The interrelationship between dopamine and noradrenaline in the prefrontal cortex: From physiology to therapy

Dopamine release and noradrenaline release in the prefrontal cortex are required for the control of neurobiological functions, whose alteration is considered to be critical in the aetiology of widespread diseases such as schizophrenia, depression and attention deficit hyperactivity disorder (ADHD). The therapeutic agents used in treating these diseases may either increase or reduce dopamine and noradrenaline transmission by acting at receptor or at reuptake site level. The capacity of noradrenaline terminals to capture dopamine by means of the noradrenaline transporter (NET) has opened up new perspectives on the mechanism of action of norepinephine reuptake blockers such as long-established antidepressants or the new therapeutic agent for ADHD, atomoxetine. On the other hand, the hypothesis that dopamine and noradrenaline may be co-released from noradrenaline terminals in the prefrontal cortex suggests an additional interpretation of experimental evidence on the regulation of both dopamine and noradrenaline release through the pre-synaptic 2 receptor. Moreover, the high affinity of noradrenaline for the dopamine D4 receptor and its role in the prefrontal cortex, as well as the capacity of atypical antipsychotics to increase both noradrenaline and dopamine release in this area of the brain, support the hypothesis that dopamine-noradrenaline interaction may have a crucial role in the aetiology and in the therapy of schizophrenia. This chapter will illustrate and discuss the evidence for and against the hypothesis that there is an interdependence between dopamine and noradrenaline transmission in the prefrontal cortex, taking into consideration some recent evidence from our laboratory on the effect of chronic treatment with methylphenidate and atomoxetine on dopamine and noradrenaline release in the prefrontal cortex.