234

savoxpine to hippocampal, rather than striatal receptors, with a

receptor occupancy of greater than 24 hours. To test whether this

site specificity for limbic dopaminergic receptors could be dem-

onstrated clinically, stable schizophrenic in-patients, after signing

an informed consent, participated in a trial in which after a 4-7

day placebo washout period, they were randomized in a double-

blind design to treatment vith either savoxepine or haloperidol.

Initially, during the first 12-28 days, subjects had their dose ti-

trated in a flexible manner to 0.254.0 mg/day of savoxepine or

5-60 mg/day of haloperidol. After dosage titration, there was a

2-week fixed dose maintenance period. Extrapyramidal side-

effects (EPS) were assessed every 3-4 days during dosage titra-

tion, and weekly during dosage maintenance, using the Simpson-

Angus Scale (SAS), the Barnes Akathisia Scale (BAS), and the

Abnormal Involuntary Movement Scale (AIMS). The results

presented are a part of a larger multicenter trial. There were 1 I patients each at our site who received savoxepine or haloperidol.

Our data showed that there was a trend for savoxepine (ANOVA,

p = 0.064) to produce less EPS than haloperidol as measured by

the SAS at the end of the dosage titration period, however there

were no drug differences by the end of the dose maintenance

period. Similarly, no differences could be found on the BAS or

AIMS scales. These negative findings may in part be due to the

dosing of savoxepine. Studies using PET scanning have shown

that 0.5mg of savoxepine occupies 70-85% of striatal

dopaminergic receptors, as measured by the displacement

“C-raclopride. It is therefore possible that extremely low clini-

cal doses of savoxepine may demonstrate a site specificity for

hippocampal receptors and result in fewer EPS.

EFFECTS OF METABOLIC STRESS ON DOPAMINERGIC FUNCTION IN SCHIZOPHRENIA: RELATIONSHIP TO PREFRONTAL CORTEX VOLUME

A. Breier* , O.R. Davis, R.W. Buchanan, L.A. Moricle, R.C. Munson

Maryland Psychiatric Research Cntr., PO Box 21247, Baltimore,

MD 21228, USA

Several recent hypotheses suggest that deficits in normal pre-

frontal cortical inhibition of subcortical dopamine activity result

in dysregulated dopamine function and may contribute to the

pathophysiology of schizophrenia. Previous studies have indicated

that regulatory deficits are more consistently demonstrable during

perturbation of the dopamine system, as opposed to during the

resting state, because of the increase demands perturbation places on regulatory mechanisms. We have developed a novel paradigm

involving infusion of the glucose analogue, 2-deoxyglucose (2DG).

to examine the effects of perturbation on the dopamine metabolite,

plasma homovanillic acid (HVA), in schizophrenics and healthy

controls. Pharmacologic doses of 2DG blocks glucose metabo- lism and produces a clinical state similar to hypoglycaemia.

Schizophrenic patients (N=lS), as compared to controls (N=ll),

had significantly greater ZDG-induced plasma HVA elevations.

These effects were observed in subgroups of neuroleptic-free and

neuroleptic-treated patients. Other neuroendocrine (plasma cort-

sol), physiologic (heart rate, diastolic blood pressure, temperature)

and behavioral (self-ratings of stress, fatigue) variables were

significantly affected by 2DG but did not differentiate schizophrcn-

its and controls suggesting that the effects on plasma HVA may

be relatively specific. MRI-derived volumes of the prefrontal

cortex were significantly and inversely correlated to 2DG-related

peak changes in plasma HVA levels in the schizophrenics. These

data support the hypothesis that schizophrenia is associated with

abnormal regulation of dopamine and that this deficit may be

related to reduced frontal cortex size.

DIFFERENTIAL LOCOMOTOR INTERACTIONS BETWEEN DOPAMINE Dl/D2 RECEPTOR AGONISTS AND NMDA ANTAGONISTS

M.L. Carlsson*, A. Svensson, A. Carlsson

Department of Pharmacology, University of Gbtehorg,

Medicinarq 7. S-413 90 Giiteborg, Sweden

Previous work in our laboratory has shown that the noncom-

petitive N-methyl-D-aspartate antagonist dizocilpine (MK-801)

interacts synergistically with the mixed dopamine (DA) receptor

agonist apomorphine and the DA Dl agonist SKF 38393 to pro-

mote locomotion in monoamine-depleted mice. The purpose of

the present study was to investigate the relative importance of DA

DI receptors compared to DA D2 receptors in this interaction. To

that end, dizocilpine was given in combination with either the DA

Dl receptor agonist SKF 38393 or the DA D2 receptor agonist

quinpirole or the preferential DA D2 agonist bromocriptine. The

experiments showed that in genera1 the locomotor stimulation was

more pronounced when dizocilpine was combined with the DA

Dl receptor agonist than with a DA D2 receptor agonist. How-

ever, baseline activity. which partly depends on how much time

is allowed to elapse between administration of the DA agonist and

commencement of locomotor recording, and partly on the dose of

the DA agonist, seems to be an important factor that determines

whether dizocilpine will have a weakening or a potentiating

effect. Interestingly, the competitive NMDA antagonist D-CPPene

displayed a different pattern of interaction with SKF 39393 and

quinpirole in that synergistic effects were observed with both DA

agonists, most conspicuously so with the DA D2 receptor ago-

nist. The results are interpreted in the light of present knowledge

of basal ganglia neuroanatomy; they are discussed in relation to

the “direct” and “indirect” pathways from the striatum to

the thalamus, proposed to form part of positive and negative

cortico-striate-thalamo-cortical loops, respectively, as well as the

presumed presynaptic D2 receptors on corticostriatal glutamatergic

neurons.