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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Role of receptor systems targeted by drugs
Repeated stimulation of receptors by drugs can lead to alterations in receptor
number and function. For example, long-term exposure to nicotine increases
the number of nicotinic acetylcholine receptors in the brain (Wonnacott,
1990; Marks et al., 1992).
The development of tolerance and dependence to morphine and other
opioids has some unique features. When the µ-opioid receptor is activated
by endogenous opioids in the brain, the receptor is internalized into the cell,
as a means of turning off the activation signal (Pak et al., 1996; Law, Wong
& Loh, 2000). This process of receptor desensitization is a highly conserved
mechanism for G protein-coupled receptors. In contrast, activation of the
µ-opioid receptor by morphine (Matthes et al., 1996) does not induce receptor
internalization (or does so very slowly), and there is abnormal prolongation
of the cell surface activation signal without desensitization (Whistler et al.,
1999). This unique property of morphine is fundamental to its ability to induce
tolerance and withdrawal.

Neuronal effects
Since substance dependence induces long-lasting and near permanent
alterations in behaviour, the likelihood of persistent changes in neural
circuitry is high, brought about by remodelling and restructuring of neurons,
as a consequence of the molecular changes induced.

Synaptic plasticity
The reorganization of neural circuitry by psychoactive substances can occur
via changes in neurotransmitter release, the status of the neurotransmitter
receptors, receptor-mediated signalling, or the number of ion channels
regulating neuronal excitability. The mechanisms that mediate compulsive
drug-seeking and drug-taking appear to mimic the physiological mechanisms
for learning and memory (Hyman & Malenka, 2001; Nestler, 2001). There are
many parallels between the processes mediating learning and memory and
substance dependence, which will be examined in more detail in Chapter 3.

Alterations in synaptic structure
Structural changes in several brain regions as a consequence of substance
use have been shown. Neurons typically have multiply-branched processes
called dendrites, and following the activation of particular neurons, the
increase in dendritic spines is indicative of the activated state. Cocaine
administration has been associated with a marked increase in the number of
dendritic spines of the neurons of the nucleus accumbens and the prefrontal
cortex (Robinson & Kolb, 1999). In contrast, there is relative loss of the

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