The neuronal substrates underlying aspects of comorbidity in brain disease states may be described over psychiatric and neurologic conditions that include affective disorders, cognitive disorders, schizophrenia, obsessive-compulsive disorder, substance abuse disorders as well as the neurodegenerative disorders. Regional and circuitry analyses of biogenic amine systems that are implicated in neural and behavioural pathologies are elucidated using neuroimaging, electrophysiological, neurochemical, neuropharmacological and neurobehavioural methods that present demonstrations of the neuropathological phenomena, such as behavioural sensitisation, cognitive impairments, maladaptive reactions to environmental stress and serious motor deficits. Considerations of neuronal alterations that may or may not be associated with behavioural abnormalities examine differentially the implications of discrete areas within brains that have been assigned functional significance; in the case of the frontal lobes, differential deficits of ventromedial and dorsolateral prefrontal cortex may be associated with different aspects of cognition, affect, remission or response to medication thereby imparting a varying aspect to any investigation of comorbidity.