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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Kappa receptors, however, appear to have an opposing effect on reward.
The hypothesis of a mu/kappa control of mesolimbic dopaminergic neurons
is best documented. It is important to note the observation that heroin is
also self-administered in animals in the absence of these neurons, suggesting
the existence of dopamine-independent mechanisms in opioid reinforce-
ment (Leshner & Koob, 1999).

Mechanism of action
The three opioid receptors (mu, delta and kappa receptors) mediate activities
of both exogenous opioids (drugs) and endogenous opioid peptides, and
therefore represent the key players in the understanding of opioid-controlled
behaviours. Opioid receptors belong to the superfamily of G protein-coupled
receptors. Agonist binding to these receptors ultimately causes inhibition of
neuronal activity.
Opioid receptors and peptides are strongly expressed in the central nervous
system (Mansour et al., 1995; Mansour & Watson, 1993). In addition to its
involvement in pain pathways, the opioid system is largely represented in brain
areas involved in responses to psychoactive substances, such as the VTA and
nucleus accumbens shell (Akil et al., 1997). Opioid peptides are involved in a
wide variety of functions regulating stress responses, feeding, mood, learning,
memory, and immune functions (for review, see Vaccarino & Kastin, 2001).

Tolerance and withdrawal
With repeated administration of opioid drugs, adaptive mechanisms change
the functioning of opioid-sensitive neurons and neural networks. Tolerance
develops, and higher doses of the drugs are required to gain the desired effect.
Humans and experimental animals develop profound tolerance to opioids
over periods of several weeks of escalating chronic administration. Tolerance
involves distinct cellular and neural processes. Acute desensitization or
tolerance of the opioid receptor develops in minutes during opioid use and
abates in minutes to hours after exposure. There is also a long-term
desensitization of the receptor that slowly develops and persists for hours to
days after removal of opioid agonists. There are also counteradaptations to
opioid effects of intracellular signalling mechanisms and in neuronal circuitry
that contribute to tolerance. These processes have been recently reviewed
(Williams, Christie & Manzoni, 2001).
Cessation of chronic opioid use is associated with an intensely dysphoric
withdrawal syndrome, which may be a negative drive to reinstate substance
use. The withdrawal is characterized by watering eyes, runny nose, yawning,
sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhoea,
increased blood pressure and heart rate, chills, cramps and muscle aches,
which can last 7–10 days (Jaffe, 1990). This was once thought to be sufficient
to explain the persistence of opioid dependence (Collier, 1980). There is no

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