Dopaminergic Pathways and Receptor Physiology

pharmacological responses is the formation of a complex between the ligand (or drug or molecule) and its site of action (Taylor & Insel, 1990). Competitive binding experiments ascertain how specific the interaction is between a ligand and its binding site by examining the ability of various compounds to compete with a radiolabelled reference probe for the site. The more potently a drug binds to the receptor, the more effective it is at competing for labelled sites. The greater the potency a drug has for the receptor, the lower the concentration required before all available receptor sites are occupied or blocked. This affinity (termed Kd or Ki) for the receptor is quantified in test-tube experiments and is a function of the rate of drug association and dissociation from the receptor. It is empirically measured as the concentration of drug required to block half the total receptor population. High-affinity drugs have low Kd values. These drugs are better at ‘occupying’ receptors. In living animals, including humans, receptor occupancy by drugs is also determined by the rate of association and dissociation of the drug from the receptors, the concentration of drug at the receptor and the concentration of endogenous neurotransmitter at the receptor (Strange, 2001). Rehearsing these dry pharmacological concepts is important to our understanding of antipsychotic drug action, in particular how dopamine is the ‘comeback kid’ for hypotheses of antipsychotic drug action, a lead candidate for antipsychotic drug discovery and relevant to the modern clinical management of schizophrenia. Here we shall discuss the dopamine hypothesis of drug action, review studies that have refined understanding of its relevance, and attempt to synthesise the current view with respect to clinical management. DOPAMINERGIC PATHWAYS AND RECEPTOR PHYSIOLOGY