Distinctions in metabolism of serotonin and dopamine in rat brain during latent inhibition

Latent inhibition (LI) is a behavioral phenomenon, in which repeated presenting of a non-reinforced stimulus retards conditioning to this stimulus when it is coupled with a reinforcer. In order to find specific serotonin (5-HT- and dopamine (DA) changes mediating the LI, the 5-HT and DA metabolism was investigated in certain brain regions. Oxidative deamination of 5-HT and DA by monoamine oxidase (MAO) was determined in the prefrontal cortex, striatim, amygdala, and hippocampus at preexposure and testing stages of the LI using the passive avoidance procedure in rats. Preexposed animals demonstrated high MAO activity for 5-HT deamination in the amygdala and striatum and lower MAO activity for DA deamination in the amygdala and hippocampus. After testing the LI, a high level of 5-HT deamination by MAO was revealed in the amygdala, white the lower level of 5-HT deamination by MAO was shown in the prefrontal cortex. At the same time, no changes in DA metabolism were found in all the brain regions studied. Thus, the role of dopaminergic system in the LI effect may be limited by the preexposure stage. The obtained evidence suggests that the enhanced 5-HT activity in the amygdala and striatum induced by the preexposed stimulus is a principal biochemical mechanism underlying the LI.     

Change in serotonin metabolism in the rat brain in response to the repeated stimulus presentation

The content of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase (MAO) activity and kinetic parameters (K(m) and Vmax) for the reaction of 5-HT deamination, were examined in various regions of the rat brain after repeated presentation of a contextual stimulus. Habituation to the stimulus was accompanied by an increase of 5-HT metabolism and active transport of 5-HIAA in the amygdala, striatum and midbrain, while these changes were not found in the prefrontal cortex and hippocampus. Kinetic studies have revealed that the enhancement of 5-HT deamination by MAO in the brain structures was mediated by different catalytic mechanisms. A significant decrease in K(m) value for 5-HT deamination in the amygdala indicated an increase in the affinity of enzyme towards 5-HT. In the striatum the enhanced MAO activity was provided by increasing maximal rate of 5-HT deamination. It is concluded that an activation of presynaptic mechanisms of the serotonergic transmission in the amygdala and striatum is involved in the inhibition of biological significance and attention to repeated presentation of stimulus.     

Impairment of latent inhibition in OXYS rats with hereditary syndrome of premature aging

The effect of latent inhibition has been tested in OXYS (strain selected for accelerated aging) and Wistar (control) rats at the age of 4 months using a conditioned passive avoidance reaction. The OXYS rats displayed a higher level of anxiety in the elevated plus-maze as compared to Wistar strain. The experimental procedure consisted of preexposure stage (presentation of non-reinforced environmental stimulus), conditioning (presentation of a preexposed stimulus paired with shock), and testing the effect of latent inhibition. The effect of latent inhibition was revealed only in Wistar rats, in which the latency of transition to the dark compartment of the experimental chamber was reduced. Contrastingly, in OXYS rats the conditioned performance was not inhibited. It is suggested that aging-associated factors such as the low rate of habituation to experimental situation at the preexposure stage and the high general anxiety level of OXYS rats can interfere with inhibition of the attention to irrelevant information.     

Changes in brain monoamine oxidase activity in conditioned passive avoidance reaction in rats]

Activity of the enzyme monoamine oxidase (MAO) and kinetic parameters (Km, Vmax) for the 5-hydroxytryptamine (5-HT) and dopamine deamination were examined in the brain of rats with conditioned passive avoidance recall. Changes of the 5-HT and dopamine deamination were found in amygdala, striatum and frontal cortex. MAO activity was not changed in hippocampus. In amygdala the rate of 5-HT deamination was significantly increased and kinetic studies revealed increased affinity of the enzyme for 5-HT. The metabolism of dopamine in amygdala was unchanged. In frontal cortex the deamination of 5-HT was not changed, but the dopamine deamination significantly decreased. This decrease was due to lowering of MAO affinity for dopamine. In striatum the metabolism of both 5-HT and dopamine was reduced, and kinetic studies showed the lowering of Vmax for 5-HT and dopamine deamination.     

Monoamine oxidase activity in embryos of pike (Esox lucius)

1. Mitochondrial MAO specific activity was measured in eggs and early embryos of the teleostean fish Esox lucius using tryptamine, 5-hydroxytryptamine (5-HT) and phenylethylamine (PEA) as substrates. 2. Tryptamine is the most readily deaminated substrate in mitochondria isolated from unfertilized eggs and embryos at the stages of cleavage, blastula and gastrula. 3. Monoamine oxidase activity gradually decreases during development and at the gastrula stage it is respectively 80% (tryptamine), 70% (5-HT) and 50% (PEA) of that found in the egg using the corresponding substrate. 4. The inhibition of egg MAO activity by clorgyline and deprenyl measured in E. lucius eggs using tryptamine as substrate, indicates the presence of a single form of MAO not corresponding to the MAO A and MAO B described in terrestrial vertebrates.     

Interaction of N-(2-Nitro-4-Azidophenyl)-Serotonin with Two Types of Monoamine Oxidase in Rat Brain

The effects of N-(2-nitro-4-azidophenyl) serotonin (NAP-5-HT) on types A and B monoamine oxidase (MAO) in rat brain cortex were studied. In the dark this compound acted as a competitive inhibitor for both types A and B MAO (Ki values of 0.19 microM and 0.21 microM for types A and B MAO, respectively). Upon photolysis, NAP-5-HT became an irreversible inhibitor for only type B MAO. A 50% inhibition was obtained by irradiation of the enzyme in the presence of 35 nM NAP-5-HT. Furthermore the inhibition of type B MAO could be protected by including its substrate phenylethylamine during the irradiation. Under the same photolytic conditions photodependent inhibition of type A MAO by NAP-5-HT was not clearly observed. These results provide further evidence that there is a fundamental difference in the active site of the two types of MAO in brain. NAP-5-HT may be a useful photoaffinity probe for characterizing the active site of type B MAO.     

Effects of context novelty vs. familiarity on latent inhibition with a conditioned taste aversion procedure

The latent inhibition phenomenon is observed when a conditioned stimulus is preexposed without any consequence before conditioning. The result of this manipulation is a reduction in conditioned response intensity to such a stimulus. In this study, we analyse the role of context novelty/familiarity on LI modulation by changing the context using a three-stage conditioned taste aversion procedure. Experiment 1 revealed that, similar to other learning procedures, a context change between preexposure and conditioning/testing (but not between preexposure/conditioning and testing) resulted in LI attenuation when the experimental contexts were novel. Experiment 2, using animals’ home cages as one of the contexts, revealed a different pattern of results, with an unexpected increase in LI magnitude when the context change was introduced between conditioning and test stages. The Schmajuk et al. (1996) computational model explains these results in terms of the increased novelty of the conditioned stimulus during preexposure, conditioning, and testing.     

Latent inhibition as a function of CS intensity in taste aversion learning

An experiment is reported in which the relationship between the intensity of a preexposed stimulus and latent inhibition was investigated, using the taste aversion learning paradigm in rats. Two concentrations of a saline solution (high, 1%; and low, 0.25%) were used during preexposure and conditioning phases in a factorial design. Two control conditions without preexposure were added, one for each stimulus concentration during conditioning. The known effect of conditioned stimulus (CS) intensity during conditioning was confirmed: the more concentrated the solution used in conditioning, the higher the acquisition rate. A direct relationship was observed between the CS intensity used during preexposure and the latent inhibition effect: the more concentrated the solution during preexposure, the lower the acquisition rate of conditioning. The implications of these results for latent inhibition theories are considered.     

Effect of inhibition of MAO and COMT on intrarenal dopamine and serotonin and on renal function

The purpose of the present investigation was to study the effects of inhibition of monoamine oxidase (MAO) and/or catechol-O-methyltransferase (COMT), enzymes involved in the degradation of dopamine (DA) and serotonin (5-HT), on intrarenal DA and 5-HT, as reflected in the renal interstitial fluid (RIF) microdialysate and urine, and on renal function. Inhibition of MAO selectively increased RIF 5-HT from 3.16 +/- 0.38 to 8.03 +/- 1.83 pg/min (n = 7, P < 0.05), concomitant with decreases in mean arterial blood pressure and glomerular filtration rate (2.09 +/- 0. 18 to 1.57 +/- 0.22 ml/min, n = 7, P < 0.05). Inhibition of COMT significantly increased RIF DA (3.47 +/- 0.70 to 8.68 +/- 1.96 pg/min, n = 9, P < 0.05), urinary DA (2.00 +/- 0.16 to 2.76 +/- 0.26 ng/min, n = 9, P < 0.05), and absolute excretion of sodium (6.42 +/- 2.00 to 9.82 +/- 1.62 micromol/min, n = 10, P < 0.05). Combined inhibition of MAO and COMT significantly increased RIF DA, urinary DA, and urinary 5-HT, which was accompanied with increases in urine flow rate, and absolute (3.03 +/- 0.59 to 8.40 +/- 1.61 micromol/min, n = 9, P < 0.01) and fractional excretion of sodium. We conclude that inhibition of MAO selectively increases RIF 5-HT. COMT appears to be more important than MAO in the metabolism of intrarenal DA. Physiological increases in intrarenal DA/5-HT induced by inhibition of their degrading enzymes are accompanied with significant alterations of renal function.     

The dynamics of latent inhibition in rats under the action of substance P]

The role of substance P in latent inhibition was studied in experiments on rats. Administration of neuropeptide during pre-exposition of conditioned stimulus and before conditioning disturbed all signs of latent inhibition: level of reproduction, retention and resistance to amnestic action of conditioned reaction in the task of passive avoidance. Single administration of haloperidol before learning prevented the disturbance. Significance of hyperfunction of substance P in selective attention and pathogenesis of schizophrenia is discussed.     

Monoamine oxidase A mediates iodotyrosine formation induced by monoamines in bovine thyroid particulate fraction

Monoamines are able to increase the thyroid iodine organification in vitro. A predominance of the A form of monoamine oxidase (MAO) has been previously demonstrated to exist in bovine thyroid tissue. In the present study we have investigated the form of MAO that could be involved in the iodotyrosine formation induced by tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) in a bovine thyroid subcellular fraction. The relative capacity of these monoamines to generate H2O2 and to incorporate iodine into tyrosine has also been studied. The MAO A inhibitor clorgyline (10(-9) M) produced a strong inhibition on the iodotyrosine formation induced by tyramine, 5-HT and PEA. In contrast, only a slight reduction was observed with deprenyl as MAO B inhibitor. Among the three monoamines, tyramine produced the highest H2O2 generation and iodotyrosine formation. The lowest Km value obtained was for 5-HT and the highest for PEA. Regarding the Vmax, the lowest value was for 5-HT and the highest for tyramine. The amount of iodine incorporated to tyrosine was not equivalent to the H2O2 generated by the monoamines nor to that exogenously added. Our results indicate that in bovine thyroid tissue mainly the A form of MAO is involved in the monoamine metabolism.     

Mitochondrial monoamine oxidase activity during preneural developmental stages of Bufo bufo

Monoamine oxidase specific activities against PEA and 5-HT have been measured in mitochondria isolated from early embryos of Bufo bufo. During the early development up to the neural fold stage, MAO activity undergoes a continuous decrease that is more evident when PEA is used as the substrate. The inhibition patterns of deprenyl and clorgyline demonstrate that, at the neural fold stage, both type A and B MAO are present. Both in eggs and embryos MAO type A activity appears slightly more sensitive to the inhibitory effect of various concentrations (0.1-2 M) of the denaturing agent urea.     

Some characteristics of mitochondrial monoamine oxidase activity in eggs of carp (Cyprinus carpio) and rainbow trout (Salmo gairdneri)

1. Monoamine oxidase (MAO) activity towards tryptamine, 5-hydroxytryptamine (5-HT) and phenylethylamine (PEA) has been measured in mitochondria isolated from carp and trout eggs. 2. In carp eggs all the tested substrates are metabolized and the highest affinity is found with tryptamine. In trout eggs a consistent level of MAO activity is obtained using tryptamine. 3. The inhibition dose-response curves of clorgyline and deprenyl indicate that both in carp and trout eggs there is only one form of mitochondrial MAO, distinct from MAO A and B which have been described in vertebrate tissues. 4. Both in carp and trout egg mitochondria a semicarbazide-sensitive amine oxidase is not involved in the deamination of the used substrates. 5. MAO found in carp and trout eggs might be involved in metabolism of some neurotransmitter monoamines during early developmental stages.     

The interaction of the serotonin and dopaminergic systems of the brain in the mechanisms of latent inhibition in rats

Decrease of serotonin concentration in the septo-hippocampal region of Wistar male rats was obtained by introduction of 5,7-dihydroxytryptamine in the raphe median nucleus. In seven days, after 20 pre-expositions of the conditioned stimulus (presentation of the experimental chamber) conditioned reaction of passive avoidance was elaborated. In sham-operated control the pre-exposition of the conditioned stimulus caused latent inhibition, determined by several parameters: low level of conditioned reaction reproduction, its prolonged preservation at the formed level and nonsubjection to amnesia. Introduction of haloperidol in a dose of 0.5 mg/kg one hour before learning restored the state of latent inhibition disturbed by switching off of the mesolimbic serotonin system. It is supposed that in the state of pre-exposition, the decrease of attention to nonreinforced stimulus takes place because of the intensification of inhibitory influence of the serotoninergic system and reciprocal decrease of dopaminergic system activity.     

Monoamine Oxidase Activity and Monoamine Metabolism in Brains of Parkinsonian Patients Treated with l-Deprenyl

Monoamine oxidase (MAO) type A and type B were measured using kynuramine, 3,4-dihydroxyphenylethylamine (dopamine, DA), and 5-hydroxytryptamine (5-HT, serotonin) in 20 brain areas. The highest activities were found in the striatum (caudate nucleus, putamen, globus pallidus, and substantia nigra), hypothalamus, and c-mammilare. The ratio of DA to 5-HT deamination varied in the different regions, being in favor of DA in the striatum. With kynuramine as the substrate IC50 values of a number of inhibitors indicated that l-deprenyl was far more potent an inhibitor of human brain MAO than clorgyline or harmaline. N-Desmethylpropargylindane hydrochloride (AGN 1135) was also shown to have MAO-B inhibitory selectivity similar to that of l-deprenyl. Brains obtained at autopsy from l-deprenyl-treated Parkinsonian patients showed that, whereas MAO-B was fully inhibited by the therapeutic doses of l-deprenyl, substantial MAO-A activity was still evident. These results are matched by the significant increases of DA noted in caudate nucleus, globus pallidus, putamen, and substantia nigra and the unaltered 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the same regions. These data indicate that the therapeutic actions of l-deprenyl may lie in its selective inhibition of MAO-B resulting in increased brain levels of DA formed from L-dihydroxyphenylacetic acid (L-DOPA).     

Neuronal activity of the cerebral cortex in cats with conditioned inhibition

Unit activity of the somatosensory cortex was studied in chronic experiments on cats during alimentary instrumental conditioned reflex performance and elaboration of conditioned inhibition (CI). First presentations of the CI signal at the beginning of CI formation caused, due to orienting reaction to a new stimulus, a levelling of the response of the neurones to the positive conditioned signal included into the CI complex. At the stage of consolidated CI, this depression proceeded gradually during the development of conditioned inhibition caused by consecutive presentations of the nonreinforced CI combination. Two groups of neurones were involved in the process of the CI performance: one of them being the same which was activated also in response to positive stimulation during performance of the conditioned response, and the second one being areactive to the positive conditioned stimulus but reducing the frequency of the background activity.     

5-HYDROXYTRYPTAMINE CATABOLISM IN THE RAT BRAIN DURING ONTOGENESIS

Although the serotoninergic innervation is immature in the brains of young rats, the 5-HIAA content is similar to that found in adults. As indicated by the ratio of 5-HIAA to 5-HT levels in the brain stem and the forebrain, the catabolism of the indolamine was more rapid during the first 3 postnatal weeks than in adults. This was contirmed by measuring the total formation of [³H]5-HIAA from [³H]5-HT newly synthesized from L-[³H]tryptophan in brain stem slices of young and adult rats. Electrolytic lesions of midbrain raphe nuclei (B7 and B8) performed on the 5th postnatal day resulted in parallel decreases in brain 5-HT and 5-HIAA levels; this ruled out the possibility that 5-HIAA might be formed from 5-HT synthesized outside serotoninergic neurons, using peripheral 5-hydroxytryptophan. Inhibition of 5-HT storage by reserpine pretreatment did not alter the higher capacity of newborn tissues to catabolize exogenous [³H]5-HT. Therefore, possible differences in 5-HT binding in serotoninergic neurons between newborn and adult rats were not likely to account for the differences in 5-HT catabolism. Estimation of the rate of 5-HIAA efflux from the brain after MAO inhibition did not reveal marked changes with age. The activity of MAO type A, the enzyme involved in 5-HT catabolism, was higher during early life than later on. This could be shown by using 5-HT as substrate and clorgyline as a selective inhibitor. An opposite pattern of development was seen for MAO B, measured with benzylamine as substrate and deprenyl as selective inhibitor. These results suggest that the high 5-HIAA levels found in the brains of young rats can be attributed mainly to the presence of high MAO A activity during early life.     

Monoamine Oxidase Activities in Catfish (Parasilurus Asotus) Tissues

Abstract

The substrate- and inhibitor-related characteristics of monoamine oxidase (MAO) were studied for catfish brain and liver. The kinetic constants for MAO in both tissues were determined using 5-hydroxytryptamine (5-HT), tyramine and β-phenylethylamine (PEA) as substrates. For both tissues, the V_max values were highest with 5-HT and lowest with PEA. The K_m value for the brain was highest with 5-HT, followed by tyramine and PEA; but for the liver its value was highest with PEA, followed by 5-HT and tyramine, although all values were in the same order of magnitude. The inhibition of MAO by clorgyline and deprenyl by use of 5-HT, tyramine and PEA as substrates showed that the MAO-A inhibitor clorgyline was more effective than the MAO-B inhibitor deprenyl for both catfish tissues; a single form was present since inhibition by clorgyline or deprenyl with 1000 μM PEA showed single phase sigmoid curves. It is concluded that catfish brain and liver contain a single form of MAO, relatively similar to mammalian MAO-A.     

The spectral correlations of human brain electrical activity (the EEG) in the alpha-rhythm range occurring while performing latent inhibition]

Changes in perception of a stimulus and impairment of retrieval of memory trace resulted from the stimulus loss of novelty are called the latent inhibition (LI). The present study was undertaken to investigate the human LI using the analysis of changes in frequency power and coherence of the alpha rhythm. The results indicate that the loss of novelty of a stimulus is accompanied by a significant increase in the power of the upper alpha in the frontal regions of the right hemisphere and temporal regions of both hemispheres resulting in an impairment of memory retrieval in the frontal regions. Analysis of coherence changes revealed the reduction of interaction between the right temporal region and anteriofrontal, temporo-occipital, and right parietooccipital regions in response to administration of the conditioned words in comparison with the control ones. The findings suggest that the LI is a manifestation of the more general physiological process--the hidden inhibition.