The anatomy of co-morbid neuropsychiatric disorders based on cortico-limbic synaptic interactions

Many brain disorders appear to involve dysfunctions of aminergic systems. Alterations in dopamine activity may underpin both schizophrenia and the establishment and maintenance of drug dependence while disruption of serotonergic signalling may be crucial in both depression and schizophrenia. The co-existence of nicotine and alcohol abuse with depression and schizophrenia is well-documented as is the particular vulnerability of adolescents. At the same time, a common group of brain structures is increasingly implicated in neuropathological studies. For example, depression may involve a lack of serotonin signalling, particularly in the prefrontal cortex, while in schizophrenia there is evidence for reduced dopamine signalling in the same brain region, co-existing with hyperactivity in the mesolimbic dopamine pathway. Increased dopamine release from the mesolimbic dopamine pathway is also a common factor of drugs of abuse. Furthermore, the control of motivational behaviour and dopamine release is apparently modified by hippocampal and amygdala activity, both brain regions showing pathological changes in schizophrenia and depression. Our work has focused on the intricate synaptic interactions of aminergic terminals and cortical and subcortical neurons in order to unravel the anatomical basis for these disorders and their treatments. We show convergence of dopamine and cortical inputs onto single neurons in the nucleus accumbens, and between different cortical inputs to individual neurons, providing a basis for the gating mechanisms attributed to these interactions. We have also examined local and extrinsic connections in the prefrontal cortex and the basis for regulation of both cortical neurons and midbrain dopamine neurons by serotonin from the raph é nucleus. Together with data concerning subcellular receptor distributions, this information provides a detailed synaptic framework for interpreting behavioural, pharmacological and physiological data and enhances our understanding of possible circuitry underlying comorbidity of disorders such as schizophrenia and depression with drug abuse, information invaluable in the introduction of enhanced therapies.