Abstract
The behavioural effects of apomorphine and GABAergic drugs alone and in combination were studied in eight monkeys (Cercopithecus aethiops) showing behavioural supersensitivity to dopamine agonists after long-term haloperidol treatment. Apomorphine (0.1–0.5 mg/kg SC) produced an increase in locomotion, repetitive movements of head, limbs and trunk, oral hyperkinesia (licking and chewing) and reactivity. Gamma-acetylenic GABA (GAG, a GABA transaminase inhibitor, 50–100 mg/kg SC) reduced spontaneous activity in two monkeys, but otherwise had no behavioural effect when given alone. Muscimol (a direct GABA receptor agonist, 0.25–1.0 mg/kg SC) caused decreased locomotion, slight ataxia (lack of coordinated movements), and myoclonic jerks at the highest doses, whereas 4,5,6,7-tetrahydroisoazolo-(5,4-c)-pyridin-3-ol (THIP, another GABA receptor agonist, 1.0–10.0 mg/kg SC) produced dose-dependent bradykinesia, dystonia, ataxia, and myoclonic jerks. All three GABA agonists reduced apomorphine-induced locomotion, repetitive movements and reactivity, whereas oral hyperkinesia was unchanged during THIP and slightly decreased by GAG and muscimol. Picrotoxin (a GABA antagonist, 0.4 mg/kg SC) also decreased apomorphine-induced responses, but at the same time produced signs of toxicity, especially vomiting and convulsions. These findings suggest that apomorphine and GABA agonists induce distinct types of behaviour, possibly related to a differential influence on separate dopamine/GABA receptors, and that GABA agonists in relatively high doses counteract apomorphine-induced behaviour with the exception that THIP does not influence oral hyperkinesia. This is consistent with the reported limited therapeutic effect of GABA agonists in tardive dyskinesia.
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References
Arnt J, Scheel-Krüger J (1979) Intranigral GABA antagonists produce dopamine-independent biting in rats. Eur J Pharmacol 62:51–61
Baldessarini RJ, Cole JO, Davis JM, Simpson G, Tarsy D, Gardos G, Preskorn SH (1980) Tardive dyskinesia: Summary of a Task Force Report of the American Psychiatric Association. Am J Psychiatry 137:1163–1172
Casey DE (1981) Responses to dopamine agonists before, during, and after neuroleptic treatment in non-human primates. In: Perris C, Struwe G, Jansson B (eds) Biological psychiatry. Elsevier/North Holland Biomedical Press, pp 833–836
Casey DE, Gerlach J, Christensson E (1980a) Behavioural aspects of dopamine receptor hypersensitivity in primates. In: Radouco-Thomas, Garcin F (eds) Abstracts of the 12th CINP Congress, Pergamon Press, Oxford, p 101
Casey DE, Gerlach J, Magelund G, Rosted Christensen T (1980b) γ-Acetylenic GABA in tardive dyskinesia. Arch Gen Psychiatry 37:1376–1379
Casey DE, Gerlach J, Korsgaard S (1981) Clinical pharmacological approaches to evaluating tardive dyskinesia. In: Usdin E, Dahl S, Gram LF, Lingjærde O (eds) Clinical pharmacology in psychiatry; Neuroleptic and antidepressant research. MacMillan Publishers Ltd., London, pp 369–383
Christensen AV (1981) Behavioural effect of THIP. In: Perris C, Struwe G, Jansson B (eds) Biological psychiatry. Elsevier/North Holland Biomedical Press, pp 429–432
Christensen AV, Svendsen O (1982) Behavioural effects of THIP after systemic administration. Brain Res Bull in press
Christensen AV, Arnt J, Scheel-Krüger J (1979) Decreased anti-stereotypic effect of neuroleptics after additional treatment with a benzodiazepine, a GABA agonist or an anticholinergic compound. Life Sci 24:1395–1402
Christensen AV, Møller Nielsen I (1980) On the supersensitivity of DA-receptors after single and repeated administration of neuroleptics. In: Fann WE, Smith RC, Davis JM, Domino EF (eds) Tardive dyskinesia, Spectrum Publ. pp 35–50
Clow A, Jenner P, Marsden CD (1979) Changes in dopamine-mediated behaviour during one year's neuroleptic administration. Eur J Pharmacol 57:365–375
Costall B, Naylor RJ (1976) Dissociation of stereotyped biting responses and oro-bucco-lingual dyskinesias. Eur J Pharmacol 36:423–429
Cott J, Engel J (1977) Suppression by GABAergic drugs of the locomotor stimulation induced by morphine, amphetamine, and apomorphine: Evidence for both pre- and post-synaptic inhibition of catecholamine systems. J Neural Transm 40:253–268
Fray PJ, Sahakian BJ, Robbins TW, Koob GF, Iversen SD (1980) An observational method for quantifying the behavioural effects of dopamine agonists: contrasting effect of d-amphetamine and apomorphine. Psychopharmacology 69:253–259
Gerlach J (1979) Tardive dyskinesia. Dan Med Bull 26:209–245
Gunne L-M, Bárány S (1976) Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 50:237–240
Gunne L-M, Bárány S (1979) A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia. Psychopharmacology 63:195–198
Klawans H, Hitri A, Nausicda PA, Weiner WJ (1977) Animal models of dyskinesia. In: Hanin I, Usdin E (eds) Animal models in psychiatry and neurology. Pergamon Press, pp 351–363
Korsgaard S, Casey DE, Gerlach J, Hetmar O, Kaldan B, Mikkelsen LB (1982) The effect of THIP, a new GABA agonist, in tardive dyskinesia. Arch Gen Psychiatry 39:1017–1021
krogsgaard-Larsen P, Johnston GAR, Lodge D, Curtis DR (1977) A new class of GABA agonists. Nature 268:53–55
Ljungberg T, Ungerstedt U (1978) Classification of neuroleptic drugs according to their ability to inhibit apomorphine-induced locomotion and gnawing. Evidence for two different mechanisms of action. Psychopharmacology 56:239–247
Meldrum B, Anlezark G, Trimble M (1979) Drugs modifying dopaminergic activity and behaviour, the EEG and epilepsy in Papio papio. Eur J Pharmacol 32:203–213
Meldrum B, Horton R (1980) Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy. Eur J Pharmacol 61:231–237
Nair NPV, Lal S, Schwartz G et al (1980) Effect of sodium valproate and baclofen in tardive dyskinesia: Clinical and neuroendocrine studies. In: Cattabeni F, Racagni G et al. (eds) Long-term effects of neuroleptics. Adv Biochem Psychopharmacol, vol 24, New York, Raven Press, pp 437–441
Ridley RM, Scraggs PR, Baker HF (1979) Modification of the behavioural effects of amphetamine by a GABA agonist in a primate species. Psychopharmacology 64:197–200
Schechter PJ, Grove J (1980) Biochemical and pharmacological similarities and differences among four irreversible enzyme-activated GABA-T inhibitors. Brain Res Bull 5 suppl. 2:627–631
Schechter PJ, Tranier Y (1978) The pharmacology of enzyme-activated inhibitors of GABA-transaminase. In: Seiler N, Jung MJ, Koch-Weser J (eds) Enzyme-activated irreversible inhibitors. Elsevier/North Holland, pp 149–162
Scheel-Krüger J (1971) Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain. Eur J Pharmacol 14:47–59
Scheel-Krüger J, Christensen AV, Arnt J (1978) Muscimol differentially facilitates stereotypy, but antagonized motility induced by dopaminergic drugs. A complex GABA dopamine interaction. Life Sci 22:75–84
Scheel-Krüger J, Magelund G, Olianna MC (1981) Role of GABA in the striatal output system: Globus pallidum, nucleus ento-peduncularis, substantia nigra, and nucleus subthalamicus. In: DiChiara G, Gessa GL (eds) GABA and the basal ganglia. Adv Biochem Psychopharm, vol 30. Raven Press, New York, pp 165–185
Schlemmer RF, Narasimhachari N, Davis JM (1980) Dose-dependent behavioural changes induced by apomorphine in selected members of a primate social colony. J Pharm Pharmacol 32:285–289
Shintomi K, Yamamura M (1975) Effects of penfluridol and other drugs on apomorphine-induced behaviour in monkeys. Eur J Pharmacol 31:273–280
Tamminga CA, Crayton JW, Chase TN (1979) Improvement in tardive dyskinesia after muscimol therapy. Arch Gen Psychiatry 36:595–598
Tarsy D, Baldessarini RJ (1974) Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with synaptic function of catecholamines. Neuropharmacol 13:927–940
Tarsy D, Baldessarini RJ (1977) The pathophysiologic basis of tardive dyskinesia. Biol Psychiatry 12:431–450
Worms P, Depoortere H, Lloyd KG (1979) Neuropharmacological spectrum of muscimol. Life Sci 25:607–614
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Bjørndal, N., Gerlach, J., Casey, D.E. et al. Effect of apomorphine and Gabaergic drugs in monkeys pretreated with haloperidol. Psychopharmacology 79, 220–225 (1983). https://doi.org/10.1007/BF00427816
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DOI: https://doi.org/10.1007/BF00427816