There is more to dopamine than just pleasure. Commentary on Volkow et al. 'Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies'.

The neurobiology of drug addiction is receiving increasing attention in a field where psychosocial theories have predominated. The use of neuroimaging techniques such as PET has been at the forefront of characterizing both the effects of drugs on the human brain and also the underlying neurochemistry of drug addicts. Volkow and her colleagues have been leaders in using this technology, in particular to define how psychostimulants affect the dopaminergic system and the role of this system in addiction to such drugs. Such work now gives us a foundation to address pharmacotherapy of drug abuse and addiction. Dopamine been the pre-eminent neurotransmitter studied in addiction. All drugs of abuse (except benzodiazepines) have been shown to increase dopamine in the critical nucleus accumbens of the mesolimbic dopaminergic system that is proposed to mediate reward and reinforcement. It is the same system that is involved in mediating ‘natural’ rewards and pleasures. As Volkow et al. (2002) state, dopamine has long been known to be involved in reinforcement but this is an ‘acute’ effect. What other pertinent processes is dopamine involved in? Does dopamine still play a role in determining ‘reinforcing’ effects after chronic drug use? Volkow et al. (2002) first discuss the role of dopamine in drug intoxication. In the literature the terms ‘positive reinforcement’, ‘high’ and ‘reward’ are often used interchangeably and can be difficult to distinguish conceptually. A positive reinforcer is defined in animal models as ‘‘a stimulus that increases the frequency of behavior that leads to its presentation’’ and has also been used to denote a reward. It is not unreasonable to suppose that the response to such a stimulus is therefore pleasurable since it is less likely that behaviours will be repeated if aversive. As stated by Volkow et al., self-report of a ‘high’ has been reported to be reliable and consistent and there is no other measure that is better at predicting human self-administration (as a marker for reinforcement). However, the subjective experience of a ‘high’ may not be the only mechanism involved in reward or reinforcement. Clearly, in the series of experiments described by Volkow et al., increases in dopamine relate to being ‘high’ from an acute dose of a psychostimulant. However, other mechanisms, including non-dopaminergic ones, may also be involved in reinforcement by these drugs. In addition it has yet to be shown that increases in dopamine levels mediate the pleasurable effects for all drugs of abuse whose primary target is not the dopaminergic system e.g. alcohol, opiates. The pharmacodynamics (i.e. molecular target) of a drug of abuse have received intense interest but as Volkow et al. have shown, pharmacokinetics are as important. In the case of methylphenidate, whilst a potential drug of abuse, since it increases dopamine levels in the mesolimbic system, its kinetics dramatically reduce its addictive potential. As every addict knows, speed of onset in achieving as a high a concentration of their drug as fast as possible is as important as the pharmacodynamics in experiencing the wanted effects of the drug. Hence addicts graduate from ‘oral’ to a ‘parenteral’ form of administration, with its inherent clinical consequences. It is also important to recognise the role of kinetics so as not to prevent drugs being developed that may be therapeutically advantageous but which increase dopamine levels. The role of dopamine after chronic drug use is less clear, since Volkow’s studies showed that dopamine release in cocaine addicts is reduced and therefore may not play a role in reinforcement. Volkow and others have shown that the markers of the dopaminergic system, including dopamine transporters