MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

3‐Methoxytyramine (3‐MT) and 3,4‐dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3‐MT formation was found to comprise >60% of total DA turnover (sum of 3‐MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3‐MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3‐MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O‐methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3‐MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3‐MT, the ratio of 3‐MT to DOPAC rates of formation can be a useful index of reuptake inhibition.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency.

No abstract

Morphological, physiological and pharmacological evidence indicates that opioid peptides, which in the brain are located intraneurally, may function as neurotransmitters. Similar evidence is not yet available for the opioid peptides that are stored in chromaffin cells of adrenal medulla and in axon terminals located in adrenal medulla and sympathetic ganglia. The present report contributes evidence suggesting that the opioid peptides which are stored in the axon terminals of the splanchnic nerves located in adrenal medulla may function as neuromodulators of the acetylcholine receptors located on chromaffin cells that are involved in catecholamine release. We support this functional role of the opioid peptides by showing that primary cultures of chromaffin cells of bovine medulla contain opiate receptors. When these receptors are occupied by specific agonists, the number of nicotinic receptors and the amount of catecholamine released by maximal doses of nicotine are reduced. Thus, like in other neuronal systems also in adrenal medulla, the action of opioid peptides is inhibitory. The specificity of this action is in part supported by the inability of opiate receptor agonists to reduce the Ca2+-dependent release of catecholamines elicited by K+ ions.

No abstract

Motor deficits produced in rats by unilateral substantia nigra lesions have been found to be reduced by grafts of fetal rat substantia nigra to the dopamine-denervated caudate nucleus. In the present study these grafts were examined behaviorally, histochemically, and biochemically over six-to 10-month periods. The grafts were found to survive in a healthy condition and contain catecholaminergic cells and fibers after eight to ten months. Concentrations of dopamine in adjoining parts of the caudate nucleus were increased when examined six months after grafting. Apomorphine-induced rotation was reduced by the grafts, and these reductions persisted for at least six months. Although signs of aging were observed in the brains of the host animals when sacrificed eight to ten months after grafting, the grafts remained healthy and showed no signs of aging or deterioration. It is concluded that substantia nigra grafts can become permanent, functional constituents of the brains of host animals with prior substantia nigra lesions.Freed WJ, Perlow MJ, Karoum F, et al: Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: long-term behavioral, biochemical, and histochemical studies.Ann Ncurol 8: [510][511][512][513][514][515][516][517][518][519] 1980 We recently reported that fetal rat substantia nigra The initial study [31] was terminated two months after grafting. In the present study, we sought to determine whether the grafts would become permanent or whether they would eventually be rejected. Therefore, we studied additional animals for six to ten months after grafting. We also report further behavioral data to substantiate our earlier findings and demonstrate that the grafts and adjacent caudate nucleus contain dopamine. These findings strengthen our hypothesis that the behavioral changes brought about by the grafts are the result of release of dopamine from neurons in the grafts and consequent changes in concentrations of dopamine in the caudate nucleus. MethodsSUBSTANTIA NIGRA LESIONS. Lesions were created in group-housed male Sprague-Dawley rats weighing 150 to 160 gm by administration of 6-hydroxydopamine (GOHDA) into the right SN under chloral hydrate anesthesia. The stereotaxic coordinates were 4.2 mm posterior and 1.1 rnm lateral to the bregma and 7.5 mm below the dura, with the incisor bar 2.4 mm below the interaural line (atlas of Konig and Klippel [171). Eight micrograms (free base) of 6-hydroxydopamine (Sigma Chemical Company) in 4 pl of saline solution containing 0.2 mgiml of ascorbic acid was administered through a 27-gauge needle at a rate of 1 pl per minute, after which the needle was left in place f u r an additional 2 minutes. After removal of the needle.

Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.