PSY 374 Study Guide - Midterm Guide: Knockout Mouse, Nucleus Accumbens, Substantia Nigra
EXAM #3 STUDY GUIDE (Part 4)
Chapter 12: Psychomotor Stimulants: Cocaine and the Amphetamines
Basic Pharmacology of Cocaine
The cocaine alkaloid is extracted from coca leaves and then converted to a hydrochloride (HCl)
salt and crystallized.
Cocaine HCl is water-soluble and thus can be taken orally, intranasally (snorting), or by IV
injection, but because cocaine HCl is not heat-stable, it cannot be smoked unless converted into
freebase cocaine or “crack”
Extremely rapid absorption occurs with IV injection and freebasing (smoking), absorption is
slower with snorting and oral use
Smoking crack cocaine results in a large surge of cocaine in the brain; rapid entry into the brain
is an important factor in the strong addictive properties of crack cocaine.
Cocaine is broken down by enzymes in the blood and liver and is rapidly eliminated, with a half-
life ranging from 0.5 to 1.5 hrs, while the cocaine “high” typically lasts only about 30 minutes
Breakdown products such as benzoylecgonine persist and can be detected in the urine for
several days.
Cocaine plus alcohol produce a unique metabolite called cocaethylene, which has activity
similar to cocaine, but a longer half-life.
Cocaine’s Mechanism of Action
Cocaine is an agonist for the dopaminergic, noradrenergic, and serotonergic systems
Cocaine blocks the reuptake transporter channels on dopamine (DA) norepinephrine (NE)
serotonin (5-HT) neurons
These transmitters are normally cleared from the synaptic cleft by membrane transporters;
cocaine binds to the transporters and prevents re-uptake.
Inhibition of the transporters leads to increased neurotransmitter levels in the synaptic cleft and
a corresponding increase in transmission at the affected synapses.
Cocaine binds most strongly (with highest affinity) to the 5-HT transporter, followed by the DA
transporter, and then the NE transporter.
But blocking DA reuptake appears to be most important for cocaine’s stimulating, reinforcing,
and addictive properties.
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At high concentrations, cocaine also inhibits voltage-gated Na+ channels in axons, blocking nerve
conduction; when cocaine or Procaine (Novocain) and lidocaine (Xylocaine) are applied locally,
they act as a local anesthetic by preventing transmission of signals along sensory nerves.
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Acute Behavioral and Physiological Effects of Cocaine
Typical aspects of the cocaine “high” are feelings of exhilaration and euphoria, a sense of
wellbeing, enhanced alertness, heightened energy, and great self-confidence.
Increased aggressive behavior may contribute to the street violence associated with cocaine
use.
In animal models, low doses result in increased locomotion, rearing, and mild sniffing behavior,
and at high doses cocaine produces focused stereotypies (repetitive, seemingly aimless
behaviors performed in a relatively invariant manner)
Cocaine is sympathomimetic—it produces symptoms of sympathetic nervous system activation
including increased heart rate, vasoconstriction, hypertension, hyperthermia.
DA plays the most important role in mediating behavioral responses to cocaine and
amphetamine.
Of special relevance are the dopaminergic projections from the midbrain (substantia nigra and
ventral tegmental area) to the striatum and nucleus accumbens.
Neurochemical mechanisms of cocaine action have also been studied using genetic knockout
mice.
Mutant mice with a DA transporter that is still functional for DA (i.e., able to take up DA from
the extracellular fluid) but insensitive to cocaine fail to self-administer the drug.
Nucleus accumbens DA has also been implicated in cocaine reward using paradigms that test for
drug-seeking behavior as a model of relapse.
Reinstatement of cocaine-seeking behavior in previously extinguished rats can be stimulated by
microinjection of DA receptor agonists directly into the nucleus accumbens.
PET imaging has been used to estimate DAT occupancy by behaviorally active doses of cocaine
or methylphenidate; this research indicates that those with high baseline level of DA activity in
the mesolimbic pathway will experience greater addictive potential for cocaine
Cocaine and Dopamine Receptor Sub-types
There are five DA receptor subtypes (D1 – 5).
D1 receptors are required for the locomotor-stimulating and reinforcement effects of cocaine; D1
receptor knockout mice do not self-administer cocaine
D2 knockout mice do self-administer cocaine, suggesting that the D2 receptor in not necessary
for the reinforcing effects of cocaine
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Document Summary
Chapter 12: psychomotor stimulants: cocaine and the amphetamines. The cocaine alkaloid is extracted from coca leaves and then converted to a hydrochloride (hcl) salt and crystallized. Cocaine hcl is water-soluble and thus can be taken orally, intranasally (snorting), or by iv injection, but because cocaine hcl is not heat-stable, it cannot be smoked unless converted into freebase cocaine or crack . Extremely rapid absorption occurs with iv injection and freebasing (smoking), absorption is slower with snorting and oral use. Smoking crack cocaine results in a large surge of cocaine in the brain; rapid entry into the brain is an important factor in the strong addictive properties of crack cocaine. Cocaine is broken down by enzymes in the blood and liver and is rapidly eliminated, with a half- life ranging from 0. 5 to 1. 5 hrs, while the cocaine high typically lasts only about 30 minutes. Breakdown products such as benzoylecgonine persist and can be detected in the urine for several days.
