An investigation of experimentally induced behavioural hyperactivity: a neuropharmacological study

ABSTRACT

The cardinal features of the hyperkinetic child syndrome is excessive non-goal directed motor overactivity and impulsivity. Although hyperactive children constitute a small part of their age group, 4 percent - Steward et al 1966, their effects on peers and demands on teachers and parents are far out of proportion to their number. In addition, the linkage between hyperkinesia and adult psychopathology (like-emotional immaturity, inability to attain goals, feelings of hopelessness and poor self image) has been inferred from longitudinal, retrospective and family studies (Arnold et al 1972, Huessy 1974, Robins 1966). The present drugs of choice for the treatment of hyperkinesia (central nervous system stimulants like methylphenidate and d-amphetamine), have serious side effects and long periods of administration are known to cause psychosis (Laufer and Denhoff 1957). In the light of the above problems, fundamental research aimed at elucidating the biochemical determinants of hyperkinesia would be very useful, as this might result in better pharmaco-therapy for the syndrome. However, caution should be excercised in extrapolating results from animal to man. Since a functional interrelationship exists between dopaminergic and cholinergic systems (Sethy and Van Woert 1974), in the extrapyramidal system (this is important for the control of motor activity in man and other mammals), it was therefore hypothesized that motor hyperactivity could be due to a cholinergic inbalance in the brain. Rats' motor activity would seem a reasonable model for this study, as the main symptom of this syndrome is motor hyperactivity. Female rats (mean body weight 200 ñ 5G) were used for this study. Motor activity was measured with jiggle platforms which monitor the gross motor activity of the test animals as opposed to photoelectric activity cages which only measure animals locomotion. All drugs used for this study were injected intraperitoneally at a volume of 0.1ml, and the testing period for each rat was 60-min. Physostigmine at dose levels (0.01 - 0.18mg/kg) significantly increased rats motor activity as compared to saline controls. This increase in motor activity was also obtained when physostigmine at 0.05mg/kg was injected daily for four days. Atropine sulphate (5 and 10 mg/kg) attentuated the physostigmine induced increase in motor activity. However, the physostigmine induced excitation was potentiated by d-amphetamine at 1, 2 and 4mg/kg. These effects occurred whether physostigmine was injected before or after atropine and d-amphetamine. The effect of physostigmine on motor activity is central as neostigmine did not induce any stimulation of rats' motor activity. In addition reserpine, phenobarbitone, haloperidol and practocol (a beta-adrenergic blocking drug), attentuated the physostigmine-induced increase in motor activity, while phentolamine and tranylcypromine (MAO Inhibitor) did not affect the physostigmine-induced excitation. These results are discussed in conjunction with the findings of other workers and is concluded that (i) increasing the acetylcholine level of the rats brain with an anticholinesterase (physostigmine) induces motor hyperactivity (ii) anticholinergics and neuroleptics are capable of attenuating this physostigmine-induced motor hyperactivity. (iii) the fact that d-amphetamine potentiated the physostigmine-induced motor hyperactivity may exlain the observation that following d-amphetamine or methylphenidate treatment, some hyperkinetic children (30 percent) manifest a worsening of their symptoms. (Satterfield et al 1972). If in some subtypes of hyperkinetics, a cholinergic dysfunction is present, then it follows on the basis of the present study that d-amphetamine will excercebate their condition, while anticholinergics might be useful therapy (AU)