Abstract
Increasing evidence shows that the rostral agranular insular cortex (RAIC) is important in the modulation of nociception in humans and rats and that dopamine and GABA appear to be key neurotransmitters in the function of this cortical region. Here we use immunocytochemistry and path tracing to examine the relationship between dopamine and GABA related elements in the RAIC of the rat. We found that the RAIC has a high density of dopamine fibers that arise principally from the ipsilateral ventral tegmental area/substantia nigra (VTA/SN) and from a different set of neurons than those that project to the medial prefrontal cortex. Within the RAIC, there are close appositions between dopamine fibers and GABAergic interneurons. One target of cortical GABA appears to be a dense band of GABAB receptor-bearing neurons located in lamina 5 of the RAIC. The GABAB receptor-bearing neurons project principally to the amygdala and nucleus accumbens with few or no projections to the medial prefrontal cortex, cingulate gyrus, the mediodorsal thalamic nucleus or contralateral RAIC. The current anatomical data, together with previous behavioral results, suggest that part of the dopaminergic modulation of the RAIC occurs through GABAergic interneurons. GABA is able to exert specific effects through its action on GABAB receptor-bearing projection neurons that target a few subcortical limbic structures. Through these connections, dopamine innervation of the RAIC is likely to affect the motivational and affective dimensions of pain.
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ALBANESE, A. & MINCIACCHI, D. (1983) Organization of the ascending projections from the ventral tegmental area: A multiple fluorescent retrograde tracer study in the rat. Cerebral Cortex 216, 406–420.
ALLEN, G. V., SAPER, C. B., HURLEY, K. M. & CECHETTO, D. F. (1991) Organization of visceral and limbic connections in the insular cortex of the rat. Journal of Comparative Neurology 311, 1–16.
ATTWELL, D., BARBOUR, B. & SZATKOWSKI, M. (1993) Nonvesicular release of neurotransmitter. Neuron 11, 401–407.
BACKONJA, M. & MILETIC, V. (1991) Responses of neurons in the rat ventrolateral orbital cortex to phasic and tonic nociceptive stimulation. Brain Research 557, 353–355.
BACKONJA, M., WANG, B. & MILETIC, V. (1994) Responses of neurons in the ventrolateral orbital cortex to Dopaminergic input to GABAergic neurons in the RAIC 139 noxious cutaneous stimulation in a rat model of peripheral mononeuropathy. Brain Research 639, 337–340.
BENES, F. M. (1997) The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia. Journal of Psychiatric Research 31,257–275.
BENES, F. M., VINCENT, S. L. & MOLLOY, R. (1993) Dopamine-immunoreactive axon varicosities form nonrandom contacts with GABA-immunoreactive neurons of rat medial prefrontal cortex. Synapse 15, 285–295.
BERGER, B., GASPAR, P. & VERNEY, C. (1991) Dopaminergic innervation of the cerebral cortex: Unexpected differences between rodents and primates. Trends in Neuroscience 14, 21–27.
BORMANN, J. (1988) Electrophysiology of GABAA and GABAB receptor subtypes. Trends in Neuroscience 11, 112–116.
BURKEY, A. R., CARSTENS, E. & JASMIN, L. (1999) Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception. Journal of Neuroscience 19, 4169–4179.
BURKEY, A. R., CARSTENS, E., WENNIGER, J. J., TANG, J. & JASMIN, L. (1996) An opioidergic cortical antinociception triggering site in the agranular insular cortex of the rat that contributes to morphine antinociception. Journal of Neuroscience 16, 6612–6623.
CABIB, S. & PUGLISI-ALLEGRA, S. (1996) Stress, depression and the mesolimbic dopamine system. Psychopharmacology (Berl) 128, 331–342.
CARR, D. B. & SESACK, S. R. (2000) GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex. Synapse 38, 114–123.
COOPER, S. J. (1975) Anaesthetisation of prefrontal cortex and response to noxious stimulation. Nature 254, 439–440.
DEFELIPE, J., HENDRY, S. H., JONES, E. G. & SCHMECHEL, D. (1985) Variability in the terminations of GABAergic chandelier cell axons on initial segments of pyramidal cell axons in the monkey sensory-motor cortex. Journal of Comparative Neurology 231, 364–384.
DEL ARCO, A. & MORA, F. (2000) Endogenous dopamine potentiates the effects of glutamate on extracellular GABA in the prefrontal cortex of the freely moving rat. Brain Research Bulletin 53, 339–345.
DEUTCH, A. Y., LEE, M. C., GILLHAM, M. H., CAMERON, D. A., GOLDSTEIN, M. & IADAROLA, M. J. (1991) Stress selectively increases fos protein in dopamine neurons innervating the prefrontal cortex. Cerebral Cortex 1, 273–292.
DI CHIARA, G., LODDO, P. & TANDA, G. (1999) Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: Implications for the psychobiology of depression. Biological Psychiatry 46, 1624–1633.
FERRON, A., THIERRY, A. M., LE DOUARIN, C. & GLOWINSKI, J. (1984) Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex. Brain Research 302, 257–265.
FOLLETT, K. A. & DIRKS, B. (1995) Responses of neurons in ventrolateral orbital cortex to noxious visceral stimulation in the rat. Brain Research 669, 157–162.
FREUND, T. F., MARTIN, K. A., SMITH, A. D. & SOMOGYI, P. (1983) Glutamate decarboxylaseimmunoreactive terminals of Golgi-impregnated axoaxonic cells and of presumed basket cells in synaptic contact with pyramidal neurons of the cat's visual cortex. Journal of Comparative Neurology 221, 263–278.
GASPAR, P., BLOCH, B. & LE MOINE, C. (1995) D1 and D2 receptor gene expression in the rat frontal cortex: Cellular localization in different classes of efferent neurons. European Journal of Neuroscience 7, 1050–1063.
GERFEN, C. R. & CLAVIER, R. M. (1979) Neural inputs to the prefrontal agranular insular cortex in the rat: Horseradish peroxidase study. Brain Research Bulletin 4, 347–353.
GODBOUT, R., MANTZ, J., PIROT, S., GLOWINSKI, J. & THIERRY, A. M. (1991) Inhibitory influence of the mesocortical dopaminergic neurons on their target cells: Electrophysiological and pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics 258, 728–738.
GOLDMAN-RAKIC, P. S. (1998) The cortical dopamine system: Role in memory and cognition. Advances in Pharmacology 42, 707–711.
GOLDMAN-RAKIC, P. S., LERANTH, C., WILLIAMS, S. M., MONS, N. & GEFFARD, M. (1989) Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proceeding of the National Academy of Science USA 86, 9015–9909.
GONZALEZ-ISLAS, C. & HABLITZ, J. J. (2003) Dopamine enhances EPSCs in layer II–III pyramidal neurons in rat prefrontal cortex. Journal of Neuroscience 23, 867–875.
GORELOVA, N., SEAMANS, J. K. & YANG, C. R. (2002) Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. Journal of Neurophysiology 88, 3150–3166.
GRATTON, A., HOFFER, B. J. & FREEDMAN, R. (1987) Electrophysiological effects of phencyclidine in the medial prefrontal cortex of the rat. Neuropharmacology 26, 1275–1283.
GROBIN, A. C. & DEUTCH, A. Y. (1998) Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat. Journal of Pharmacology and Experimental Therapeutics 285, 350– 357.
GULLEDGE, A. T. & JAFFE, D. B. (2001) Multiple effects of dopamine on layer V pyramidal cell excitability in rat prefrontal cortex. Journal of Neurophysiology 86, 586–595.
HARDY, S. G. (1985) Analgesia elicited by prefrontal stimulation. Brain Research 339, 281–284.
HUANG, X., TANG, J. S., YUAN, B. & JIA, H. (2001) Morphine applied to the ventrolateral orbital cortex produces a naloxone-reversible antinociception in the rat. Neuroscience Letters 299, 189–192.
HURD, Y. L., SUZUKI, M. & SEDVALL, G. C. (2001) D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. Journal of Chemical Neuroanatomy 22, 127–137.
HURLEY, K. M., HERBERT, H., MOGA, M. M. & SAPER, C. B. (1991) Efferent projections of the infralimbic cortex of the rat. Journal of Comparative Neurology 308, 249–276.
JASMIN, L., RABKIN, S. D., GRANATO, A., BOUDAH, A. & OHARA, P. T. (2003) Analgesia and hyperalgesia from GABAergic modulation of the cerebral cortex. Nature 424, 316–320.
JONES, M. W., KILPATRICK, I. C. & PHILLIPSON, O. T. (1986) The agranular insular cortex: A site of unusually high dopamine utilisation. Neuroscience Letters 72, 330–334.
KAPP, B. S., SCHWABER, J. S. & DRISCOLL, P. A. (1985) The organization of insular cortex projections to the amygdaloid central nucleus and autonomic regulatory nuclei of the dorsal medulla. Brain Research 360, 355–360.
KARLER, R., CALDER, L. D., THAI, D. K. & BEDINGFIELD, J. B. (1998) The role of dopamine and GABA in the frontal cortex of mice in modulating a motor-stimulant effect of amphetamine and cocaine. Pharmacology Biochemistry and Behavior 60, 237–244.
KRETTEK, J. E. & PRICE, J. L. (1977a) The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. Journal of Comparative Neurology 171, 157–191.
KRETTEK, J. E. & PRICE, J. L. (1977b) Projections from the amygdaloid complex to the cerebral cortex and thalamus in the rat and cat. Journal of Comparative Neurology 172, 687–722.
KRUSHEL, L. A. & VAN DER KOOY, D. (1988) Visceral cortex: Integration of the mucosal senses with limbic information in the rat agranular insular cortex. Journal of Comparative Neurology 270(39–54), 62–33.
LARISCH, R., KLIMKE, A., VOSBERG, H., LOFFLER, S., GAEBEL, W. & MULLER-GARTNER, H. W. (1997) In vivo evidence for the involvement of dopamine-D2 receptors in striatum and anterior cingulate gyrus in major depression. Neuroimage 5, 251–260.
LE MOINE, C. & GASPAR, P. (1998) Subpopulations of cortical GABAergic interneurons differ by their expression ofD1andD2dopamine receptor subtypes. Molecular Brain Research 58, 231–236.
LEONARD, C. M. (1969) The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections. Brain Research 12, 321–343.
LOPANTSEV, V. & SCHWARTZKROIN, P. A. (2001) GABA(A)-dependent chloride influx modulates reversal potential of GABA(B)-mediated IPSPs in hippocampal pyramidal cells. Journal of Neurophysiology 85, 2381–2387.
MARGETA-MITROVIC, M., MITROVIC, I., RILEY, R. C., JAN, L. Y. & BASBAUM, A. I. (1999) Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. Journal of Comparative Neurology 405, 299–321.
MCDONALD, A. J. (1991) Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44, 1–14.
MCDONALD, A. J., MASCAGNI, F. & GUO, L. (1996) Projections of the medial and lateral prefrontal cortices to the amygdala: A Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71, 55–75.
MOORE, H., ROSE, H. J. & GRACE, A. A. (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 24, 410–419.
MORA, F., SWEENEY, K. F., ROLLS, E. T. & SANGUINETTI, A. M. (1976) Spontaneous firing rate of neurones in the prefrontal cortex of the rat: Evidence for a dopaminergic inhibition. Brain Research 116, 516– 522.
NEGYESSY, L., HAMORI, J. & BENTIVOGLIO, M. (1998) Contralateral cortical projection to the mediodorsal thalamic nucleus: Origin and synaptic organization in the rat. Neuroscience 84, 741–753.
ONGUR, D. & PRICE, J. L. (2000) The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex 10, 206– 219.
PARFITT, K. D., GRATTON, A. & BICKFORD-WIMER, P. C. (1990) Electrophysiological effects of selective D1 and D2 dopamine receptor agonists in the medial prefrontal cortex of young and aged Fischer 344 rats. Journal of Pharmacology and Experimental Therapeutics 254, 539–545.
PAXINOS, G. & WATSON, C. (1998) The Rat Brain in Stereotaxic Coordinates. New York: Academic Press.
PENIT-SORIA, J., AUDINAT, E. & CREPEL, F. (1987) Excitation of rat prefrontal cortical neurons by dopamine: An in vitro electrophysiological study. Brain Research 425, 263–274.
PETERSON, S. L., OLSTA, S. A. & MATTHEWS, R. T. (1990) Cocaine enhances medial prefrontal cortex neuron response to ventral tegmental area activation. Brain Research Bulletin 24, 267–273.
PETROVICH, G. D., RISOLD, P. Y. & SWANSON, L. W. (1996) Organization of projections from the basomedial nucleus of the amygdala:APHALstudy in the rat. Journal of Comparative Neurology 374, 387–420.
PIROT, S., GODBOUT, R., MANTZ, J., TASSIN, J. P., GLOWINSKI, J. & THIERRY, A. M. (1992) Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: Evidence for the involvement of both dopaminergic and GABAergic components. Neuroscience 49, 857–865.
PORRO, C. A., CAVAZZUTI, M., BARALDI, P., GIULIANI, D., PANERAI, A. E. & CORAZZA, R. (1999) CNS pattern of metabolic activity during tonic pain: Evidence for modulation by beta-endorphin. European Journal of Neuroscience 11, 874–888.
READER, T. A., FERRON, A., DESCARRIES, L. & JASPER, H. H. (1979) Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies. Brain Research 160, 217–229.
SAPER, C. B. (1982) Convergence of autonomic and limbic connections in the insular cortex of the rat. Journal of Comparative Neurology 210, 163–173.
SEAMANS, J. K., GORELOVA, N., DURSTEWITZ, D. & YANG, C. R. (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. Journal of Neuroscience 21, 3628–3638.
SEROOGY, K. B., DANGARAN, K., LIM, S., HAYCOCK, J. W. & FALLON, J. H. (1989) Ventral mesencephalic neurons containing both cholecystokinin-and tyrosine hydroxylase-like immunoreactivities project to forebrain regions. Journal of Comparative Neurology 279, 397–414.
SESACK, S. R., BRESSLER, C. N. & LEWIS, D. A. (1995a) Ultrastructural associations between dopamine terminals and local circuit neurons in the monkey prefrontal cortex: A study of calretinin-immunoreactive cells. Neuroscience Letters 200, 9–12.
SESACK, S. R., SNYDER, C. L. & LEWIS, D. A. (1995b) Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA-immunoreactive dendrites in rat and monkey cortex. Journal of Comparative Neurology 363, 264–280.
SESACK, S. R., HAWRYLAK, V. A., MELCHITZKY, D. S. & LEWIS, D. A. (1998) Dopamine innervation of a subclass of local circuit neurons in monkey prefrontal cortex: Ultrastructural analysis of tyrosine hydroxylase and parvalbumin immunoreactive structures. Cerebral Cortex 8, 614–622.
SHI, C. J. & CASSELL, M. D. (1998) Cortical, thalamic, and amygdaloid connections of the anterior and posterior insular cortices. Journal of Comparative Neurology 399, 440–468.
SNOW, P. J., LUMB, B. M. & CERVERO, F. (1992) The representation of prolonged and intense, noxious somatic and visceral stimuli in the ventrolateral orbital cortex of the cat. Pain 48, 89–99.
STRATFORD, T. R. & WIRTSHAFTER, D. (1990) Ascending dopaminergic projections from the dorsal raphe nucleus in the rat. Brain Research 511, 173–176.
SUHARA, T., NAKAYAMA, K., INOUE, O., FUKUDA, H., SHIMIZU, M., MORI, A. & TATENO, Y. (1992) D1 dopamine receptor binding in mood disorders measured by positron emission tomography. Psychopharmacology (Berl) 106, 14–18.
SWANSON, L. W. (1982) The projections of the ventral tegmental area and adjacent regions: A combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Research Bulletin 9, 321–353.
TASSIN, J. P., BOCKAERT, J., BLANC, G., STINUS, L., THIERRY, A. M., LAVIELLE, S., PREMONT, J. & GLOWINSKI, J. (1978) Topographical distribution of dopaminergic innervation and dopaminergic receptors of the anterior cerebral cortex of the rat. Brain Research 154, 241–251.
THIERRY, A. M., PIROT, S., GIOANNI, Y. & GLOWINSKI, J. (1998) Dopamine function in the prefrontal cortex. Advances in Pharmacology 42, 717–720.
TILLET, Y., BATAILLER, M., KRIEGER-POULLET, M. & THIBAULT, J. (1990) Presence of dopamineimmunoreactive cell bodies in the catecholaminergic group A15 of the sheep brain. Histochemistry 93, 327– 333.
URBAN, N. N., GONZALEZ-BURGOS, G., HENZE, D. A., LEWIS, D. A. & BARRIONUEVO, G. (2002) Selective reduction by dopamine of excitatory synaptic inputs to pyramidal neurons in primate prefrontal cortex. Journal of Physiology 539, 707–712.
VERNEY, C., ALVAREZ, C., GEFFARD, M. & BERGER, B. (1990) Ultrastructural double-labelling study of dopamine terminals and GABA-containing neurons in rat anteromedial cerebral cortex. European Journal of Neuroscience 2, 960–972.
VINCENT, S. L., KHAN, Y. & BENES, F. M. (1995) Cellular colocalization of dopamine D1 and D2 receptors in rat medial prefrontal cortex. Synapse 19, 112– 120.
WANG, X., ZHONG, P. & YAN, Z. (2002) Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. Journal of Neuroscience 22, 9185–9193.
WATANABE, M., KODAMA, T. & HIKOSAKA, K. (1997) Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. Journal of Neurophysiology 78, 2795–2798.
YANG, C. R. & SEAMANS, J. K. (1996) Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: Modulation of dendritic-somatic signal integration. Journal of Neuroscience 16, 1922–1935.
YANG, S. & FOLLETT, K. A. (1998) The effect of morphine on responses of ventrolateral orbital cortex (VLO) neurons to colorectal distension in the rat. Brain Research 808, 101–105.
ZHANG, S., TANG, J. S., YUAN, B. & JIA, H. (1997) Involvement of the frontal ventrolateral orbital cortex in descending inhibition of nociception mediated by the periaqueductal gray in rats. Neuroscience Letters 224, 142–146.
ZHANG, S., TANG, J. S., YUAN, B. & JIA, H. (1998) Inhibitory effects of electrical stimulation of ventrolateral orbital cortex on the rat jaw-opening reflex. Brain Research 813, 359–366.
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Ohara, P.T., Granato, A., Moallem, T.M. et al. Dopaminergic input to GABAergic neurons in the rostral agranular insular cortex of the rat. J Neurocytol 32, 131–141 (2003). https://doi.org/10.1023/B:NEUR.0000005598.09647.7f
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DOI: https://doi.org/10.1023/B:NEUR.0000005598.09647.7f