effect in control subjects

• DA system in dependent individuals less responsive to DA reuptake blocking » behavioral tolerance

• hypodopaminergic state » less D2 receptors

systemic effects of chronic cocaine

organ systems: heart, lungs, GI system, kidneys

perforation of nasal septum (from snorting)

pregnancy: attention, behavioral, or cognitive abnormalities in child

high dose » panic attacks, paranoid psychosis, delusions and hallucinations

elevated body temp » multiple organ failure

GLP-1 (glucagon-like peptide)

possible treatment for cocaine abuse

satiety hormone, neuropeptide

direct projections to VTA and NAcc

regulate intake of highly palatable food » VTA injection of agonist reduces intake of palatable food

amphetamine

synthetic derivative of phenylethylamine

• parent compound of synthetic psychostimulants, structurally related to DA

indirect catecholamine agonists (NET, DAT)

amphetamine and methamphetamine modes of action

1. enter DA/NE nerve terminals by uptake (DAT/NET) and cause vesicles to release DA/NE into cytoplasm

2. reversal of DAT/NET

   1. mediated by phosphorylation by CaMKII and PKC

leads to high synaptic levels of DA/NE

methamphetamine

usually synthesized from pseudoephedrine

inexpensive, highly addictive

some users go on binges of repeated IV admin to experience recurrent highs

• “run” » ingested every 2 hours for 3-6 days, little sleep or eating

barbiturates or other depressants sometimes used to “take the edge off” or aid sleep

amphetamine/methamphetamine metabolism

slower metabolism by the liver

long half-lives:

• amphetamine: ~6 hours

• methamphetamine: ~12 hours

therapeutic uses:

nasal and bronchial decongestants (off the market in 1959)

narcolepsy (Modafinil)

appetite suppression and weight loss (Desoxyn)

psychostimulants in low doses produce calming effect in more than half of children with ADHD

stimulant meds for ADHD

amphetamines:

• Dexedrine (D-amphetamine)

• Adderall (amphetamine salts)

• Vyanse (lisdexamfetamine)

DAT and NET blocker: Ritalin (Methylphenidate)

non-stimulant meds for ADHD

Strattera (atomoxietine): NET inhibitor

• major source of DA uptake in PFC

• acts like methylphenidate in PFC » increases extracellular NE and DA

Intuniv (guanfacine): a2 agonist (post-synaptic)

amphetamine-induced psychosis

chronic, high-dose abuse » psychotic reactions

• visual, olfactory, and/or auditory hallucinations

• paranoid state with delusions of persection

• formication: tactile hallucinations

• extreme anxiety and fear

amphetamine neurotoxicity

causes damage to DA axons and terminals

also damages serotonergic fibers (neocortex, hippocampus, striatum)

potential mechanisms:

• oxidative stress, excitotoxicity, neroinflammation (microglia), mitochondrial dysfunction

meth mouth

broken, discolored, rotting death

salivary glands dry out » allows mouth’s acids to eat away at tooth enamel » cavities

teeth damaged by obsessive teeth grinding, sugary food/drink binging, neglecting to brush or floss

synthetic cathinones (“bath salts”, “zombie drugs”, Flakka)

contain one or more human-made chemicals related to cathinone

• chemically similar to amphetamines, cocaine, MDMA

• marketed as cheap substitutes

PO, snorted, smoked, or IV

symptoms:

• excited delirium, paranoia

• increased sociability and sex drive

• hallucinations

• panic attacks

withdrawal from psychostimulants

often have no visible physical symptoms

thought not to be addicting for many years

rapid cocaine withdrawal after last dose (short half-life)