Effect of apomorphine and Gabaergic drugs in monkeys pretreated with haloperidol

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.