Page 75 - Pagetit

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

There is a large body of data showing that sensitization is associated with
marked changes in the mesolimbic dopamine system. There are both
presynaptic changes (increased dopamine release) and postsynaptic changes
(changes in receptor sensitivity). In addition, structural changes in output
neurons in the nucleus accumbens and prefrontal cortex have also been seen
following sensitization to amphetamine and cocaine (Robinson & Kolb, 1997;
1999).

Sensitization and tolerance

It is important at this point to emphasize again that this discussion focuses
on sensitization of the mesolimbic dopamine system, i.e. the increase in
dopamine in the nucleus accumbens that is observed on repeated drug
presentations, and that has been reported for psychoactive substances of all
classes.
Tolerance can be defined as a given drug producing a decreasing effect
with repeated dosing, or when larger doses must be administered to produce
the same effect (Jaffe, 1985, 1990). There is differential tolerance to
psychomotor stimulants, meaning that tolerance develops to some of the
drug effects, but not to others. Indeed, as will be discussed, some drug effects
are increased upon repeated drug use. In humans, rapid tolerance develops
to the anorexic effects and the lethal effects of amphetamine and cocaine
(Angrist & Sudilovsky, 1978; Hoffman & Lefkowitz, 1990). However, no
tolerance or change in sensitivity of behavioural responses was observed after
repeated daily oral doses of 10 mg of D-amphetamine (Johanson, Kilgore
&Uhlenhuth, 1983). Similarly, no tolerance developed to the subjective “high”
after repeated daily oral doses of 10 mg of methamphetamin, but tolerance
did develop to the cardiovascular effects with repeated daily dosing (Perez-
Reyes et al., 1991). Some acute tolerance appears to develop to the
cardiovascular effects of cocaine even over a 4-hour infusion period (Ambre
et al., 1988). Subjective, behavioural and cardiovascular effects also decline
after sequential oral doses of D-amphetamine, despite substantial plasma
levels, also suggesting acute tolerance (Angrist et al., 1987). Tolerance does
not develop to the stereotyped behaviour and psychosis induced by
stimulants, and in fact these behavioural effects appear to show sensitization
or an increase with repeated administration (Post et al., 1992). Similar results
have been observed in animal studies, with tolerance developing to the
anorexic and lethal effects of amphetamine but not to stereotyped behaviour
(Lewander, 1974). The same is also true of tolerance to nicotine, alcohol and
benzodiazepines, which develops to some drug effects but not others.
Tolerance to specific classes of psychoactive substances will be discussed
further in Chapter 4.
Tolerance can also develop as a result of metabolic enzyme induction, i.e.
enzymes that are involved in the metabolism of a drug can increase their
activity in the presence of increasing concentrations of the drug. The

54

Chapter_3 54 19.1.2004, 11:37