AbstractsBiology & Animal Science

Bipolar disorder, schizophrenia and schizoaffective disorder are extremely debilitating illnesses that encompass affective and/or psychotic symptoms. Not only is there common symptomatology and genetic susceptibility, but the pharmacotherapy approaches are also similar. Nonetheless, molecular mechanisms underpinning these diseases are not yet fully understood. The theory that there is a dopaminergic dysfunction cannot account for all of the symptoms. Nor can the compounds that act on dopaminergic mechanisms successfully alleviate the symptoms. There is evidence to suggest that there are imbalances in other neurotransmitter systems, particularly the main excitatory pathway - the glutamatergic system. Glutamatergic transmission is essential for development,learning and memory and many other physiological functions of the brain. Glutamatergic receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type mediate the majority of the fast synaptic neurotransmission. Here, Gria1−/− mice, lacking the GluA1 subunit of AMPA receptors, with concurrent schizophrenia-like and affective symptoms were used. The predictive validity was addressed using the standard and novel glutamate-modulating pharmacotherapeutics. The hyperactivity, the most robust feature of Gria1−/− mice and a hallmark of psychotic disorders, was attenuated by drug-treatments. Importantly, chronic treatments with lithium, valproate, topiramate, lamotrigine and perampanel were effective, evidence of their pharmacological efficacy after the acute, often sedative, treatment phase. In addition, excessive novelty-induced activation of the dorsal hippocampus of Gria1−/− mice as measured by c-Fos expression was blunted by the drug-treatments of which all are known to reduce the activity of the glutamatergic transmission. Other behaviours relevant to the schizoaffective symptomatology such as disinhibited risk-taking, less despair-like behaviour and highly exploratory phenotype as well as social deficits were partially responsive to treatment with mood-stabilisers. Moreover, Gria1−/− mice exhibited a slightly higher preference for sucrose and made more impulsive choices towards sucrose. The Gria1−/− mice may represent a suitable model for the screening of the preclinical efficacy of novel drugs on the hyperactive behaviour linked to manic episode of bipolar disorder, schizophrenia and schizoaffective disorder. Neuropsykiatriset sairaudet kuten maanis-depressiivinen sairaus ja skitsofrenia tuottavat runsaasti harmia sairastuneille, heidän lähipiirilleen ja yhteiskunnalle. Nykyinen lääkehoito ei ole optimaalista, ja näiden sairauksien perussyyt tunnetaan vielä huonosti. Tässä työssä keskityttiin hyperaktiiviseen oireeseen, mikä on yleistä näissä sairaustiloissa, ja käytettiin kokeellista poistogeenistä (yhden glutamaattireseptorin inaktivaatio) mallia, jonka tyypillinen vaste uuteen ympäristöön joutumisesta oli liikeaktiivisuuden kaksinkertaistuminen. Sen ei kuitenkaan katsottu johtuvan dopamiinin aktiivisuuden lisääntymisestä vaan aivojen…