AUTORADIOGRAPHIC MAPPING OF OPIATE RECEPTORS

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The endogenous opiate system subserves several functions, as well as being the target of opium-like drugs, the addiction to which is a major social problem. Albeit it's importance information concerning this system in the human brain is scarce. Therefore we propose to study in detail the neuroanatomical distribution of the mu, delta, and kappa opiate receptors in, at least, 30 brains, 15 suicides and 15 sex and age matched controls. Both group will cover a large age span (13 to 87 years) as well as adequate representation of both sexes. All brains will be drug and neuropathology free. The neuroanatomical distribution of the opioid binding sites will be studied by in vitro quantitative autoradiography. Triatiated ligands, [3H] DAGO, [3H]DSLET and [3h]U69593, will be used to label the mu, delta and kappa binding sites, respectively. Extensive mapping will be performed on coronal sections obtained at several rostro- caudal levels, so that adequate representation of neocortex, limbic system structures, thalamus, basal ganglia and brain stem will be included. Characterization of the mapped sites, in terms of their dissociation constant (Kd), maximal binding capacity (Bmax), and pharmacological properties will be carried out through saturation and displacement experiments. These will be performed on membrane preparations of prefrontal cortex samples from the same brains. The size and demographic composition of this sample of brains will enable us to provide quantitative normative information on the distribution of opioid binding sites in the human brain. This information is valuable for understanding the involvement of the endogenous opiate system in pain perception and appetitive behavior as well as a variety of pathological conditions in which the opiate system is involved. The effects of age and sex on opioid binding sites can be deduced from our sample and help understand the role played by these factors in a variety of behaviors subserved by the opiate system. Comparison between the distributions obtained from brains of suicide victims and appropriately matched controls will help to understand the role of the opiate system in suicidal behavior and possibly depression. Data will be analyzed using multivariate techniques. In addition to the characterization of age, sex and suicide effects and the interactions between them, the distribution of opioid binding sites will be correlated with the distributions of markers of manoaminergic systems derived from the same brains. This latter analysis will promote the understanding of interrelationships between different neurohumoral systems in the human brain.