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Motor effects of GABAA antagonism in globus pallidus: studies of locomotion and tremulous jaw movements in rats

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Abstract

Rationale

Although most rodent studies related to parkinsonian symptoms have focused on locomotion, tremulous jaw movements also have been used as a rodent model of tremor for investigating the circuitry of the basal ganglia.

Objective

There are multiple pathways involved in the generation of parkinsonian symptoms. The globus pallidus is a basal ganglia relay nucleus, and the present study was conducted to investigate the effect of pallidal GABA antagonism on locomotion and tremulous jaw movements.

Methods

Suppression of locomotion and induction of tremulous jaw movements were produced by repeated (i.e., 14 day) systemic administration of the dopamine D2 antagonist haloperidol, and by acute systemic injection of the muscarinic agonist pilocarpine. The GABAA antagonist bicuculline was injected into the globus pallidus, and its effects on locomotion in haloperidol- and pilocarpine-treated rats were assessed in the first group of experiments. In the second group of experiments, the effects of intrapallidal infusions of bicuculline on haloperidol- and pilocarpine-induced jaw movements were observed.

Results

Pallidal GABA antagonism stimulated locomotion when no other treatment was present, and also when animals were coadministered haloperidol or pilocarpine. Bicuculline suppressed haloperidol-induced jaw movements in a dose-related manner, and had no effect on pilocarpine-induced jaw movements.

Conclusions

These results support the notion that there are distinct pathways conveying basal ganglia outflow and demonstrate that the striatopallidal pathway is involved in the generation of the haloperidol-induced tremulous jaw movements. These findings are consistent with some features of current models of basal ganglia function and may lead to an understanding of the specific mechanisms that generate parkinsonian symptoms.

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References

  • Ahtee I, Kaariainen I (1974) The role of dopamine in pilocarpine-induced catalepsy. Naunyn Schmiedeberg's Arch Pharmacol 284:25–38

    Google Scholar 

  • Alexander EG, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271

    CAS  PubMed  Google Scholar 

  • Amalric M, Koob GF (1989) Dorsal pallidum as functional motor output of the corpus striatum. Brain Res 483: 389–394

    CAS  PubMed  Google Scholar 

  • Aquilonius SM (1980) Cholinergic mechanisms in the CNS related to Parkinson's disease. In: Rinne UK, Klingler M, Stamm G (eds) Parkinson's disease: current progress, problems and management. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 17–27

  • Arai M (2000) Parkinsonism onset in a patient concurrently using tiapride and donepezil. Intern Med 39:863

    CAS  PubMed  Google Scholar 

  • Balsara JJ, Jadhav JH, Chandorkar AG (1980) Effects of intraperitoneally administered GABA on haloperidol-induced catalepsy in the rat. Psychopharmacology 68:105–107

    CAS  PubMed  Google Scholar 

  • Barnes DE, Robinson B, Csernansky JG, Bellows EP (1990) Sensitization versus tolerance to haloperidol-induced catalepsy: multiple determinants. Pharmacol Biochem Behav 36:883–887

    Article  CAS  PubMed  Google Scholar 

  • Baskin P, Salamone JD (1993) Vacuous jaw movements in rats induced by acute reserpine administration: interactions with different doses of apomorphine. Pharmacol Biochem Behav 46:793–797

    CAS  PubMed  Google Scholar 

  • Ben-Pazi H, Bergman H, Goldberg JA, Giladi N, Hansel D, Reches A, Simon ES (2001) Synchrony of rest tremor in multiple limbs in Parkinson's disease: evidence for multiple oscillators. J Neural Trans 108:287–296

    Article  Google Scholar 

  • Bevan MD, Smith AD, Bolam JP (1996) The substantia nigra as a site of synaptic integration of functionally diverse information arising from the ventral pallidum and the globus pallidus in the rat. Neurosci 75:5–12

    CAS  PubMed  Google Scholar 

  • Bourke D, Drukenbrod RW (1998) Possible association between donepezil and worsening Parkinson's disease. Ann Pharmacother 32:610–611

    CAS  Google Scholar 

  • Brotchie J, Crossman A, Mitchell I, Duty S, Carroll C, Cooper A, Henry B, Hughes N, Maneuf Y (1993) Chemical signaling in the globus pallidus in parkinsonism. Prog Brain Res 99:125–139

    CAS  PubMed  Google Scholar 

  • Cabeza-Alvarez CI, Gonzolez-Rubio M, Carcia Montero R, Alvarez-Tejerina A (1999) Parkinsonism syndrome related to tacrine. Neurologia 14:96

    CAS  PubMed  Google Scholar 

  • Carlson BB, Trevitt JT, Salamone JD (2000) Effects of H1 antagonists on cholinomimetic-induced tremulous jaw movements: studies of diphenhydramine, doxepin, and mepyramine. Pharmacol Biochem Behav 65:683–689

    CAS  PubMed  Google Scholar 

  • Carlsson ML (1993) Are the disparate pharmacological profiles of competitive and un-competitive NMDA antagonists due to different baseline activities of distinct glutamatergic pathways? J Neural Transm Gen Sect 94:1-10

    CAS  Google Scholar 

  • Celada P, Palladini CA, Tepper JM (1999) GABAergic control of rat substantia nigra dopaminergic neurons: role of globus pallidus and substantia nigra pars reticulata. Neurosci 89:813–825

    CAS  Google Scholar 

  • Chapman MA, See RE (1995) Differential effects of unique profile antipsychotic drugs on extracellular amino acids in the ventral pallidum and globus pallidus of rats. J Pharmacol Exp Ther 277:1586–1594

    Google Scholar 

  • Cousins MS, Carriero DL, Salamone JD (1997) Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine; effects of antiparkinsonian drugs. Eur J Pharmacol 322:137–145

    CAS  PubMed  Google Scholar 

  • Cousins MS, Atherton A, Salamone JD (1998) Behavioral and electromyographic characterization of the local frequency of tacrine-induced tremulous jaw movements. Physiol Behav 64:153–158

    CAS  PubMed  Google Scholar 

  • Cousins MS, Finn M, Trevitt J, Carriero DL, Conlan A, Salamone JD (1999) The role of ventrolateral striatal acetylcholine in the production of tacrine-induced jaw movements. Pharmacol Biochem Behav 62:439–447

    CAS  PubMed  Google Scholar 

  • DeLong MR (1990) Primate model of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285

    CAS  PubMed  Google Scholar 

  • De Montis GM, Olianas MC, Serra G, Tagliamonte A, Scheel-Kruger J (1979) Evidence that nigral gabaergic-cholinergic balance controls posture. Eur J Pharmacol 53:181–190

    Article  PubMed  Google Scholar 

  • Deuschl G, Raethjen J, Baron R, Lindemann M, Wilms H, Krack P (2000) The pathophysiology of parkinsonian tremor: a review. J Neurol 247:V33–V48

    PubMed  Google Scholar 

  • Duvoisin RC (1967) Cholinergic-anticholinergic antagonism in parkinsonism. Arch Neurol 17:124–136

    CAS  PubMed  Google Scholar 

  • Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 547:142–151

    Article  CAS  PubMed  Google Scholar 

  • Findley LJ (1988) Tremors: differential diagnosis and pharmacology. In: Jankovic J, Tolosa E (eds) Parkinson's disease and movement disorders. Urban and Schwarzenberg, Baltimore

  • Finn M, Mayorga AJ, Conlan A, Salamone JD (1997a) Involvement of pallidal and nigral GABA mechanisms in the generation of tremulous jaw movements in rats. Neurosci 80:532–544

    Google Scholar 

  • Finn M, Jassen A, Baskin P, Salamone JD (1997b) Tremulous characteristic of vacuous jaw movements induced by pilocarpine and ventrolateral striatal dopamine depletions. Pharmacol Biochem Behav 57:243–249

    CAS  PubMed  Google Scholar 

  • Fonnum F, Gottesfeld Z, Grofova I (1978) Distribution of glutamate decarboxylase, choline acetyltransferase and aromatic amino acid decarboxylase in the basal ganglia of normal and operated rats: evidence for striatopallidal, striatoentopeduncular and striatonigral GABAergic fibers. Brain Res 143:125–138

    PubMed  Google Scholar 

  • Fowler SC, Zarcone TJ, Vorontsova E (2001) Haloperidol-induced microcatalepsy differs in CD-1, BALB/c, and C57BL/6 mice. Exp Clin Psychopharmacol 9:277–284

    Article  CAS  PubMed  Google Scholar 

  • Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432

    CAS  PubMed  Google Scholar 

  • Gerfen CR, Keefe KA, Gauda EB (1995) D1 and D2 dopamine receptor function in the striatum: co-activation of D1- and D2-dopamine receptors on separate populations of neurons in potentiated immediate early gene response in D1-containing neurons. J Neurosci 15:8167–8176

    CAS  PubMed  Google Scholar 

  • Grimm JW, See RE (2000) Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats. Neuroscience 100:507–514

    Article  CAS  PubMed  Google Scholar 

  • Hersch SM, Levey AI (1995) Diverse pre- and post-synaptic expression of m1-m4 muscarinic receptor proteins in neurons and afferents in the rat neostriatum. Life Sci 56:931–938

    Article  CAS  PubMed  Google Scholar 

  • Hornykiewicz O (1973) Dopamine in the basal ganglia. Br Med Bull 29:172–178

    CAS  PubMed  Google Scholar 

  • Iwasaki Y, Wakata N, Kinoshita M (1988) Parkinsonism induced by pyridostigmine. Acta Neurol Scand 78:236

    CAS  PubMed  Google Scholar 

  • Jicha G, Salamone JD (1991) Vacuous jaw movements and feeding deficits in rats with ventrolateral striatal dopamine depletions: possible model of parkinsonian symptoms. J Neurosci 11:3822–3829

    CAS  PubMed  Google Scholar 

  • Kao KP, Kwan SY, Lin KP, Chang YC (1993) Coexistence of Parkinson's disease and myasthenia gravis: a case report. Clin Neurol Neurosurg 95:137–139

    CAS  PubMed  Google Scholar 

  • Kelley AE, Bakshi VP, Delfs JM, Lang CG (1989) Cholinergic stimulation of the ventrolateral striatum elicits mouth movements in rats: pharmacological and regional specificity. Psychopharmacology 99:542–549

    Google Scholar 

  • Keltner NL (1994) Tacrine: a pharmacological approach to Alzheimer's disease. J Psychosoc Nurs Ment Health Serv 32:37–39

    CAS  Google Scholar 

  • Keppel G, Zedeck S (1989) Data analysis for research designs. Freeman, New York

  • Kikuchi de Beltran K, Koshikawa N, Saigusa T, Watanabe K, Koshida Y, Kobayashi M (1992) Cholinergic/dopaminergic interaction in the rat striatum assessed from drug -induced repetitive oral movements. Eur J Pharmacol 214:181–189

    Article  PubMed  Google Scholar 

  • Kincaid AE, Penney JB, Young AB, Newman SW (1991) Evidences for a projection from the globus pallidus to the entopeduncular nucleus in the rat. Neurosci Lett 128:121–125

    Article  CAS  PubMed  Google Scholar 

  • Klawans HL, Barr A (1983) The extrapyramidal system: a review of function. Clin Neuropharm 6 [Suppl 1]:s3–s8

  • LeMoine C, Bloch B (1995) D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of dorsal and ventral striatum. J Comp Neurol 355:418–426

    Google Scholar 

  • Matsui Y, Kamioka T (1978) Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with Haloperidol or benzodiazepines. Naunyn Schmiedebergs Arch Pharmacol 305:219–225

    CAS  PubMed  Google Scholar 

  • Mayorga AJ, Carriero DL, Cousins MS, Gianutsos G, Salamone JD (1997) Tremulous jaw movements produced by acute tacrine administration: possible relation to parkinsonian side effects. Pharmacol Biochem Behav 56:273–279

    CAS  PubMed  Google Scholar 

  • Mayorga AJ, Trevitt JT, Conlan A, Ginutsos G, Salamone JD (1999a) Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats. Psychopharmacology 143:72–81

    Google Scholar 

  • Mayorga AJ, Cousins MS, Trevitt JT, Conlan A, Gianutsos G, Salamone JD (1999b) Characterization of the muscarinic receptor subtype mediating pilocarpine-induced tremulous jaw movements in rats. Eur J Pharmacol 364:7-11

    Article  CAS  PubMed  Google Scholar 

  • McEvoy JP (1983) The clinical use of anticholinergic drugs as treatments for extrapyramidal side effects of neuroleptic drugs. J Clin Psychpharmacol 3:288–302

    CAS  Google Scholar 

  • McSwain ML, Forman LM (1995) Severe parkinsonian symptom development on combination treatment with tacrine and haloperidol. J Clin Psychopharmacol 15:284

    Google Scholar 

  • Naik SR, Kelkar MR, Amladi SR, Sheth UK (1981) Effects of muscimol, a central GABA agonist, on the catalepsy, striatal homovanillic acid increase, and analgesia induced by pilocarpine in rats. Psychopharmacology 72:393–394

    Google Scholar 

  • Noring U, Povlesen UJ, Casey DE, Gerlach J (1984) Effect of a cholinomimetic drug (RS 86) in tardive dyskinesia and drug-related parkinsonism. Psychopharmacology 84:569–571

    Google Scholar 

  • Ossowska K, Wedzony K, Wolfarth S (1984) The role of the GABA mechanisms of the globus pallidus in mediating catalepsy, stereotypy and locomotor activity. Pharmacol Biochem Behav 21:825–831

    CAS  PubMed  Google Scholar 

  • Ott BR, Lannon MC (1992) Exacerbation of parkinsonism by tacrine. Clin Neuropharm 15:322–325

    CAS  PubMed  Google Scholar 

  • Pycock C, Horton RW, Marsden CD (1976) The behavioural effects of manipulating GABA function in the globus pallidus. Brain Res 116:353–359

    CAS  PubMed  Google Scholar 

  • Rodriguez Diaz M, Abdala P, Barroso-Chinea P, Obeso J, Gonzalez-Hernandez T (2001) Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson's disease. Behav Brain Res 122:79–92

    PubMed  Google Scholar 

  • Rupniak NM, Jenner P, Marsden CD (1983) Cholinergic manipulation of perioral behaviour induced by chronic neuroleptic administration to rats. Psychopharmacology 79:226–230

    Google Scholar 

  • Rupniak NM, Jenner P, Marsden CD (1985) Pharmacological characterization of spontaneous or drug-associated purposeless chewing movements in rats. Psychopharmacology 85:71–79

    Google Scholar 

  • Salamone JD, Lalies MD, Channell SL, Iversen SD (1986) Behavioural and pharmacological characterization of the mouth movements induced by muscarinic agonists in the rat. Psychopharmacology 88:467–471

    Google Scholar 

  • Salamone JD, Johnson CJ, McCullough LD, Steinpreis RE (1990) Lateral striatal cholinergic mechanisms involved in oral motor activities in the rat. Psychopharmacology 102:529–534

    Google Scholar 

  • Salamone JD, Baskin P (1996) Vacuous jaw movements induced by acute reserpine and low-dose apomorphine: possible model of parkinsonian tremor. Pharmacol Biochem Behav 53:179–183

    CAS  PubMed  Google Scholar 

  • Salamone JD, Mayorga AJ, Trevitt JT, Cousins MS, Conlan A, Nawab A (1998) Tremulous jaw movements in rats: a model of parkinsonian tremor. Prog Neurobiol 56:591–611

    CAS  PubMed  Google Scholar 

  • Salamone J, Correa M, Carlson B, Wisniecki A, Mayorga A, Nisenbaum E, Nisenbaum L, Felder C (2001) Neostriatal muscarinic receptor subtypes involved in the generation of tremulous jaw movements in rodents. Implications for cholinergic involvement in parkinsonism. Life Sci 68:2579–2584

    CAS  PubMed  Google Scholar 

  • Santiago MP, Potter LT (2001) Biotinylated m4-toxin demonstrates more M4 muscarinic receptor protein on direct than indirect striatal projection neurons. Brain Res 894:12–20

    Google Scholar 

  • Scheel-Kruger J (1983) The GABA receptors and animal behaviour: evidence that GABA transmits and mediates dopaminergic function in the basal ganglia and limbic system. In: Enna SJ (ed) The GABA receptors. Humana, Clifton, NJ, pp 215–256

  • Scheel-Kruger J, Magelund G, Olianas MC (1981a) Role of GABA in the striatal output system: globus pallidus, nucleus entopendicularis, substantia nigra and nucleus subthalamicus. In: Di Chira G, Gessa GL (eds) GABA and the basal ganglia. Raven, New York

  • Scheel-Kruger J, Magelund G, Olianas M (1981b) The role of GABA in the basal ganglia and limbic system for behaviour. In: DeFeudis FV, Mandel P (eds) Amino acid neurotransmitters. Raven, New York

  • Schiess MC, Zheng H, Soukup VM, Bonnen JG, Nauta HJ (2000) Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis. Parkinsonism Relat Disord 6:69–76

    Article  PubMed  Google Scholar 

  • Schmidt WJ, Tzschentke TM, Kretschmer BD (1999) State-dependent blockade of haloperidol -induced sensitization of catalepsy by MK-801. Eur J Neurosci 11:3365–3368

    CAS  PubMed  Google Scholar 

  • Shea C, MacKnight C, Rockwood K (1998) Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients. Int Psychogeriatr 10:229–238

    CAS  PubMed  Google Scholar 

  • Smith DA, Bolam JP (1990) The output neurons and the dopaminergic neurons of the substantia nigra receive a GABA-containing input from the globus pallidus in the rat. J Comp Neurol 296:47–64

    CAS  PubMed  Google Scholar 

  • Steinpreis RE, Baskin P, Salamone JD (1993) Vacuous jaw movements induced by sub-chronic administration of haloperidol: interactions with scopolamine. Psychopharmacology 111:99–105

    Google Scholar 

  • Steinpreis RE, Salamone JD (1993) Effects of acute haloperidol and reserpine administration on vacuous jaw movements in three different age groups of rats. Pharmacol Biochem Behav 46:405–409

    CAS  PubMed  Google Scholar 

  • Stewart BR, Jenner P, Marsden CD (1989) Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced chewing behavior. Psychopharmacology 97:228–234

    CAS  PubMed  Google Scholar 

  • Svensson K, Eriksson E, Carlsson A (1993) Partial dopamine receptor agonists reverse behavioral, biochemical and neuroendocrine effects of neuroleptics in the rat: potential treatment of extrapyramidal side effects. Neuropharmacol 32:1037–1045

    Article  CAS  Google Scholar 

  • Trevitt J, Atherton A, Aberman J, Salamone JD (1998) Effects of subchronic administration of clozapine, thioridazine and haloperidol on tests related to extrapyramidal motor function in the rat. Psychopharmacology 137:61–66

    Google Scholar 

  • Trevitt JT, Carlson BB, Correa M, Keene A, Morales M, Salamone JD (2002) Interactions between D1 receptors and GABA mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies. Psychopharmacology 159:229–237

    Google Scholar 

  • Williams SW, Herberg LJ (1987) Motivational vs. motor effects of striatal and pallidal gabaergic projections to subthalamic and entopendicular nuclei, ventromedial thalamus, and ventral globus pallidus. Pharmacol Biochem Behav 26:49–55

    Article  CAS  PubMed  Google Scholar 

  • Worms P, Lloyd KG (1980) Biphasic Effects of direct, but not indirect, GABA mimetics and antagonists on Haloperidol-induced Catalepsy. Naunyn Schmiedebergs Arch Pharmacol 311:179–184

    CAS  PubMed  Google Scholar 

  • Young AB, Penney JB (1993) Biochemical and functional organization of the basal ganglia. In: Jankowic J, Tolosa E (eds) Parkinson's disease and movement disorders. Williams and Wilkins, Baltimore, pp 1–12

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Acknowledgements

Many thanks to Jamie Bunce for his assistance with the photomicrograph.

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Author notes

  1. Merce Correa

    Present address: Area de Psicobiologia, Universitat Jaume I, Campus Riu Sec, 12080, Castello de la Plana, Spain

Authors and Affiliations

  1. Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA

    Anna Wisniecki, Merce Correa, Maria N. Arizzi, Keitha Ishiwari & John D. Salamone

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  1. Anna Wisniecki
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  2. Merce Correa
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  3. Maria N. Arizzi
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Correspondence to John D. Salamone.

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This work was supported by grants to J.S. from NIH/NINDS, and to M.C. from Generalitat Valenciana, Post 00-09-137, Spain

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Wisniecki, A., Correa, M., Arizzi, M.N. et al. Motor effects of GABAA antagonism in globus pallidus: studies of locomotion and tremulous jaw movements in rats. Psychopharmacology 170, 140–149 (2003). https://doi.org/10.1007/s00213-003-1521-z

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  • DOI: https://doi.org/10.1007/s00213-003-1521-z

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