ADDICTION AS ABERRANT LEARNING—EVIDENCE FROM PARKINSON'S DISEASE

Ambermoon et al. 1 review the phenomenon of levodopa abuse in Parkinson's disease (PD), and conclude that it ought to be labeled an addiction. The case is strong: affected patients display both behavioral and neurochemical features reminiscent of addiction to stimulant drugs. They take excessive amounts of levodopa, beyond the amount needed for relief of motor symptoms, even when this causes unpleasant side effects. Attempts by their physician to reduce dosage are met with anxiety, compulsive drug-seeking, hoarding and attempts to obtain multiple prescriptions. Neurochemically, levodopa is converted to dopamine and, like almost all drugs of abuse, ingestion leads to relatively rapid increases in synaptic dopamine. There is some evidence that levodopa-abusing patients display sensitization 2, i.e. a progressive increase in efficacy with repeated use. Note, however, that sensitization should not be considered a sine qua non of addiction. Indeed, sensitization to the clinical antiparkinsonian effects of levodopa occurs normally after initiation of treatment 3. The clinical features of levodopa abuse have implications for addiction in general. For example, the risk factors for its development in PD are also risk factors for addiction in the general population. These include the personality trait of novelty seeking, a family history of addiction or mood disorder and younger age, features that suggest a pre-existing vulnerability. Certain PD patients develop a slightly different medication-induced behavioral syndrome that manifests as pathological gambling, hypersexuality or compulsive shopping 4, 5. These disorders are also reminiscent of drug addiction, and indeed there is a move to re-classify them as behavioral addictions rather than ‘impulse control disorders’6. As in drug addiction, affected individuals engage in compulsive uncontrolled behaviors that persist in the face of adverse effects. There is a key difference, however, between behavioral addictions and dopaminergic medication abuse in PD: the former appear to be caused almost exclusively by dopamine agonists 7, 8 such as pramipexole and ropinirole, while medication abuse is essentially only described in patients receiving levodopa 9. What is the cause of this dichotomy? A clue resides in the mode of action of the two types of drugs, and the dichotomy may tell us something about the neurochemistry of addiction and reward. Levodopa increases dopamine neurotransmission at both D1 and D2 dopamine receptors. Conversely, all the clinically approved dopamine agonists act specifically at the D2/D3 receptor family, with little D1 action. (The one exception is apomorphine, which is a D1 and D2 agonist and which, in its parenteral form, can also be addictive.) Dopamine has long been implicated in reinforcement learning, notably via actions on the basal ganglia. In the striatum, D1 and D2 receptor systems are segregated, the D1 receptor being expressed on neurons of the direct pathway and the D2 on neurons of the indirect pathways 10. Converging evidence from animal experiments 11, computational modeling 12, genetics 13 and cellular biology 14 suggests that D1 receptor stimulation in the direct pathway directly promotes reinforcement learning, while dopamine acting on D2 receptors in the indirect pathway prevents inhibitory or negative learning. Dopamine, therefore, is reinforcing both by activating the direct Go pathway and inhibiting the indirect No-Go pathway. Thus, a drug acting at both D1 and D2 receptors (such as levodopa) would be reinforcing, while a drug acting only at the D2 receptor would prevent negative learning without being very (or at all) rewarding. Such a drug would then not be reinforcing in itself, but could promote or enhance the effects of other reinforcers. Indeed, the animal literature appears to support this model. While there are unequivocal reports of self-administration of D1 agonists in animals 11, the best evidence is that D2 agonists themselves are not self-administered; rather, it appears that they act to enhance the effects of other conditioned stimuli 15. One conceptualization of impulsivity is that it represents impaired inhibition. Similarly, addiction could be said to result from insensitivity to the negative consequences of drug-taking or reward-seeking. In the case of PD patients receiving dopamine agonists, insensitivity to the costs of reward-seeking could be a consequence of excessive stimulation of the D2 receptor. This is consistent with a considerable amount of human and animal evidence implicating variations in D2 receptor signaling as a cause of impulsivity and a risk factor for drug addiction 16-20. None.

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