Concurrent Risperidone Administration Attenuates the Development of Locomotor Sensitization Following Sub-Chronic Phencyclidine in Rats.

INTRODUCTION: In schizophrenia early treatment may prevent disorder onset, or at least minimize its impact, suggesting possible neuroprotective properties of antipsychotics. The present study investigates the effects of chronic treatment with the atypical antipsychotic, risperidone, on locomotor sensitization in the subchronic phencyclidine-treated rat. METHODS: Rats were treated with phencyclidine sub-chronically (2 mg/kg bi-daily for one week followed by a one-week wash-out period) or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5 mg/kg IP) twice daily for 15 days, beginning 3 days before the start of phencyclidine administration. 6 weeks after treatment all rats were injected with a phencyclidine-challenge (3.2 mg/kg) and immediately after their locomotor activity measured for 20 min. RESULTS: Co-administration of risperidone at the time of phencyclidine administration significantly reduced the phencyclidine-challenge locomotor effect administered 6 weeks later. DISCUSSION: These results demonstrate that concurrent risperidone is neuroprotective, and clearly suggests its functionality can be translated to a clinical setting for treating the so-called prodrome.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain.

In human subjects, the acute tryptophan (TRP) depletion (ATD) paradigm has been shown to have effects on mood and cognition. It is assumed that these effects are mediated through the serotonin system. In this study, we have examined the effects of ATD on the central concentrations of the monoamine transmitters, noradrenaline (NA) and dopamine (DA) as well as on serotonin (5-HT). Effects on NA and DA could also affect mood and cognition. Following oral administration of TRP-containing (TRP+) and TRP-free (TRP-) amino acid mixtures, neurotransmitter concentrations and free plasma TRP concentrations were determined by High Performance Liquid Chromatography (HPLC) with electrochemical detection. Free plasma TRP was significantly and substantially reduced (79%) in rats given a TRP- amino acid mixture when compared with those given a TRP+ mixture. ATD also significantly decreased 5-HT and 5-hydroxyindolacetic acid in the frontal cortex, remaining cortex and hippocampus, but did not significantly reduce these in the striatum. Furthermore, ATD did not significantly alter the concentration of NA and DA in any brain region examined. This study demonstrates that the administration of a TRP- amino acid mixture in rats can reduce free plasma TRP to levels comparable to those reported in human studies. These results indicate that behavioural and cognitive changes produced by ATD in preclinical or clinical studies are likely to be due to specific effects on the serotonergic system.

Ziprasidone and aripiprazole attenuate olanzapine-induced hyperphagia in rats.

Weight gain induced by some second-generation anti-psychotics such as olanzapine has emerged as a most debilitating side-effect. This study investigates whether co-administration with either ziprasidone or aripiprazole, which have little propensity to induce weight gain, can attenuate the hyperphagic effect of olanzapine. Female hooded-Lister rats (n=8 per group) were treated acutely with either vehicle, olanzapine (1 mg/kg), ziprasidone (1 mg/kg), aripiprazole (2 mg/kg) or olanzapine in combination with ziprasidone or aripiprazole and placed in automated locomotor activity (LMA) boxes with preweighed palatable mash. Food intake and LMA were measured for 60 min postdrug treatment. All olanzapine-treated groups demonstrated significant increases in food intake (P<0.001). This effect was attenuated following co-administration of olanzapine with either ziprasidone or aripiprazole (P<0.001), neither of which affected food intake alone. The lack of hyperphagia induced by aripiprazole and ziprasidone may reflect an inherent pharmacological mechanism preventing weight gain.

Deficits of neuronal glutamatergic markers in the caudate nucleus in schizophrenia.

Abnormal glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. In the present study we investigated two potential neuronal glutamatergic markers, the Excitatory Amino Acid Transporter 3 (EAAT3) and the Vesicular Glutamate Transporter 1 (VGluT1), in post-mortem striatal tissue from control subjects and from subjects with schizophrenia (n = 15 per group). We also investigated the possible influence of chronic antipsychotic administration (typical and atypical) on striatal VGluT1 expression in the rat brain. We found deficits in EAAT3 in all striatal regions examined in schizophrenia when compared to controls. Following correction for confounding factors (post-mortem interval), these deficits only remained significant in the caudate nucleus (p = 0.019). We also found significant deficits in VGluT1 in the caudate nucleus (p = 0.009) in schizophrenia. There were no significant differences in VGluT1 in the striatum of antipsychotic treated rats when compared to their vehicle treated controls. The data provides additional evidence for a glutamatergic synaptic pathology in the caudate nucleus in schizophrenia and may reflect a loss of glutamatergic cortico-striatal pathways. The absence of an effect of antipsychotic administration on VGluT1 indicates that the deficits in schizophrenia are unlikely to be a consequence of pharmacotherapy and thus likely to be a correlate of the disease process.

Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.

Post-mortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia. The calcium-binding proteins (CBPs), parvalbumin (PV), calbindin (CB) and calretinin (CR) can be used as markers for specific subpopulations of GABAergic neurons in the brain. Isolation rearing of rats is a non-pharmacological, non-lesion manipulation that leads to deficits in prepulse inhibition of the startle reflex (PPI) and other behavioural and neurochemical alterations reminiscent of schizophrenia. Female rats were reared in social housing (groups of three) or singly for 11 weeks post weaning and PPI was measured. Brains were removed and hippocampal CBP- containing neurons determined following immunocytochemical staining. Compared to socially housed rats, isolated rats exhibited PPI deficits and reductions in PV and CB-immunoreactive cells in the hippocampus, with no significant change in CR. These findings demonstrate selective abnormalities of sub-populations of GABAergic interneurons in the hippocampus of isolation reared rats, which resemble the neuronal deficits seen in this region in schizophrenia.

Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.

Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.

The neuronal pathology of schizophrenia: molecules and mechanisms.

There is an accumulation of evidence for abnormalities in schizophrenia of both the major neurotransmitter systems of the brain - those of GABA (gamma-aminobutyric acid) and glutamate. Initial studies have found deficits in the putative neuronal marker, N-acetylaspartate, in a number of brain regions in schizophrenia. The animal models have provided some interesting correlates and discrepancies with these findings. The deficit in inhibitory interneurons within structures implicated in schizophrenic symptomatology may well have direct functional relevance, and can be induced by animal models of the disease such as subchronic phencyclidine administration or social isolation. Their association with these animal models suggests an environmental involvement. A loss of glutamatergic function in schizophrenia is supported by decreases in markers for the neuronal glutamate transporter in striatal structures that receive cortical glutamatergic projections. Deficits in the VGluT1 (vesicular glutamate transporter-1) in both striatal and hippocampal regions support this observation, and the association of VGluT1 density with a genetic risk factor for schizophrenia points to genetic influences on these glutamatergic deficits. Further studies differentiating neuronal loss from diminished activity and improved models allowing us to determine the temporal and causal relationships between GABAergic and glutamatergic deficits will lead to a better understanding of the processes underlying the neuronal pathology of schizophrenia.

The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm.

Phencyclidine (PCP), an NMDA antagonist, has been shown to mimic some aspects of schizophrenia including positive, negative and cognitive symptoms. Previous studies in this laboratory have shown a selective reversal-learning deficit following acute PCP administration, a deficit that is attenuated by atypical, but not classical, antipsychotic treatment. However, acute PCP has limitations for modelling the chronic psychotic illness and persistent cognitive deficits observed in many schizophrenic patients. Therefore, the aim of this study was to examine the cognitive deficit induced by PCP over a longer term using a previously established operant reversal-learning procedure. Moreover, the efficacy of the atypical antipsychotics clozapine, ziprasidone and olanzapine to reverse the sub-chronic PCP deficit was compared with that of the classical antipsychotics, haloperidol and chlorpromazine. Female hooded-Lister rats were trained to respond for food using an operant reversal-learning paradigm. When animals achieved criterion of 90% correct responding they were treated with PCP (2mg/kg) or vehicle twice daily for 7 days, and 7 days later tested for their cognitive ability. PCP induced a significant impairment in the reversal phase relative to the initial phase of the task. Acute ziprasidone (2.5mg/kg), olanzapine (1.5mg/kg) and clozapine (5mg/kg) produced a significant attenuation of the impairment induced by sub-chronic PCP in the reversal phase. In marked contrast to these effects, acute administration of the classical agents haloperidol (0.05 mg/kg) and chlorpromazine (2mg/kg) failed to significantly reverse the PCP-induced cognitive impairment. These data clearly demonstrate that sub-chronic PCP produces enduring and persistent cognitive deficits, effects that are significantly attenuated by atypical but not classical antipsychotics.

Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs.

The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The levels of the mRNAs encoding TNF, IL-2, IL-6, TGF 1, 2, 3, IL-3 and GM-CSF were measured in the prefrontal cortex, cortex, hippocampus, ventral and dorsal striatum regions of male hooded Long Evans rats after acute drug administration. Antipsychotic drugs and PCP significantly reduced the levels of TNF in the prefrontal cortex compared to vehicle-treated animals, whilst other cytokines remained unchanged. In addition, significant reductions in the levels of TNF mRNA in the prefrontal cortex still occurred 24h after acute PCP administration. However, levels of TNF mRNA were restored to control values after chronic PCP treatment, whereas increased expression was detected in animals co-administered with haloperidol. Levels of TNF mRNA were also found to be significantly increased in the prefrontal cortex of schizophrenic subjects. The relationship between TNF levels and schizophrenia are discussed.

Antioxidant capacity in postmortem brain tissues of Parkinson's and Alzheimer's diseases.

Oxidative stress has been associated with damage and progressive cell death that occurs in neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). The aim of this study was to investigate the antioxidant capacity in postmortem motor cortex (MC), nucleus caudatus (NC), gyrus temporalis (GT) and substantia nigra (SN) from controls (C) and patients with PD and AD. The initial samples consisted of 68 subjects of PD, AD and C. Brains were matched for age, sex and postmortem time. Brain tissue was homogenized in a phosphate buffer pH 7.3 and separated with two-step centrifugation at 15,000rpm for 30 min and 15,000 rpm for 10 min at 4 degrees C. Antioxidant capacity in the supernatants was measured using the oxygen radical absorbance assay (ORAC). The results showed that in the SN of parkinsonian's brain the balance between production of free radicals and the neutralization by a complex antioxidant system is disturbed. No changes in the antioxidant capacity of postmortem MC and NC of parkinsonian's brain in comparison with C were found. In the SN of parkinsonian's brain, antioxidant capacity seems to be lower in comparison with C (p < 0.05). Antioxidant capacity against peroxyl radical showed that MC of AD patients was lower than in the MC of C (p < 0.005). In NC of AD patients the antioxidant capacity against hydroxyl radical was increased in comparison with C (p < 0.04). No changes in the antioxidant capacity were found in brain tissues of AD in comparison with C, when CuSO4 was used as a free radical generator.

Increased N-acetylaspartate in rat striatum following long-term administration of haloperidol.

N-acetylaspartate (NAA) is present in high concentrations in the CNS and is found primarily in neurons. NAA is considered to be a marker of neuronal viability. Numerous magnetic resonance spectroscopy (MRS) and postmortem studies have shown reductions of NAA in different brain regions in schizophrenia. Most of these studies involved patients chronically treated with antipsychotic drugs. However, the effect of chronic antipsychotic treatment on NAA remains unclear. In the present study, we measured NAA in brain tissue taken from 43 male Long-Evans rats receiving 28.5 mg/kg haloperidol decanoate i.m. every 3 weeks for 24 weeks and from 21 controls administered with vehicle. Determination of tissue concentrations of NAA was achieved by HPLC of sections of frozen tissue from several brain regions with relevance to schizophrenia. Chronic administration of haloperidol was associated with a significant increase (+23%) in NAA in the striatum (p<0.05) when compared to controls, with no significant changes in the other regions investigated (frontal and temporal cortex, thalamus, hippocampus, amygdala, and nucleus accumbens). NAA appears to be selectively increased in the striatum of rats chronically receiving haloperidol. This increase may reflect a hyperfunction of striatal neurons and relate to the reported increase in somal size of these cells and/or the increase in synaptic density seen in this region following antipsychotic administration. The lack of effect in other regions indicates that the well-documented NAA deficits seen in chronically treated schizophrenia patients is not an effect of antipsychotic medication and may in fact be related to the disease process.

Region specific changes in forebrain 5-hydroxytryptamine1A and 5-hydroxytryptamine2A receptors in isolation-reared rats: an in vitro autoradiography study.

The neurochemical correlates of the behavioural consequences of isolation rearing of rats are complex and involve many neurotransmitters, including the serotonergic system. Impaired functioning of the ascending serotonergic system has been implicated in many neuropsychiatric syndromes, including attention deficit hyperactivity disorder and schizophrenia. In the present investigation serotonergic function was assessed using in vitro receptor autoradiography. The 5-hydroxytryptamine(2A) (5-HT(2A)) receptor antagonist [(3)H]ketanserin and the 5-HT(1A) receptor antagonist, [(3)H]WAY100, 635 were used to compare 5-HT receptor subtype densities in the forebrains of socially and isolation-reared rats. Regions of highest receptor density were observed in the frontal cortex for 5-HT(2A) receptors and in the frontal cortex, dorsal hippocampus and lateral septum for 5-HT(1A) receptors. In isolation-reared rats, 5-HT(2A) receptor binding site densities were significantly increased by between 36 and 67% in the prelimbic, motor and cingulate cortices compared with socially reared controls. By contrast, 5-HT(1A) receptor binding site densities were significantly reduced by 22% in the prelimbic cortex, and significantly increased by between 10 and 50% in the motor cortex, somatosensory cortex, dentate gyrus and CA fields of the hippocampus. These data demonstrate that isolation-rearing produces significant effects on forebrain 5-HT(1A) and 5-HT(2A) receptor densities in the adult rat. It is hypothesised that altered serotonergic function, particularly in the hippocampus and prefrontal cortex, may underlie some of the behavioural abnormalities associated with isolation-rearing.

Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats.

Rearing rats in social isolation from weaning into adulthood leads to deficits in prepulse inhibition and alterations in monoamine systems that modulate prepulse inhibition. For example, rats reared in social isolation have elevated dopamine levels in the nucleus accumbens. Previous studies in rats have shown that nucleus accumbens dopamine depletion with 6-hydroxydopamine blocks the prepulse inhibition-disruptive effects of amphetamine, an indirect dopamine agonist. We tested the hypothesis that prepulse-inhibition deficits in isolation-reared rats are dependent on elevated dopamine levels in the nucleus accumbens. Specifically, we examined whether nucleus accumbens dopamine depletion would attenuate the isolation-induced disruption of prepulse inhibition. Isolation-housed female Long-Evans rats exhibited deficient prepulse inhibition. At 9 weeks post weaning, bilateral injections of 6-hydroxydopamine (8 microg/side) or ascorbic acid vehicle (0.1%) into the nucleus accumbens of social and isolation-reared rats were performed (8-10 rats per group). One week after surgery, prepulse inhibition deficits were exhibited by isolation-reared rats that received vehicle infusion into the nucleus accumbens, but not by those that received 6-hydroxydopamine infusions into the nucleus accumbens. 6-Hydroxydopamine infusions did not significantly change prepulse inhibition in socially reared rats. Behavioral and neurochemical evidence of nucleus accumbens dopamine depletion included: 1) a blockade of amphetamine-stimulated locomotor activity in nucleus accumbens 6-hydroxydopamine-infused isolated and socially reared rats; and 2) high performance liquid chromatography measurements demonstrating a significant depletion of accumbens dopamine and its major metabolites, in addition to decreases in dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the frontal cortex and anterior caudate. These data indicate that dopamine in the nucleus accumbens plays an essential role in the prepulse inhibition deficits associated with isolation rearing in female Long-Evans rats. The implication of a central role of nucleus accumbens dopamine in prepulse inhibition deficits in an animal model provides further evidence for a link between overactive dopamine function and sensorimotor-gating deficits in patients with schizophrenia.

The atypical antipsychotic ziprasidone, but not haloperidol, improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat.

The glutamate/N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) has been shown to induce both positive and negative symptoms of schizophrenia, as well as cognitive deficits, thus providing a relatively valid model of psychosis. Isolation rearing from weaning in the rat has been proposed as a non-pharmacological model of psychosis. The aim of the present study was to explore the validity of a combination of these techniques to model cognitive dysfunction associated with schizophrenia. The present study evaluates the effects of the novel antipsychotic ziprasidone and the typical antipsychotic haloperidol in their ability to reverse the cognitive deficit induced by PCP in isolation reared rats and social controls. Rats housed in social isolation (n = 25) or in groups of five (n = 25) from weaning were food deprived and trained to respond for food in an operant reversal learning paradigm. PCP at 1.0 and 1.5 mg/kg (intraperitoneally, i.p.) significantly and selectively impaired reversal task performance in both groups of rats. This impairment was not significantly improved following the coadministration of haloperidol (0.05 mg/kg, i.p.). Higher haloperidol doses (0.1 and 0.25 mg/kg, i.p.) were found to impair task performance, with the social animals being more sensitive than isolation-reared animals. In contrast, ziprasidone (2.5 mg/kg, i.p.) reversed the impairment caused by PCP. This was significant in social animals, while in isolates there was a non-significant enhancement in performance of the reversal task with ziprasidone compared to PCP alone. Thus, PCP produced a selective reversal learning deficit in rats, which was ameliorated following treatment with ziprasidone but not haloperidol. Rearing conditions did not influence performance of the test or the deficit produced by PCP.

Neuronal calcium-binding proteins and schizophrenia.

Calcium-binding proteins (CBPs) such as calbindin, parvalbumin and calretinin are used as immunohistochemical markers for discrete neuronal subpopulations. They are particularly useful in identifying the various subpopulations of GABAergic interneurons that control output from prefrontal and cingulate cortices as well as from the hippocampus. The strategic role these interneurons play in regulating output from these three crucial brain regions has made them a focus for neuropathological investigation in schizophrenia. The number of pathological reports detailing subtle changes in these CBP-containing interneurons in patients with schizophrenia is rapidly growing. These proteins however are more than convenient neuronal markers. They confer survival advantages to neurons and can increase the neuron's ability to sustain firing. These properties may be important in the subtle pathophysiology of nondegenerative phenomena such as schizophrenia. The aim of this review is to introduce the reader to the functional properties of CBPs and to examine the emerging literature reporting alterations in these proteins in schizophrenia as well as draw some conclusions about the significance of these findings.

Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons.

Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.

Relationship of symptomatology, gender, and antipsychotic drug treatment with plasma homovanillic acid in schizophrenia.

AIM: To study the role of dopamine neurotransmission in schizophrenia and its drug treatment by assessing the relationship of plasma homovanillic acid (pHVA), a major central dopamine metabolite to various clinical parameters in schizophrenic patients. METHODS: pHVA was measured by high-performance liquid chromatography with electrochemical detection in a large cohort of both medicated and unmedicated DSM-IV schizophrenic patients. Prior to the measurement of pHVA, the patients were rated on the schedule for the assessment of positive and negative symptoms (PANSS). RESULTS: (1) pHVA in 46 patients receiving antipsychotic drugs was decreased, and in 58 drug-free patients increased, (7.4+/-2.7) microg/L and (10+/-4) microg/L compared with a matched control group (9 microg/L+/-3 microg/L, n=62) (ANOVA F=8.57, df=2, P < 0.01), respectively. Within the drug-free group, pHVA was higher in the patients with a more negative symptom profile. (2) No significant correlation of pHVA with overall SAPS or SANS scores was apparent in the drug-free patients, although within the SANS subscales, a significant relationships to anhedonia-asociality (r=0.32, P < 0.05) was apparent. The male drug-free patients showed a positive correlation of pHVA with negative symptoms (r=0.42, P < 0.05) while females showed no significant relationship with any PANSS subscales. CONCLUSION: The results suggest that an increased dopaminergic metabolism is apparent in (male) schizophrenic patients with predominantly negative symptoms, supporting reports that this change in neuronal activity may be related to the neuropathological abnormalities seen in the disease, which may differ between males and females. Such neuronal deficits of developmental origin may thus result in an elevation/disinhibition of central dopamine metabolism in schizophrenia.