Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-23T07:49:36.382Z Has data issue: false hasContentIssue false

The Effects of Agonists of Ionotropic GABAA and Metabotropic GABAB Receptors on Learning

Published online by Cambridge University Press:  10 January 2013

Evgeniya A. Zyablitseva
Affiliation:
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences (Russia)
Nikolay S. Kositsyn
Affiliation:
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences (Russia)
Galina I. Shul'gina*
Affiliation:
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences (Russia)
*
Correspondence concerning this article should be addressed to: Shulgina Galina I., Doctor of Biological Sciences, Leading Researcher, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117465 Moscow, Butlerova 5A. (Russia). Phone: 7 (495) 789 38 52 (w), 7 (495) 940 37 74 (h), 7 (905) 700 0502 (mob). E-mail: [email protected]

Abstract

The research described here investigates the role played by inhibitory processes in the discriminations made by the nervous system of humans and animals between familiar and unfamiliar and significant and nonsignificant events. This research compared the effects of two inhibitory mediators of gamma-aminobutyric acid (GABA): 1) phenibut, a nonselective agonist of ionotropic GABAA and metabotropic GABAB receptors and 2) gaboxadol a selective agonist of ionotropic GABAA receptors on the process of developing active defensive and inhibitory conditioned reflexes in alert non-immobilized rabbits. It was found that phenibut, but not gaboxadol, accelerates the development of defensive reflexes at an early stage of conditioning. Both phenibut and gaboxadol facilitate the development of conditioned inhibition, but the effect of gaboxadol occurs at later stages of conditioning and is less stable than that of phenibut. The earlier and more stable effects of phenibut, as compared to gaboxadol, on storage in memory of the inhibitory significance of a stimulus may occur because GABAB receptors play the dominant role in the development of internal inhibition during an early stage of conditioning. On the other hand this may occur because the participation of both GABAA and GABAB receptors are essential to the process. We discuss the polyfunctionality of GABA receptors as a function of their structure and the positions of the relevant neurons in the brain as this factor can affect regulation of various types of psychological processes.

Este trabajo investiga el papel de los procesos inhibitorios en la discriminación realizada por el sistema nervioso de los humanos y los animales entre sucesos familiares y no familiares y significativos y no significativos. Se comparó los efectos de dos mediadores inhibitorios del ácido gamma-aminobutírico (GABA): 1) Phenibut, un agonista no selectivo de los receptores del GABAA ionotrópico y del GABAB metabotrópico y 2) gaboxadol, un agonista selectivo de los receptores del GABAA ionotrópico, sobre el desarrollo de reflejos condicionados de defensa activa e inhibitorios en conejos en alerta y no inmovilizados. Se encontró que el phenibut, pero no el gaboxadol, acelera el desarrollo de reflejos defensivos en una etapa temprana del condicionamiento. Tanto el phenibut como el Gaboxadol facilitaron el desarrollo de la inhibición condicionada, pero el efecto del gaboxadol ocurre en etapas tardías del condicionamiento y es menos estable que el del phenibut. Los efectos más estables y más tempranos del phenibut, en comparación con el gaboxadol, sobre el almacenaje en la memoria de la significación inhibitoria de un estímulo pueden deberse a que los receptores del GABAB tienen el papel dominante en el dearrollo de la inhibición interna durante la fase inicial del condicionamiento. Por otro lado esto puede deberse a que la participación de los receptores tanto del GABAA como del GABAB son esenciales para el proceso. Comentamos la multifuncionalidad de los receptores del GABA como función de su estructura y de las posiciones de las neuronas relevantes en el cerebro, dado que este factor puede afectar la regulación de varios tipos de procesos psicológicos.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Allikmets, L. X., Rjago, L. K. (1983). Uchastie raznich neyromediatornich system v mekhanismakh deystviya proizvodnich GAMK. [Participation of different neurotransmitter systems in mechanisms of action of GABA derivatives]. Summary of papers from the All-USSR Symposium “Pharmacology of derived gamma-aminobutyric acid. Tartu, 25-27 May 1983, p.7.Google Scholar
Avoli, M. (1996). GABA-mediated synchronous potentials and seizure generation. Epilepsia, 37, 10351042.Google Scholar
Basyan, A. S. (2001). Vzaimodeystvie mediatornikh i neuromodulatornikh system golovnogo mozga i ikh vozmozhnaya rol' v formirovanii psikhofisiologicheskikh i psikhopatologicheskikh sostoyaniy. [Interaction of brain mediatory and neuromodulator systems and their possible role in formation of psychophysiological and psychopathological states]. Zhurnal uspekhi fiziologicheskikh Nauk, 32, 322.Google Scholar
Bormann, J., Hamill, O. P., Sakmann, B. (1987). Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultures spinal neurones. Journal Physiology, 385, 243286.CrossRefGoogle ScholarPubMed
Brown, N., Kerby, J., Bonnert, T. P., Whiting, P.J., Wafford, K.A. (2002). Pharmacological characterization of a novel cell expressing human alpha(4)beta(3)delta GABAA receptors. British Journal of Pharmacology, 136, 965974.Google Scholar
Caraiscos, V. B., Elliott, E. M., You-Ten, K. E., Cheng, V. Y., Bellali, D., Newell, J. G. et al. , (2004). Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by a5 subunit-containing gamma-aminobutiric acid type A receptors. The Proceedings of the National Academy of Sciences of the USA, 101, 36623667.Google Scholar
Cheng, S. C., Brunner, E.A. (1985). Inducing anesthesia with a GABA analog, THIP. Anesthesiology, 63, 147151.Google Scholar
Clemente, C.D. (1968). Forebrain mechanisms related to internal inhibition and sleep. Conditional Reflex, 3, 145174.Google Scholar
Costa, E., Davis, J. M., Dong, E., Grayson, D. R., Guidotti, A., Tremolizzo, L., & Veldic, M. (2004). GABAergic cortical deficit dominates schizophrenia pathophysiology. Critical Review of Neurobiology, 16, 123.Google Scholar
Drew, C. A., Johnston, G. A., Weatherby, R.P. (1984). Bicucullineinsensitive GABA receptors: studies on the binding of (-)-baclofen to rat cerebellar membranes. Neuroscience Letters, 52, 317321.Google Scholar
Eccles, J.C. (1964). The physiology of synapses. Berlin: Springer.Google Scholar
Eccles, J.C. (1969). The inhibitory pathways of the central nervous system. London: Liverpool University Press.Google Scholar
Eccles, J. C., McGreer, P. L. (1979). Ionotropic and metabotropic neurotransmission. Trends in Neuroscience, 2, 3940.Google Scholar
Enomoto, T.F. & Ajmone-Marsan, C. (1959). Epileptic activation of single cortical neurons and their relationship with electroencephalographic discharges. Electroencephalography and Clinical Neurophysiology, 11, 199218.CrossRefGoogle ScholarPubMed
Farrant, M. (2001) Amino Acids: Inhibitory. In Webster, R.A. (Ed.), Neurotransmitters, Drugs and Brain Function. Hoboken, NJ: John Wiley & Sons. (pp. 225250).Google Scholar
Faulhaber, J., Steiger, A., Lancel, M. (1997). The GABAA agonist THIP produces low wave sleep and reduces spindling activity in NREM sleep in humans. Psychopharmacology, 130, 285291.Google Scholar
Hill, D. R., Bowery, N.G. (1981). 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA(B) sites in rat brain. Nature, 290 (5802), 149152.CrossRefGoogle ScholarPubMed
Huckle, R. (2004). Gabaxadol. Current Opinion in Investigational Drugs. 5, 766773.Google Scholar
Johnston, G. A. R. (1996). GABAC receptors: relatively simple transmitter – gated ion channels. Trends in Pharmacological Sciences, 17, 319323.Google Scholar
Johnston, G. A. R. (2005). GABAA receptor channel pharmacology. Current Pharmaceutical Design, 11, 18671885.Google Scholar
Kalkman, H. O., Loetschar, E. (2003). GAD (67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. Journal of Neural Transmission, 110, 803812.CrossRefGoogle ScholarPubMed
Kaluev, A. V., Natt, D. Dj. (2003). O roli GAMK v patogeneze trevogy i depressii. [About the role of GABA in pathogenesis of anxiety and depression]. Vestnik biologicheskoy psikhiatrii, N° 12, 1016.Google Scholar
Khaunina, R. A., Lapin, I. P. (1989). Primenenie phenibuta v psichiatrii i nevrologii i ego mesto sredi drugikh psikhotropnikh sredstv. [Application of phenibut in psychiatry and neurology and its place among the other psychotropic preparates]. Zhurnal nevropatologii i Psikhhiatrii im. S. S. Korsakova. 89, 142151.Google Scholar
Krnjevic, K., Schwartz, S. (1967). The action of γ-aminobutiric acid on cortical neurons. Experimental Brain Research, 3, 320.CrossRefGoogle Scholar
Krnjevic, K. (1974). Chemical nature of synaptic transmission in vertebrates. Physiological Review. 54, 418.Google Scholar
Krogsgaard, P., Frølund, B., Liljefars, T., Ebert, B. (2004). GABAA agonists and partial agonists: THIP (Gaboxadol) as a nonopioid analgesic and a novel type of hypnotic. Biochemical Pharmacology, 68, 15731580.Google Scholar
Krogsgaard, Larsen P., Frølund, B., Kristiansen, U., Frydenvang, K., Ebert, B. (1997). GABAA and GABAB receptor agonists, partial agonists, antagonists and modulators – design and therapeutic prospects. European Journal of Pharmaceutical Sciences, 5, 355384.Google Scholar
Lancel, M., Langabartels, A. (2000). Gamma – amino butyric acid (A) (GABAA) agonist 4,5,6,7-tetrahydroisoxsolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. Journal of Pharmacology and. Experimental Therapy. 293, 10841090.Google Scholar
Lapin, I. (2001). Phenibut (beta-phenil-GABA): a tranquilizer and nootropic drug. CNS Drug Review. 7, 471481.Google Scholar
Lavalée, Ph., Urbain, N., Dufresne, C.Bokor, H., Acsády, L. & Deschênes, M. (2005). Feedforward inhibitory control of sensory information in higher-order thalamic nuclei. Journal of Neuroscience, 25, 74897498.Google Scholar
Lin, C.-S., Nicolelis, M. A. L., Schneider, J. S., & Chapin, J. K. (1990). A major direct GABAergic pathway from zona incerta to neocortex. Science, 248, 15531556.Google Scholar
Lloyd, K.G. (1986). La théorie GABAergique de l'epilepsie. Thérapeutique neurologique, 36 (5), 243254.Google Scholar
Lubow, R.E. (1989). Latent inhibition and conditioned-attention theory. Cambridge, UK: Cambridge University Press.Google Scholar
Lubow, R. E., & Gewirtz, J.C. (1995). Latent inhibition in humans: Data, theory, and implications for schizophrenia. Psychological Bulletin, 117, 87103.Google Scholar
Luscher, W. (2002). Basic pharmacology of valproate: A review after 35 years of clinical use for the treatment of epilepsy. Central Nervous System Drugs, 16, 669695.Google Scholar
Mashkovsky, M. D. (2002). Lekarstvennye sredstva [Pharmaceuticals]. Moscow.: Novaya Volna.Google Scholar
Mathias, S., Zihi, J., Steiger, A., Lancel, M. (2005). Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects. Neuropsychopharmacology, 30, 833841.Google Scholar
McGreer, P. L., Eccles, J.C. & McGreereer, E. G. (1978). Molecular Neurobiology of the Mammalian Brain, N.Y.: Plenum PressGoogle Scholar
Mechilane, L. C., Ryago, L. K., Allikmets, L. X. (1990). Farmakologija i klinika fenibuta. [Pharmacology and clinic of phenibut]. Tartu: Tartu University PressGoogle Scholar
Moroni, F., Forchetti, M. C., Krogssgaard-Larsen, P., Guidotti, A. (1982). Relative disposition of the GABA agonists THIP and muscimol in the brain of the rat. Journal of Pharmacy and Pharmacology. 34, 676678.Google Scholar
Mortensen, M., Wafford, K. A., Wingrove, P., Ebert, B. (2003). Pharmacology of GABAA receptors exhibiting different levels of spontaneous activity. European Journal of Pharmacology, 476, 1724.Google Scholar
Onodera, S., Hicks, T. Ph. (1998). Projections from substantia nigra and zona incerta to the cat's nucleus of Darkschewitsch. Journal of Comparative Neurology, 396, 461482.Google Scholar
Pavlov, I.P. (1954). Lektsiya 22. Obschaya harakteristika dannogo issledovaniya, ego zadacha, ego trudnosti i nashi oshibki. [General description of the investigation, its problems, its hardships and our mistakes]. Izbrannye trudy. (Usievich, M. A., ed.), Moscow: Gosudarstvennoie Uchebno-pedagogicheskoe izdatelstvo MP RSFSR, (pp. 387401).Google Scholar
Pavlov, I.P. (1973). Dvadtsatiletniy opyt objektivnogo izucheniya vysshey nervnoy deiyatelnosti (povedeniya) zhivotnykh [Twenty years' experience with empirical study of higher nervous activity (behavior) in animals]. Moscow: Nauka.Google Scholar
Perekalin, V. V. & Zobacheva, M. M. (1959). Sintez gamma-amino kislot i pirrolidonov [The synthesis of gamma-amino acids and pyrrolidones] Zhurnal obschey khimii, 29, 29052910.Google Scholar
Rode, F., Jensen, D. G., Blackburn-Munro, G., Bjerrum, O.J. (2005). Centrally-mediated antinociceptive actions of GABAA receptor agonists in the rat spared nerve injury model of neuropathic pain. European Journal of Pharmacology, 516, 131138.Google Scholar
Rudolph, U.Crestani, F., Möler, H. (2001). GABAA receptor subtypes: dissecting their pharmacological functions. Trends in Pharmacological Sciences, 22, 188194.Google Scholar
Semyanov, A. V. (2002). GAMK-ergischeskoe tormozhenie v CNS: tipy GAMK – receptorov i mechanizmi tonischeskogo GAMK – oposredovannogo deystviya. [GABAergic inhibition in CNS: Types GABA – receptors and mechanisms of tonic GABA mediated inhibitory action]. Neurofisiologiya, 34, 8292.Google Scholar
Semyanov, A. V. (2004). Diffuse extrasynaptic neurotransmission by means of glutamate and GABA. Diffuznaya vnesinaptischeskaya neuroperedascha posredstvom glutamate i GAMK. Zhurnal vysshey nervnoy deyatelnosti. 54, 6884.Google Scholar
Shehab, S., McGonigle, D., Hughes, D. I., Todd, A. J., Redgrave, P. (2005). Anatomical evidence for an anticonvulsant relay in the rat ventromedial medulla. Journal of Neuroscience, 22, 1431.Google ScholarPubMed
Shmuilevisch, L. M., Kudrin, A. N. (1987). Gamma-aminomaclyanaya kislota i lekarstvennie preparati na ee osnove. [Gamma-aminobutiric acid and drugs containing it]. Farmatsiya, N° 4, 7680.Google Scholar
Shulgina, G. I. (1976). O funktsional'noyi roli medlennikh kolebaniyi potentsiala i uporyadoschennykh potokov impul'satsii. [On the functional role of potential slow oscillations and regular flows of action potentials]. Zhurnal uspekhi fiziologicheskikh nauk, 1, 4766.Google Scholar
Shulgina, G. I. (1987). K experimental'nomu i teoretischeskomu obosnovaniyu giperpolarizationnoy theorii vnutrennego tormozheniya. [Experimental and theoretical evidence of hyperpolarization theory of internal inhibition]. Zhurnal uspekhi fiziologischeskikh nauk. 18, 8097.Google Scholar
Shulgina, G. I. (2005). The neurophysiological validation of the hyperpolarization theory of internal inhibition. The Spanish Journal of Psychology, 8, 8699.Google Scholar
Shulgina, G. I., Ziablitseva, E. A.(2005). Vliyanie proizvodnogo GAMK phenibuta na obuschenie. [Influence of the GABA derivative phenibut on learning]. Vestnik rossyisky akademii meditsinskikh nauk, 2, 3540.Google Scholar
Shulgina, G. I., Petricheva, A. P., & Kuznetzova, G.G. (1985). Vliyanie proizvodnogo GAMK – fenibuta na povedenie i aktivnost' nevronov zritelnoy kory krolikov pri vyrabotke oboronitel'nogo refleksa i vnutrennego tormozheniya [Effect of the GABA-derivative – phenibut on the behavior and activity of neurons in the visual cortex of rabbits during conditioning of defensive reflex and internal inhibition]. Zhurnal vysshey nervnoi deyatelnosti, 25, 695702.Google Scholar
Sitinskiy, I. A. (1977). Gamma-aminomaslyanaya kislota – mediator tormozheniya. [Gamma-aminobutiric acid – mediator of inhibition]. Leningrad: Nauka..Google Scholar
Soriano, E., Frotscher, M. (1989). A GABAergic axo-axonic cell in the fascia dentata controls the main excitatory hippocampal pathway. Brain Research, 503, 170174.CrossRefGoogle ScholarPubMed
Sperk, G., Schwarzer, C., Tsunashi, K., Kandlhover, S. (1998). Expression of GABAA receptor subunits in the hippocampus of the rat after kainic acid-induced seizures. Epilepsy Research, 32, 129139.Google Scholar
Steriade, M. (2005). Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends in Neuroscience, 28, 317324.Google Scholar
Steriade, M., Gloor, P., Llinas, R. R., Lopes de Silva, F. H., Mesulam, M.M. (1990). Basic mechanisms of cerebral rhythmic activities. Electroencephalography and clinical Neurophysiology, 76, 481508.Google Scholar
Sukhov, A. G. (1968). K voprosu o korkobikh tormoznikh neyronakh.[On cortical inhibitory neurons] Fiziologicheskiy zhurnal USSR, 54, 270275.Google Scholar
Talalaenko, A. N. (1989). Farmakologicheskiy analis anxiolititcheskogo deystviya proizvodnich bezodiazepina, GAMK i β- carbolina v razlitschikh (razlichnikh??) testakh naprjazheniya. [Pharmacological analyses of anxiolitic action of derivative of benzodiazepine, GABA, and β - carboline in different tests of stress-reaction]. Farmakologiya i toxikologiya. 52, 2629.Google Scholar
Tebecis, A.K. (1974). Transmitters and identified neurons in the mammal's central nervous system. Bristol UK: Scientechnica.Google Scholar
Trageser, J. C., Keller, A. (2004). Reducing the uncertainty: gating of peripheral inputs by zona incerta. Journal of Neuroscience, 24, 89118915.Google Scholar
Vaitl, D., Bauer, U., Schaler, G., Stark, R., Zimmerman, M.,& Kirsh, P. (2002). Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses. Schizophrenia Research, 55, 147158.Google Scholar
Voronin, L. G., Sokolov, E. N. (1962). Korkovye mekhanizmy orientirovochnogo refleksa. Otnoshenie orientirovochnogo refleksa k uslovnomu refleksu [The cortical mechanisms of the orienting reflex. The relationship of the orienting reflex to the conditioned reflex]. In Elektroencefalograficheskoe issledovanie vysshey nervnoy deyatelnosti. [Electroencephalographic Research of the Higher Nervous Activity]. Moscow: Nauka, (pp. 310321).Google Scholar
Wassef, A., Baker, J., Kochan, LD.,(2003). GABA and schizophrenia: a review of basic science and clinical studies. Journal of Clinical Psychopharmacology, 3, 601640.Google Scholar
Ziablitseva, E. A., Shulgina, G. I. (The characteristics of the nootropic action of phenibut]. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova, 106, 5758.Google Scholar
Zorn, S.H., Enna, S.J. (1987). The GABA agonist THIP attenuates antinociception in the mouse by modifying central cholinergic transmission. Neuropharmacology, 26, 433437.Google Scholar