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4. PSYCHOPHARMACOLOGY OF DEPENDENCE FOR DIFFERENT DRUG CLASSES

Tolerance and withdrawal
In general, there appears to be little tolerance to the effects of cocaine,
although there may be acute tolerance within a single session of repeated
substance use (Brown, 1989).
Cocaine withdrawal does not result in the severe symptoms that
characterize opioid withdrawal, but it does induce a “post-high down” (Brown,
1989), which can contribute to further cocaine use or use of another drug.
During protracted withdrawal, the orbitofrontal cortex of people with cocaine
dependence is hypoactive in proportion to the levels of dopamine D
2
receptors in the striatum. It is now proposed that the dependent state involves
disruption of orbitofrontal cortex circuits related to compulsive repetitive
behaviours (Volkow & Fowler, 2000).

Neurobiological adaptations to prolonged use
Cognitive deficits associated with chronic use of cocaine have been noted,
and such deficits reflect changes to the underlying cortical, subcortical and
neuromodulatory mechanisms that underpin cognition – and also interfere
directly with rehabilitative programmes (Rogers & Robbins, 2001). Individuals
who are dependent on cocaine have specific defects of executive functions,
e.g. decision-making and judgement, and this behaviour is associated with
dysfunction of specific prefrontal brain regions. PET studies suggest that
stimulation of the dopaminergic system secondary to chronic use of cocaine
activates a circuit that involves the orbitofrontal cortex, cingulate gyrus,
thalamus and striatum. This circuit is abnormal in people with cocaine
dependence and it is hypothesized that this abnormality contributes to the
intense desire to use cocaine, resulting in the loss of control over the drive to
take more cocaine (Volkow et al., 1996).
There appears to be strong evidence supporting the existence of a
neurological syndrome following long-term use of cocaine. People with
cocaine dependence exhibit impaired performance in tests of motor system
functioning and have slower reaction times than non-dependent individuals.
Evidence for EEG abnormalities among people recovering from cocaine
dependence have also been found (Bauer, 1996).
Clinical and preclinical studies provide convincing evidence for persistent
neurological and psychiatric impairments and possible neuronal
degeneration associated with chronic use of cocaine or other stimulants.
These impairments include multifocal and global cerebral ischaemia, cerebral
haemorrhages, infarctions, optic neuropathy, cerebral atrophy, cognitive
impairments, and mood and movement disorders. These may include a broad
spectrum of deficits in cognition, motivation and insight, behavioural
disinhibition, attention deficits, emotional instability, impulsiveness,
aggressiveness, depression, anhedonia, and persistent movement disorders.
The neuropsychiatric impairments accompanying stimulant use may

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