Stephen J. Gamble

Adverse effects of anticholinergic medication on positive schizophrenic symptoms

In a series of 36 patients with acute schizophrenia flupenthixol dosage was blindly adjusted to give a fixed level of sedation. Patients were than randomly allocated to procyclidine or placebo. The patients receiving procyclidine experienced more positive schizophrenic symptoms and less severe extrapyramidal features by comparison with placebo patients. Blood levels of prolactin and flupenthixol estimated by radioimmunoassay were not significantly changed by the addition of procyclidine. Flupenthixol dosage and levels and prolactin levels were significantly related. There was no significant association between clinical and laboratory measures, with the exception that a curvilinear (inverted U) relationship was demonstrated between flupenthixol levels and antipsychotic and extrapyramidal effects. This relationship may be due to the fact that, in a study of this design, patients resistant to the effects of neuroleptic medication are likely to be given the highest doses. The findings support earlier claims that anticholinergic medication has adverse effects on schizophrenic symptoms.

Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration

Abstract Rats were treated with haloperidol (1.5mg/kg/day) in their drinking water for 9 months, with or without a subsequent withdrawal period of 7–10 days. Compared with controls, spontaneous locomotion and apomorphine-induced stereotypy were reduced in rats maintained on haloperidol whereas both behaviours were increased after the withdrawal period. Maximum specific 3 H-spiperone binding to striatal membrane preparations was increased (about 65%) in drug-treated rats with or without a withdrawal period. The dissociation constant for 3 H-spiperone binding was significantly increased only in those rats maintained on haloperidol with no withdrawal period. The increase in maximum binding of 3 H-spiperone was larger than that reported after less prolonged administration of neuroleptics. The size of the change should be taken into account in assessing the increased ligand binding reported in post-mortem brains of schizophrenics.

Neuroleptic treatment for a substantial proportion of adult life: Behavioural sequelae of 9 months haloperidol administration

Rats were treated chronically with haloperidol (1.5 mg/kg per day in drinking water) for up to 9 months. At 1 week, 3.5 months and 9 months after commencing treatment, spontaneous activity in separate groups was depressed by 30-40%. Apomorphine stereotypy was also attenuated at 9 months. Following a 7-10 day withdrawal period after 9 months of treatment, both measures were elevated. Enhancement of spontaneous activity appeared to be at least in part characterised by a deficit in psychomotor habituation to the test apparatus. DA receptor blockade during haloperidol treatment for a substantial proportion of a rats adult life was found to be an enduring effect, paralleling its antipsychotic action. Developing neurochemical supersensitivity was only manifested behaviourally after withdrawal of neuroleptic. The implications of such findings for the pathophysiology of schizophrenia and tardive dyskinesia and for the functional significance of dopamine receptor heterogeneity are discussed.

Social withdrawal following amphetamine administration to marmosets

Approaches and leaves from social encounters by marmosets which had received amphetamine injected either intramuscularly or into the nucleus accumbens or caudate nucleus were recorded and used to determine whether social behaviour was disrupted as a result of behavioural competition or more active social withdrawal. The social isolation observed after the marmosets had received an IM injection of amphetamine (2 mg/kg) was not due to drug-induced increases in alternative behaviours. Drugged animals immediately withdrew from social encounters, interrupting their stereotypies in order to do so, whenever they were approached by an undrugged animal. In contrast, the reduced time spent in social encounters following amphetamine injections into the nucleus accumbens (10, 20 or 40 μg) appeared to be a direct consequence of the concurrent increase in locomotion. Animals continued to initiate social encounters despite being hyperactive. Amphetamine injections into the caudate nucleus were without effect on any of the social or individual behavioural measures.

The relationships between clinical response, psychophysiological variables and plasma levels of amitriptyline and diazepam in neurotic outpatients

In a 4 week study of the response of neurotic outpatients to treatment with amitriptyline, diazepam, amitriptyline and diazepam, or placebo, clinical and psychophysiological variables and plasma levels of the drug were assessed. Clinical improvements were substantial in all treatment groups but clear relationships between clinical change, psychophysiological change and plasma levels of the drugs were not established. There was no relationship between plasma levels of the drugs and cigarette smoking. It is concluded that neither plasma levels of amitriptyline and diazepam nor change in skin conductance responsivity offer a useful guide to clinical response to drug treatment.

Sequelae of 6 months continuous administration of cis(Z)- and trans(E)-flupenthixol in the rat

Rats were treated continuously with cis(Z)- or trans (E)-flupenthixol via drinking water for 6 months. Stereotypy responses to 0.15 mg/kg apomorphine (APOM) were enduringly, and stereospecifically, antagonised by cis (Z)-flupenthixol at either 0.5-1.0 or 1.4-3.0 mg/kg per day. Responses to 1.0 mg/kg APOM were antagonised after 5 days but enhanced after 6 months on cis (Z)-flupentixol (1.4-3.0 mg/kg per day). Distinct dopamine-dependent processes may be differentially sensitive to adaptation during extended neuroleptic treatment.

Differential effects of ageing on distinct features of apomorphine stereotypy in the adult rat

Locomotor features of stereotypy induced by 0.15 mg/kg of subcutaneous apomorphine increased over the age ranges of 2.5-8 and 8-10 months in the adult rat. Perioral features of stereotypy induced by 1 mg/kg of apomorphine, and spontaneous activity did not show age-dependent changes. Heterogeneous features of apomorphine stereotypy may have distinct physiological substrates that are differentially sensitive to parameters of maturation and ageing.

Behavioural effects of intracerebral amphetamine in the marmoset

Marmosets were implanted bilaterally with guide cannulae so that d-amphetamine could be delivered to sites within the anterior neostriatum. Six animals received a series of bilateral amphetamine (20 μg) and saline injections to six sites 1 mm apart on a line passing through the caudate and accumbens nuclei. A second group of six animals received a range of doses (0, 5, 10, 20, 40 μg) of amphetamine bilaterally to one caudate and one accumbens site only. Drug injected into the accumbens produced a dose-related increase in checking (small head movements) and locomotion and a decrease in social interaction and inactivity. Drug injected into the caudate did not affect these behaviours, except for checking which was increased by the highest dose.

Functional Heterogeneity of Multiple Dopamine Receptors during Six Months' Treatment with Distinct Classes of Neuroleptic Drugs

ABSTRACT Rats were treated for 6 months with butyrophenone, phenothiazine or thioxanthene neuroleptics. Stereotypy responses to 0.15 mg/kg apomorphine remained antagonised and striata showed similar increases in 3H-spiperone binding, suggesting enduring functional blockade and masked ‘supersensitivity’ of DA2 receptors. However, spontaneous perioral movements and ‘vacuous chewing’ and hyperlocomotion to apomorphine and SK & F 38393, a putative DA1 agonist, distinguished the phenothiazines and thioxanthenes from the butyrophenone. Either DA1 and DA2 receptors can be dissociated functionally or behaviours previously equated with DAergic processes may be independant of such processes.

Spontaneous activity and apomorphine stereotypy during and after withdrawal from \(3{\raise0.5ex\hbox{

AbstractRats were treated continuously with haloperidol (1.5 mg/kg/day in drinking water) for