1-Methyl-1,2,3,4-tetrahydroisoquinoline antagonizes a rise in brain dopamine metabolism, glutamate release in frontal cortex and locomotor hyperactivity produced by MK-801 but not the disruptions of prepulse inhibition, and impairment of working memory in rat.
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that central nervous system stimulants such as: amphetamine, cocaine, phencyclidine, and selective NMDA receptor antagonists, e.g., MK-801 produce neuropsychotoxicity (psychosis, addiction) that is indistinguishable from paranoid type schizophrenia. In rodents, phencyclidine and MK-801 are often used to evoke schizophrenia-like behavioral abnormalities which are inhibited by neuroleptics. The present study was designed to further investigate potential antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the NMDA receptor antagonist, MK-801 (0.2-0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in dopamine metabolism in different brain structures and in extraneuronal release of dopamine and glutamate in the rat frontal cortex, produced by MK-801. The concentration of dopamine (DA) and its metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), as well as the extraneuronal concentration of dopamine and glutamate were established by HPLC. MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by MK-801 as well as a rise in dopamine metabolism in specific brain structures and glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a psychosis-attenuating drug in schizophrenic patients. However, 1MeTIQ did not attenuate sensorimotor gating deficit or working memory impairment evoked by MK-801 which may be served as a model of negative symptoms of schizophrenia.
Pietraszek
Małgorzata
M
Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Krakow, Poland.
Michaluk
Jerzy
J
Romańska
Irena
I
Wasik
Agnieszka
A
Gołembiowska
Krystyna
K
Antkiewicz-Michaluk
Lucyna
L
D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D006948:Hyperkinesis / Q000139:chemically induced / Q000473:pathology; D007266:Inhibition, Psychological; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009448:Neurochemistry / Q000379:methods; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use
D018492:Dopamine Antagonists; D044005:Tetrahydroisoquinolines; D018698:Glutamic Acid; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D016291:Dizocilpine Maleate; D004298:Dopamine