DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

650 an addiction. These variables can be organized into three
categories: agent (drug), host (user), and environment
(Table 24–1).
Agent (Drug) Variables. Drugs vary in their capacity to
produce immediate good feelings in the user. Drugs that
reliably produce intensely pleasant feelings (euphoria) are
more likely to be taken repeatedly. Reinforcement refers
to the capacity of drugs to produce effects that make the
user wish to take them again. The more strongly reinforcing
a drug is, the greater is the likelihood that the drug
will be abused.
SECTION II
NEUROPHARMACOLOGY
Table 24–1
Multiple Simultaneous Variables Affecting Onset
and Continuation of Drug Abuse and Addiction
Agent (drug)
Availability
Cost
Purity/potency
Mode of administration
Chewing (absorption via oral mucous membranes)
Gastrointestinal
Intranasal
Subcutaneous and intramuscular
Intravenous
Inhalation
Speed of onset and termination of effects (pharmacokinetics:
combination of agent and host)
Host (user)
Heredity
Innate tolerance
Speed of developing acquired tolerance
Likelihood of experiencing intoxication as pleasure
Metabolism of the drug (nicotine and alcohol data
already available)
Psychiatric symptoms
Prior experiences/expectations
Propensity for risk-taking behavior
Environment
Social setting
Community attitudes
Peer influence, role models
Availability of other reinforcers (sources of pleasure
or recreation)
Employment or educational opportunities
Conditioned stimuli: environmental cues become
associated with drugs after repeated use in the
same environment
Reinforcing properties of a drug can be measured
reliably in animals. Generally, animals such as rats or
monkeys equipped with intravenous catheters connected
to lever-regulated pumps will work to obtain injections of
the same drugs in roughly the same order of potency that
humans will. Thus, medications can be screened for their
potential for abuse in humans by the use of animal models.
Other drugs such as ethanol can be self-administered
by the oral route by experimental animals. Animals can
also model relapse to drug-taking in humans. For example,
rats learn to drink alcohol in preference to water. If
alcohol availability is removed, the animals go through
withdrawal. They will restart (“relapse” to) alcohol drinking
if presented with cues previously associated with alcohol
availability or if given mild stress (foot shock).
Reinforcing properties of drugs are associated with their capacity
to increase neuronal activity in critical brain areas (Chapter 14).
Cocaine, amphetamine, ethanol, opiates, cannabinoids, and nicotine all
reliably increase extracellular fluid dopamine (DA) levels in the ventral
striatum, specifically the nucleus accumbens region. In experimental
animals, usually rats, brain microdialysis permits sampling of extracellular
fluid while the animals are freely moving or receiving drugs.
Smaller increases in DA in the nucleus accumbens also are observed
when the rat is presented with sweet foods or a sexual partner. In contrast,
drugs that block DA receptors generally produce bad feelings,
i.e., dysphoric effects. Neither animals nor humans will take such drugs
spontaneously. Despite strong correlative findings, a causal relationship
between DA and euphoria/dysphoria has not been established,
and other findings emphasize additional roles of serotonin (5-HT),
glutamate, norepinephrine (NE), endogenous opioids, and γ-
aminobutyric acid (GABA) in mediating the reinforcing effects
of drugs.
The abuse liability of a drug is enhanced by rapidity
of onset because effects that occur soon after administration
are more likely to initiate the chain of events
that leads to loss of control over drug-taking. The pharmacokinetic
variables that influence the time it takes a
drug to reach critical receptor sites in the brain are
explained in more detail in Chapter 2. The history of
cocaine use illustrates the changes in abuse liability of
the same compound, depending on the form and the
route of administration.
When coca leaves are chewed, cocaine is absorbed slowly
through the buccal mucosa. This method produces low cocaine blood
levels and correspondingly low levels in the brain. The mild stimulant
effects produced by the chewing of coca leaves have a gradual
onset, and this practice has produced few, if any, behavior problems
despite use over thousands of years by natives of the Andes mountains.
Beginning in the late 19th century, scientists isolated cocaine
hydrochloride from coca leaves and refined the technology for
extraction of pure cocaine. Cocaine could be taken in higher doses
by oral ingestion (GI absorption) or by absorption through the nasal