Gabaergic and Enkephalinergic Regulation of Locomotion in the Ventral Pallidum: Involvement of the Mesolimbic Dopamine System

  • Peter W. Kalivas
  • Mark A. Klitenick
  • Hanni Hagler
  • Mark C. Austin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 295)


It is well established that the mesolimbic dopamine projection from the AlO dopamine region in the ventromedial mesencephalon to the nucleus accumbens is important in mediating spontaneous and psychostimulant — induced locomotion (Fink and Smith, 1980; Koob et al., 1981; Clarke et al., 1988). The nucleus accumbens has a dense projection to the ventral pallidum (Nauta et al., 1978; Mogenson et al., 1983; Heimer et al., 1987; Churchill et al., 1990) which utilizes both GABA and enkephalin as neurotransmitters (Walaas and Fonnum, 1979; Zahm et al., 1985). Modulation of this projection to the ventral pallidum by dopamine in the nucleus accumbens mediates dopamine-dependent locomotion. Thus, locomotion elicited by stimulation of dopamine receptors in the nucleus accumbens is abolished following a lesion of the ventral pallidum (Swerdlow et al., 1984a). A role for GABA transmission in the accumbens-ventral pallidal pathway has been shown by the observation that stimulation of GABAa receptors in the ventral pallidum blocks motor activity produced by dopamine agonist injection into the nucleus accumbens (Jones and Mogenson, 1980; Mogenson and Nielsen, 1983; Swerdlow et al., 1984b; Austin and Kalivas, 1988). More recently, it was found that locomotion elicited by microinjection of other neurotransmitter agonists or antagonists into the nucleus accumbens, including a mu opioid agonist, GABAa antagonist, nicotinic agonist and glutamate agonist, is also blocked by muscimol injection into the ventral pallidum (Austin and Kalivas, 1989; Shreve and Uretsky, 1988). Therefore, it appears that locomotion elicited pharmacologically from the nucleus accumbens involves modulation of a GABAergic projection to the ventral pallidum, regardless of the neurochemical stimulus.


Nucleus Accumbens Mesolimbic Dopamine Delta Opioid Receptor Dopamine Transmission Mesolimbic Dopamine System 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Austin, M.C. and Kalivas, P.W., 1988, The effect of cholinergic stimulation in the nucleus accumbens on locomotor behavior, Brain Res., 441:209–214.PubMedCrossRefGoogle Scholar
  2. Austin, M.C. and Kalivas, P.W., 1989, Blockade of enkephalinergic and GABAergic mediated locomotion in the nucleus accumbens by muscimol in the ventral pallidum, Jpn. J. Pharmacol., 50:487–490.PubMedCrossRefGoogle Scholar
  3. Austin, M.C. and Kalivas, P.W., 1990, Enkephalinergic and GABAergic modulation of motor activity in the ventral pallidum, J. Pharmacol. Exp. Ther., 252:1370–1377.PubMedGoogle Scholar
  4. Austin, M.C. and Kalivas, P.W., 1991, Possible dopaminergic involvement in locomotion elicited from the ventral pallidum, Brain Res., in press.Google Scholar
  5. Baud, P., Mayo, W., Le Moal, M. and Simon, H., 1988, Locomotor hyperactivity in the rat after infusion of muscimol and 2 [D-Ala]Met-enkephalin into the nucleus basalis magnocellularis. Possible interaction with cortical cholinergic projections, Brain Res. 452:203–211.PubMedCrossRefGoogle Scholar
  6. Brudzynski, S.M. and Mogenson, G.J., 1985, Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens. Brain Res., 334:77–84.PubMedCrossRefGoogle Scholar
  7. Brudzynski, S.M., Houghton, P.E., Brownlee, R.D. and Mogenson, G.J., 1986, Involvement of neuronal cell bodies of the mesencephalic locomotor region in the initiation of locomotor activity of freely behaving rats. Brain Res. Bull. 16:407–381.CrossRefGoogle Scholar
  8. Churchill, L., Dilts, R.P. and Kalivas, P.W., 1990, Changes in gamma-aminohutyric acid, /nu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens, Brain Res. 511:41–54.PubMedCrossRefGoogle Scholar
  9. Clarke, P.B.S., Jakubovic, A. and Fibiger, H.C., 1988, Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions of damphetamine and apomorphine, Psvchopharmacoloqv 96:511–520.CrossRefGoogle Scholar
  10. Dauge, V., Rossignol, P. and Roques, B.P., 1988, Comparison of the behavioral effects induced by administration in rat nucleus accumbens or nucleus caudatus of selective mu and delta opioid peptides or kelatorphan an inhibitor of enkephalin-degrading-enzymes, Psvchopharmacoloqv 96:343–352.CrossRefGoogle Scholar
  11. Dilts, R.P. and Kalivas, P.W., 1990, Autoradiographic localization of delta opioid receptors within the mesocorticolimbic dopamine system using 125I — dpdpe, Svnapse, 6:121–132.CrossRefGoogle Scholar
  12. Fink, J.S. and Smith, G.P., 1980, Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats, Brain Res., 199:359–384.PubMedCrossRefGoogle Scholar
  13. Garcia-Rill, E., Skinner, R.D., Gilmore, S.A. and Owings, R., 1983, Connections of the mesencephalic locomotor region (MLR) II. Afferents and efferents. Brain Res. Bull., 10:63–71.PubMedCrossRefGoogle Scholar
  14. Groenewegen, H.J., 1988, Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography, Neuroscience, 24:379–431.PubMedCrossRefGoogle Scholar
  15. Haber, S.N., Groenewegen, H.J., Grove, E.A. and Nauta, W.J.H., 1985, Efferent connections of the ventral pallidum: evidence of a dual striatopallidofugal pathway, J. Comp. Neurol., 235:322–335.PubMedCrossRefGoogle Scholar
  16. Hallanger, A.E. and Wainer, B.H., 1988, Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat, J. Comp. Neurol. 274:483–515.PubMedCrossRefGoogle Scholar
  17. Heimer, L., Zaborszky, L., Zahm, D.S. and Alheid, G.F., 1987, The ventral striatopallidothalamic projection: I. The striatopallidal link originating in the striatal parts of the olfactory tubercle, J. Comp. Neurol., 255:571–591.PubMedCrossRefGoogle Scholar
  18. Hong, J.S., Yang, M.-Y., Fratta, W. and Costa, E., 1978, Rat striatal met-enkephalin content after chronic treatment with cataleptogenic and non-cataleptogenic antischizophrenia drugs, J. Pharmac. Exp. Ther., 205:141–147.Google Scholar
  19. Jones, D.L. and Mogenson, G.J., 1980, Nucleus accumbens to globus pallidus GABA projection subserving ambulatory activity. Am. J. Phvsiol., 238:R63-R96.Google Scholar
  20. Jones, M.W., Kilpatrick, I.C. and Phillipson, O.T., 1987, Regulation of dopamine function in the prefrontal cortex of the rat by the thalamic mediodorsal nucleus. Brain Res. Bull., 19:9–17.PubMedCrossRefGoogle Scholar
  21. Jones, M.W., Kilpatrick, I.C. and Phillipson, O.T., 1988, Dopamine function in the prefrontal cortex of the rat is sensitive to a reduction of tonic GABA-mediated inhibition in the thalamic mediodorsal nucleus, Exp. Brain Res., 69:623–634.PubMedCrossRefGoogle Scholar
  22. Joyce, E.M. and Iversen, S.D., 1979, The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat, Neurosci. Lett., 14:207–212.PubMedCrossRefGoogle Scholar
  23. Kalivas, P.W., Widerlov, E., Stanley, D., Breese, G. and Prange, A.J., 1983, Enkephalin action on the mesolimbic system: A dopamine-dependent and a dopamine-independent increase in locomotor activity, J. Pharmacol. Exp. Ther., 227:229–237.PubMedGoogle Scholar
  24. Kalivas, P.W., 1985, Sensitization to repeated enkephalin administration into the ventral tegmental area of the rat. II. Involvement of the mesolimbic dopamine system, J. Pharmacol. Exp. Ther., 235:544–550.PubMedGoogle Scholar
  25. Kalivas, P.W. and Bronson, M., 1985, Mesolimbic dopamine lesions produce an augmented behavioral response to enkephalin, Neuropharmacoloqv. 24:931–936.CrossRefGoogle Scholar
  26. Kalivas, P.W. and Duffy, P., 1990, The effect of acute and daily neurotensin and enkephalin on extracellular dopamine in the nucleus accumbens, J. Neurosci., 10:2940–2949.PubMedGoogle Scholar
  27. Koob, G.F., Stinus, L. and Le Moal, M., 1981, Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system, Behav. Brain Res., 3:341–359.PubMedCrossRefGoogle Scholar
  28. Mogenson, G.J., Jones, D.L. and Yim, C.Y., 1980, From motivation to action: functional interface between the limbic system and the motor system. Prog. Neurobiol., 14:69–97.PubMedCrossRefGoogle Scholar
  29. Mogenson, G.J. and Nielsen, M.A., 1983, Evidence that an accumbens to subpallidal GABAergic projection contributes to locomotor activity. Brain Res. Bull., 11:309–314.PubMedCrossRefGoogle Scholar
  30. Mogenson, G.J., Swanson, L.W. and Wu, M., 1983, Neural projections from the nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area: an anatomical and electrophysiological investigation in the rat, J. Neurosci., 3:189–202.PubMedGoogle Scholar
  31. Mogenson, G.J., Swanson, L.W. and Wu, M., 1985, Evidence that projections from the substantia innominata to zona incerta and mesencephalic locomotor region contribute to locomotor activity. Brain Res., 334:65–76.PubMedCrossRefGoogle Scholar
  32. Morris, B.J., Hollt, V. and Herz, A., 1988, Dopaminergic regulation of striatal proenkephalin mRNA and prodynrophin mRNA: contrasting effects of Dl and D2 antagonists, Neuroscience. 25:525–532.PubMedCrossRefGoogle Scholar
  33. Napier, T.C. and Marx, K., 1987, Enkephalin unilaterally microinjected into the ventral palliduin/nucleus basalis induces circling, Neuroscience Abstracts 13:445.Google Scholar
  34. Napier, T.C., An, D., Austin, M.C. and Kalivas, P.W., 1988, Opiates microinjected into the ventral pallidum/substantia innominata (VP/SI) produce locomotor responses that involve dopaminergic systems, Neuroscience Abstracts 14:293.Google Scholar
  35. Nauta, W.J.H., Smith, G.P., Faull, R.L.M. and Domesick, V.B., 1978, Efferent connections and nigral afferents of the nucleus accumbens septi in the rat, Neuroscience 3:385–401.PubMedCrossRefGoogle Scholar
  36. Niijima, K. and Yoshida, M., 1988, Activation of mesencephalic dopamine neurons by chemical stimulation of the nucleus tegmenti pedunculopontinus pars compacta. Brain Res., 345:163–171.CrossRefGoogle Scholar
  37. Pan, H.S. and Walters, J.R., 1988, Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of the globus pallidus neurons in the rat, Svnapse 2:650–656.CrossRefGoogle Scholar
  38. Patel, S. and Slater, P.L., 1988, Effects of GABA compounds injected into the subpallidal regions of rat brain on nucleus accumbens evoked hyperactivity, Behav. Neurosci. 102:596–600.PubMedCrossRefGoogle Scholar
  39. Pert, A. and Sivit, C., 1977, Neuroanatomical focus for morphine and enkephalin-induced hypermotility, Nature (Lond). 265:645–647.CrossRefGoogle Scholar
  40. Phillipson, O.T. and Griffiths, A.C., 1985, The topographic order of inputs to the nucleus accumbens in the rat, Neuroscience, 16, 275–296.PubMedCrossRefGoogle Scholar
  41. Robinson, T.E. and Whishaw, I.Q., 1988, Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats. Brain Res. 450:209–224.PubMedCrossRefGoogle Scholar
  42. Shreve, P.E. and Uretsky, N.J., 1988, Effect of GABAergic transmission in the subpallidum on the hypermotility response to administration of excitatory amino acids and Picrotoxin into the nucleus accumbens. Neuropharmacology, 27:1271–1277.PubMedCrossRefGoogle Scholar
  43. Stinus, L., Winnock, M. and Kelly, A.E., 1985, Chronic neuroleptic treatment and mesolimbic dopamine denervation induce behavioral supersensitivity to opiates, Psvchopharmacoloq., 85:323–328.CrossRefGoogle Scholar
  44. Swerdlow, N.R., Swanson, L.W. and Koob, G.F., 1984a, Electrolytic lesions of the substantia innominata and lateral preoptic area attenuate the supersensitive locomotor response to apomorphine resulting from denervation of the nucleus accumbens. Brain Res., 306:141–148.PubMedCrossRefGoogle Scholar
  45. Swerdlow, N.R., Swanson, L.W. and Koob, G.F., 1984b, Substantia innominata: critical link in the behavioral expression of mesolimbic dopamine stimulation in the rat, Neurosci. Lett., 50:19–24.PubMedCrossRefGoogle Scholar
  46. Swerdlow, N.R. and Koob, G.F., 1987, Lesions of the dorsomedial nucleus of the thalamus, medial prefrontal cortex and pedunculopontine nucleus: effects on locomotor activity mediated by nucleus accumbens-ventral pallidal circuitry. Brain Res., 412:233–243.PubMedCrossRefGoogle Scholar
  47. Vezina, P. and Stewart, J., 1984, Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA, Pharinacol. Biochein. Behav., 20:925–934.CrossRefGoogle Scholar
  48. Vezina, P., Kalivas, P.W. and Stewart, J., 1987, Sensitization occurs to the locomotor effects of morphine and the specific mu opioid receptor agonist, DAGO, administered repeatedly to the ventral tegmental area but not to the nucleus accumbens. Brain Res., 417:51–58.PubMedCrossRefGoogle Scholar
  49. Vives, F. and Mogenson, G.J., 1985, Electrophysiological evidence that the mediodorsal nucleus of the thalamus is a relay between the ventral pallidum and the medial prefrontal cortex in the rat. Brain Res., 344:329–337.PubMedCrossRefGoogle Scholar
  50. Walaas, I. and Fonnum, F., 1979, The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions. Brain Res., 177:325–336.PubMedCrossRefGoogle Scholar
  51. Zahm, D.S., Zaborsky, L., Alones, V.E. and Heimer, L., 1985, Evidence for the coexistence of glutamate decarboxylase and met-enkephalin immunoreactivities in axon terminals of rat ventral pallidum. Brain Res., 325:317–321.PubMedCrossRefGoogle Scholar
  52. Zahm, D.S., 1989, The ventral striatopallidal pars of the basal ganglia in the rat. II. Compartmentation of ventral pallidal efferents, Neurosci., 30:33–50.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Peter W. Kalivas
    • 1
    • 2
  • Mark A. Klitenick
    • 1
    • 2
  • Hanni Hagler
    • 1
    • 2
  • Mark C. Austin
    • 1
    • 2
  1. 1.Department of Veterinary Comparative Anatomy, Pharmacology and PhysiologyWashington State UniversityPullmanUSA
  2. 2.Unit on Behavioral NeuropharmacologyNational Institute of Mental HealthBethesdaUSA

Personalised recommendations