Cocaine Systems

Question 1

Describe prosecutions

Answer 1

Equivalent sentence for powdered cocaine required possession of 1 kg of drug

• Many speculate this disparity contributed to racial bias in drug prosecutions

Question 2

Describe perceptions of pCE

Answer 2

• Crack cocaine can be explicitly tested by the presence of methylecgonidine
• From 1980-89 studies showing effects of cocaine on fetal development has a 57% publication rate while
  those showing lack of effects had an 11% publication rate (Society for Pediatric Research)

Question 3

Describe effects of PCE

Answer 3

• Studies support moderate decreases in learning in the presence of distractions
• Prenatal nutrition, pre- and post-natal care, additional drug use (alcohol/tobacco), environmental
  risks, increased rates of STI (incl. HIV and hepatitis)
• Small increased risk of ADHD or increased impulsivity/distractibility

Question 4

Describe how cocaine is sympathomimetic

Answer 4

• Cocaine elevates NE signalling at noradrenergic
  locations
• Cocaine exerts activating effects on the
  sympathetic nervous system
• Many adverse effects of cocaine are due to
  sympathetic activation (stroke, heart failure,
  seizure, intracranial hemorrhage)
• Central noradrenergic effects contribute to the
  psychostimulant effects of cocaine

Question 5

Describe dopaminergic effects of cocaine

Answer 5

• Two key pathways:
• Nigrostriatal– substantia nigra to the
  striatum
• Mesolimbic– ventral tegmentum to
  nucleus accumbens

Question 6

What effect does it have on the nigrostriatal pathway?

Answer 6

Microinjection of cocaine into striatum
elicits stereotyped behaviours

Question 7

Describe the effect it has on the mesolimbic pathway

Answer 7

• elicits
  hyperactivity

Question 8

Describe basal ganglia

Answer 8

Activation of nigrostriatal dopamine
pathways promotes the direct pathway
(D1 – excitatory) over the indirect
pathway (D2 – inhibitory).

Question 9

Describe cocaine psychosis

Answer 9

• Characterized by transient paranoid psychosis with delusions and
  hallucinations
• Common feature of chronic high-dose cocaine abuse (binge use)
• Restricted to periods of drug use
• Occurs more frequently over time
• Result of sensitization to drug (increased effect over subsequent doses)
• Similar to psychosis in Schizophrenia
• Sensitive to antipsychotics – mesolimbic DA

Question 10

Describe acute cocaine tolerance

Answer 10

• TH regulates overall rate of catecholamine
  synthesis
• Phosphorylation
• Activity-dependent activation (CaM-kinase
  phosphorylation)
• Modulatory activation (such as PKC signalling)
• Acute tolerance results in large part from
  inhibition of dopamine biosynthesis
• Presynaptic autoreceptors respond to prolonged
  DA in the synapse to inhibit TH

Question 11

Describe adverse effects of cocaine use

Answer 11

• Chronic, heavy cocaine use is associated with a mild cognitive impairment
• Verbal memory, attention, and motor function
• Correlated with gray and white matter abnormalities in the cortex and striatum
• Cardiotoxic effects of chronic use
• Arrhythmia, cardiac myopathy, myocardial infarct

Question 12

Describe cocaine addiction treatment

Answer 12

• D1- and D2-family receptor
  antagonists can reduce reinforcing
  effects of cocaine
• Specific D3 antagonists (SB-277011-
  A) or partial agonists (BP897)
  decrease SA or CPP

Question 13

Describe human trials

Answer 13

• Administration of ecopipam, a D1-
  family antagonist, in cocaine users has
  had mixed results
• Reported to reduce high in IV trials
• Reported to increase high in freebase
  smoking trial
• Trials of selective DAT inhibitors or D1
  agonists as replacement therapeutics
  have been limited by decreased seizure
  thresholds
• Some studies have used disulfuram to
  treat cocaine abuse due to the high
  coincident use of alcohol and cocaine
• Disulfuram is a common treatment for
  alcohol abuse – it inhibits aldehyde
  dehydrogenase and causes an acute
  aversive reaction