The original synthesis of dopamine in the laboratories of H.E. Dale in South London, followed some 50 years later by the seminal mapping of the mesencephalic dopamine (DA) pathways into ramifying mesostriatal, mesolimbic and mesocortical projections, the identification of several DA receptors and their signalling pathways, and the discovery of phasic and tonic modes of dopaminergic activity, have led to important questions about the functions of this modulatory neurotransmitter. The triadic division of these projections has suggested discrete and even parallel functions in movement (eg, Parkinson's disease, dorsal striatum), reward (eg, drugs of abuse, nucleus accumbens) and cognition (eg, schizophrenia and attention deficit/hyperactivity disorder (ADHD), prefrontal cortex). However, several lines of evidence show that this division to be artificial, it also being important to consider interactions between prefrontal and striatal systems, between the various sectors of the striatum itself, and even its component “direct” and “indirect” pathways.
This lecture will provide several examples of how work performed in experimental animals has informed these functional considerations, while also having profound implications for understanding the functions of dopamine in health and disease. A prime example is the discovery that prefrontal cortical dopamine modulates cognitive functions such as working memory, which our own work has suggested to be a consequence of stabilising representations of the world via dopamine D1 receptor actions. This contrasts with findings that striatal dopamine often serves to promote behavioural switching, as occurs for example in Parkinson's disease, ADHD and stimulant abuse following dopaminergic therapy with l-dopa, methylphenidate, and a D2/3 agonist, respectively. The hypothesis that there exist optimal levels of dopamine activity for efficient cognitive functioning in the prefrontal cortex also has applicability in the sub-cortical brain, based for example on the discovery that optimal titration of dopaminergic therapy for motor function in Parkinson's disease can lead, not only to cognitive enhancement, but also behavioural dysregulation in certain domains, possibly arising as a consequence of an “over-dosing” of ventral striatal dopamine pathways with probable motivational consequences.
Such a motivational role is consonant with the discovery that rewarding effects of psychomotor stimulant drugs such as cocaine and amphetamine were mediated by dopamine-dependent functions of the nucleus accumbens in rats. Recent work has shown that addiction to such drugs is predicted by individual differences in the propensity for impulsive behaviour, associated with variations in dopamine receptor number in the ventral striatum. This impulsivity may reflect an aberrant engagement of pavlovian approach behaviour. However, work in animals has suggested that during the addictive process, there is a shift in control of drug-seeking behaviour from the ventral to dorsal striatum that is consistent with a role for dopamine in stimulus-response habit learning. Implications for recent findings in chronic drug abusers will also be discussed.
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