Clinical Brain Imaging

National Institute Of Mental Health

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Abstract

Decreases in opiate receptor avidity as quantified with the positron-emitting opiate antagonist 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF) occur in Alzheimer's disease (Cohen et al., 1997) and following the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning of rhesus monkeys (Cohen et al., 1998, 1999). While, It is likely that these changes reflect adaptive responses to alteration in function in the MPTP-lesioned animals, it is not clear in the Alzheimer's patients whether the avidity changes reflect primarily the direct effects of neurodegeneration or an adaptational response. To examine the question of functional vs. direct opiate receptor avidity changes in response to neurodegeneration we elected to examine opiate receptor avidity in animals with lesions of the visual system. The visual system has provided exceptionally useful models with which to study structural and biochemical neuronal plasticity in the context of development and of altered function (Daw, 1995; Milner and Goodale, 1995; Wiesel and Hubel, 1963). Opiate receptor avidity (B'max /KD) was measured in four rhesus monkeys following unilateral lesioning of the optic tract combined with transections of the corpus callosum and the hippocampal and anterior commissures depriving one hemisphere of visual input (Tract & Split), two animals with transection of corpus callosum and commissures only (Split), and nine healthy monkeys with positron emission tomography (PET) and 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. Opiate receptor avidity was found to be significantly higher in the Tract & Split animals, only, bilaterally throughout the lateral cortex and in the cingulate and posterior putamen (41%-117%). Ipsilateral changes were consistently greater than those contralateral, but this asymmetry was of statistical significance only in the parietal and occipital cortices. Cyclofoxy avidity was decreased in the medial cortex of both the Tract & Split and Split animals (~25%). The results suggest that opiate pathways undergo extensive alteration in response to changes in brain functional activities brought about through hemispheric visual deprivation. Male-female differences in neuroanatomy and/or neurochemistry are likely to be the basis of sex differences in behavior, in vulnerability to and expression of neuropsychiatric disorders and in their response to treatment (Breedlove, 1992; Kelley, 1988; Schlaepfer et al., 1995; Swaab et al., 1985). There is indirect evidence and some direct evidence that sexual dimorphism exists in mammals with respect to opiate pathways. Sex differences have been observed in response to both acute and chronic pain in rodents and with respect to the multiple pain inhibitory pathways (Archer, 1975; Bodnar et al., 1988). Under certain experimental conditions women have been found to have lower thresholds of pain response than men, and to be more sensitive to the analgesia induced by the kappa-opioid pentazocine (Gear et al., 1996). Gender differences have also been reported with respect to opiate abuse with women more often reporting using heroin initially to decrease pain and to having become more rapidly addicted (Greenfield, 1996). As noted above, we have found opiate receptor avidity to be decreased in Alzheimer's patients, i.e., the cortex and limbic and paralimbic areas were affected, but the subcortex (caudate, putamen and thalamus) was relatively spared. This finding together with the fact that both the Alzheimer's patients and our age-matched normals consisted of both males and females, suggested to us the possibility of using the data obtained from this study to evaluate possible sex differences with respect to cyclofoxy avidity in the subcortex. By using both the comparison controls as well as the Alzheimer's patients we expected to have sufficient power to detect cyclofoxy avidity differences between the sexes should they exist. Opiate receptor avidity (B'max /KD), was measured in the subcortex of 9 females (5 healthy subjects, 4 Alzheimer's patients) and 15 males (7 healthy subjects, 8 Alzheimer's patients), 51 to 75 years of age, with the opiate receptor antagonist 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF) and a positron emission tomograph. CF avidity was 27.5% less in the thalamus of healthy women compared to healthy men and 48.5% less in Alzheimer's disease female patients compared to male patients. Because cyclofoxy binds to both mu- and kappa-opiate receptors the above sex difference in opiate receptor avidity in the thalamus could have resulted from decreased receptor density and/or increased receptor occupancy. For example, an increase in the concentration of endogenous opiates at the synapse of either mu- and/or kappa-opiate receptors in women compared to men, even in the absence of a change in opiate receptor density, would result in finding decreased opiate receptor avidity in women. Regardless of their origins,sex differences in opiate receptor avidity in the thalamus are likely to have behavioral implications as well as clinical significance. Areas of the thalamus are among those regions with the highest density of opiate receptors. Opiates and opiate antagonists affect a broad range of physiological, behavioral and cognitive processes (Beluzzi and Stein, 1977; Koob and Bloom, 1982). Further, endogenous opiate pathways have important interactions with other neurotransmitter systems including the acetylcholine and dopamine pathways (Gerfen and Wilson, 1996; Mulder and Schoffelmeer, 1993 ; Wood and Stotland, 1980), pathways known to significantly contribute to attention, memory, and reward processes and to be adversely effected in Alzheimer's and Parkinson's disease.