Neurochemical studies on inter-individual differences in affect-related behaviour of the laboratory rat
Date
2012-10-22
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Abstract
Erinevate neurokeemiliste, näiteks monoamiinsete, süsteemide normaalse funktsioneerimise tasakaalu muutumine võib viia mitmete meeleolu- ja sõltuvushäirete tekkimiseni. Depressiooniga seotud häirete uurimisel kasutatakse sageli uudistaval käitumisel põhinevaid teste. Lisaks on leitud, et nii uudistavad kui ka sõltuvusega seotud käitumise regulatsioonis omavad rolli just monoamiinsed neurotransmitterid, mille süsteemide mõjutamine toob kaasa ka erinevused loomade käitumises.
Eelnevalt oleme leidnud, et uudiskasti meetodil määratud indiviididevahelised erinevused uudistamisaktiivsuses on ajas püsivad ning neid indiviididevahelisi erinevusi on ka neurotransmitterite regulatsioonis. Mikrodialüüsi katsed näitasid, et serotonergiline süsteem on eri ajupiirkondades erinevalt reguleeritud. Väheuudistavatel (LE) rottidel on frontaalkoores kõrgemad rakuvälised serotoniini sisaldused kõrgemad peale serotoniini transpordi inhibeerimist tsitalopraamiga. Vastupidised tulemused ilmnesid hipokampuses, kus kõrgemad serotoniini tasemed olid just paljuuudistavatel (HE) rottidel. Kuna hiljutised uuringud on näidanud, et monoamiinide kõrval võib ka glutamaadi süsteemil olla oluline roll depressiooni kujunemisel, siis uuriti ka glutamaadi sisaldusi erineva uudistamisaktiivsusega rottidel. Leiti, et võrreldes väheuudistavate rottidega, on paljuuudistavatel rottidel kõrgemad glutamaadi sisaldused peale glutamaadi transpordi inhibeerimist juttkehas, kuid mitte hipokampuses. Sellest järeldub, et indiviididevahelised erinevused uudistavas käitumises võivad olla seotud lisaks serotonergilisele ka glutamatergilise närviülekandega.
Uudistav käitumine on suurel määral sõltuv sinava tuuma (locus coeruleus) noradrenaliini projektsioonidest. Rotid, kellel on antud süsteemi kahjustus, käituvad uudiskasti testis nagu LE-fenotüüp, mida on seostatud madalama dopaminergilise neurotransmissiooni efektiivsusega. uuriti, kas sinava tuuma projektsioonid on olulised dopaminergilisele süsteemile toimivatele psühhostimulantide efektidele. Leiti, et ulatuslik sinava tuuma projektsioonide kahjustus närvitoksiiniga DSP-4 [N-(2-kloroetüül-N-etüül-2-bromobensüülamiin] vähendas psühhostimulandi kokaiini poolt stimuleeritud kohaeelistust ja liikumisaktiivsust.
Kuna elusündmused varajases elustaadiumis võivad samuti omada mõju neurokeemilistele süsteemidele, siis uuriti kas alkoholist tingitud efektid monoamiini süsteemidele on sõltuvad varajasest elukeskkonnast. Leiti, et erinevused serotonergilises süsteemis olid just alkoholi eelistavatel loomadel, kes olid noores eas emast kõige kauem eraldatud. Siit järeldub, et varajases eas toimuvatel sündmustel on oluline mõju alkoholi tarbimisele ning serotonergilise süsteemi toimimisele.
Leiti, et nendel alkoholi eelistavatel loomadel, kes olid noores east emast kaua eraldatud, olid serotoniini tasemed madalamad just mandelkehas, mida seostakse enim just sõltuvushäirete tekkimisega. Siit järeldub, et varajases eas toimuvatel sündmustel on oluline mõju alkoholi tarbimisele ning serotonergilise süsteemi toimimisele.
Viimastel aastatel on negatiivsete afektiivsete seisundite kõrval hakatud rohkem uurima positiivse emotsionaalsuse võimaliku rolli üle depressiooni kujunemisel. Positiivset emotsionaalsust on võimalik uurida mõõtes rottide ultraheli-häälitsusi. Nüüdseks on leitud, et rottidel on püsivad indiviidivahelised erinevused nende 50-kHz ultraheli häälitsustes, mida seostatakse rottide positiivse emotsionaalsusega. Antud töös leiti, et stressi tingimustes on vähepiuksuvatel rottidel kõrgemad serotoniini tasemed peale serotoniini transpordi tagasihaarde inhibeerimist. Lisaks on samadel rottidel kõrgemad kortikosterooni tasemed. Antud tulemustest järeldub, et madalama positiivse emotsionaalsusega rotid on stressile vastuvõtlikumad.
Võttesse arvesse neurotransmitterite erinevat regulatsiooni rottide käitumise kujunemisel võib jõuda depressiooniga seotud seisundite uudsete farmakoloogiliste ravimeetoditeni.
Inter-individual differences, that are probably caused by variations in the regulation of neurochemical pathways, exist between organisms, and are likely to be significant in the pathogenesis of affective disorders. Depression is a highly prevalent psychopathological condition. In order to investigate depression the tests based on exploratory behaviour of rats are mostly used. Studies in the present dissertation indicate that rats with different exploratory phenotype differ, in addition to catecholaminergic mechanisms, also with regard to regulation of serotonergic and glutamatergic systems. Serotonergic neurotransmission in hippocampus and prefrontal cortex was found to be regionally differentially regulated in low exploring (LE) and high exploring (HE) rats. In prefrontal cortex, the LE-rats had higher extracellular serotonin levels induced by citalopram and higher levels of serotonin transporter binding. In dentate gyrus, contrary, the HE-rats had higher levels of extracellular serotonin. Additionally, HE-rats had increased levels of glutamate after blockade of glutamate transporter in striatum. Exploratory behaviour is very much dependent on the function of the noradrenergic projections of the locus coeruleus. All rats with near complete denervation of these projections behave in the exploration box test like the spontaneous LE-phenotype that has been associated with less efficient dopaminergic neurotransmission. It appeared that extensive denervation of the noradrenergic projections from locus coeruleus indeed reduced the effect of cocaine-induced place preference and locomotor activation. Early life experiences may also affect neurochemical mechanisms and thereby influence the behavioural pattern later in life. Thus, the effect of maternal separation (as the early life stress) on alcohol consumption was studied. It appeared that animals that experienced long maternal separation had low serotonin levels in amygdala and responded with an increase in serotonin after ethanol intake, which is a key area in addiction processes. Predisposition to express positive affect at low levels had previously been linked to vulnerability to depression. We could confirm the higher sensitivity of the LC-rats that produce less 50-kHz vocalizations to chronic stress: they gained weight more slowly and had higher corticosterone levels measured from full blood after stress. LC-rats have also differences in serotonergic mechanisms after chronic stress was supported by the finding that stressed LC-rats had higher extracellular serotonin levels induced by citalopram in hippocampus, where serotonergic system has been known to mediate response to anxious stimuli. These findings support the notion that male rats with low 50-kHz USVs response to tickling, having lower positive emotionality, are behaviourally more vulnerable to stress. Taken together, the consideration of these neurobiological differences between individuals could lead to novel approaches to more personalized medical treatment of depression-related states.
Inter-individual differences, that are probably caused by variations in the regulation of neurochemical pathways, exist between organisms, and are likely to be significant in the pathogenesis of affective disorders. Depression is a highly prevalent psychopathological condition. In order to investigate depression the tests based on exploratory behaviour of rats are mostly used. Studies in the present dissertation indicate that rats with different exploratory phenotype differ, in addition to catecholaminergic mechanisms, also with regard to regulation of serotonergic and glutamatergic systems. Serotonergic neurotransmission in hippocampus and prefrontal cortex was found to be regionally differentially regulated in low exploring (LE) and high exploring (HE) rats. In prefrontal cortex, the LE-rats had higher extracellular serotonin levels induced by citalopram and higher levels of serotonin transporter binding. In dentate gyrus, contrary, the HE-rats had higher levels of extracellular serotonin. Additionally, HE-rats had increased levels of glutamate after blockade of glutamate transporter in striatum. Exploratory behaviour is very much dependent on the function of the noradrenergic projections of the locus coeruleus. All rats with near complete denervation of these projections behave in the exploration box test like the spontaneous LE-phenotype that has been associated with less efficient dopaminergic neurotransmission. It appeared that extensive denervation of the noradrenergic projections from locus coeruleus indeed reduced the effect of cocaine-induced place preference and locomotor activation. Early life experiences may also affect neurochemical mechanisms and thereby influence the behavioural pattern later in life. Thus, the effect of maternal separation (as the early life stress) on alcohol consumption was studied. It appeared that animals that experienced long maternal separation had low serotonin levels in amygdala and responded with an increase in serotonin after ethanol intake, which is a key area in addiction processes. Predisposition to express positive affect at low levels had previously been linked to vulnerability to depression. We could confirm the higher sensitivity of the LC-rats that produce less 50-kHz vocalizations to chronic stress: they gained weight more slowly and had higher corticosterone levels measured from full blood after stress. LC-rats have also differences in serotonergic mechanisms after chronic stress was supported by the finding that stressed LC-rats had higher extracellular serotonin levels induced by citalopram in hippocampus, where serotonergic system has been known to mediate response to anxious stimuli. These findings support the notion that male rats with low 50-kHz USVs response to tickling, having lower positive emotionality, are behaviourally more vulnerable to stress. Taken together, the consideration of these neurobiological differences between individuals could lead to novel approaches to more personalized medical treatment of depression-related states.
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Keywords
loomade käitumine, loomkatsed, neurotransmitterid, depressioon, stress, alkohol, animal behaviour, animal experiments, neurotransmitters, alcohol