Dopamine supersensitivity following chronic anti-dopaminergic treatment

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The dopamine (DA) system is critical for normal, everyday behaviours including eating, procreation and movement, but abnormal DA function is linked to a number of psychiatric disorders including psychosis and drug addiction. The most widely-used animal model of DA hyperactivity involves repeated stimulation of the DA system via administration of DA agonists (e.g., amphetamine) and this model has helped researchers to better understand DA function under normal and abnormal conditions. However, chronic suppression of the DA system (for example, via blockade of DA D2/3 receptors) also induces a DA hyperactive state. This alternate model of DA supersensitivity is an ideal tool to further our understanding of the DA system and its function. However, little is known about the long-term behavioural consequences of chronic DA receptor blockade or about the neurobiological processes involved in the induction of DA supersensitivity under these conditions. The primary goal of the proposed research, therefore, is to use animal models to determine the effects of chronic DA D2/3 receptor blockade on DA-dependent behaviours and to explore potential underlying mechanisms. This will be achieved by treating rats with the DA D2/3 receptor antagonist haloperidol and measuring their behavioural response in commonly-used tests of DA function, including psychomotor sensitization, intravenous drug self-administration and operant responding for conditioned reward. Prior research suggests that increased activity within a specific population of neurons that express the neuropeptide enkephalin and form the striatopallidal pathway might be a common mechanism underlying the ability of either DA agonists or DA D2/3 receptor antagonists to induce a DA supersensitive state. Therefore, I will determine whether the effects of haloperidol treatment on the DA-dependent behaviour mentioned above involve increased activity within the enkephalin/striatopallidal pathway. As such, these results will increase our basic understanding of the functions subserved by the DA system and allow us to better predict outcome when DA function is abnormal.