Pro-cognitive effect of 1MeTIQ on recognition memory in the ketamine model of schizophrenia in rats: the behavioural and neurochemical effects

• Published in: Psychopharmacology 2020-06, Vol.237 (6), p.1577-1593
• Main Authors: Bialon, Magdalena, Zarnowska, Marcelina, Antkiewicz-Michaluk, Lucyna, Wasik, Agnieszka
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotics; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; Cognitive ability; Corpus Striatum - drug effects; Disease transmission; Dopamine; Dopamine - analogs & derivatives; Dopamine - metabolism; Dopamine receptors; Emotional behavior; Excitatory Amino Acid Antagonists - toxicity; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Ketamine; Ketamine - toxicity; Male; Memory; Mental disorders; Metabolites; Microdialysis; Monoamines; Motor Activity - drug effects; Motor Activity - physiology; N-Methyl-D-aspartic acid receptors; Neostriatum; Neurophysiology; Neuroprotection; Neurosciences; Nootropic Agents - pharmacology; Nootropic Agents - therapeutic use; Norepinephrine; Norepinephrine - metabolism; Olanzapine; Original Investigation; Pattern recognition; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recognition, Psychology - drug effects; Recognition, Psychology - physiology; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Tetrahydroisoquinoline; Tetrahydroisoquinolines - pharmacology; Tetrahydroisoquinolines - therapeutic use; Treatment Outcome
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-020-05484-1

Rationale Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. Objectives In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. Methods We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. Results Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. Conclusions 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.