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Introduction: A rapidly growing body of data documents associations between disease of the brain and small molecules generated by gut-microbiota (GMB). While such metabolites can affect brain function through a variety of mechanisms, the most direct action would be on the central nervous system (CNS) itself., Objective: Identify indolic and phenolic GMB-dependent small molecules that reach bioactive concentrations in primate CNS., Methods: We conducted a PubMed search for metabolomic studies of the primate CNS [brain tissue or cerebrospinal fluid (CSF)] and then selected for phenolic or indolic metabolites that (i) had been quantified, (ii) were GMB-dependent. For each chemical we then conducted a search for studies of bioactivity conducted in vitro in human cells of any kind or in CNS cells from the mouse or rat., Results: 36 metabolites of interests were identified in primate CNS through targeted metabolomics. Quantification was available for 31/36 and in vitro bioactivity for 23/36. The reported CNS range for 8 metabolites 2-(3-hydroxyphenyl)acetic acid, 2-(4-hydroxyphenyl)acetic acid, 3-(3-hydroxyphenyl)propanoic acid, (E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid [caffeic acid], 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-acetamido-3-(1H-indol-3-yl)propanoic acid [N-acetyltryptophan], 1H-indol-3-yl hydrogen sulfate [indoxyl-3-sulfate] overlapped with a bioactive concentration. However, the number and quality of relevant studies of CNS neurochemistry as well as of bioactivity were highly limited. Structural isomers, multiple metabolites and potential confounders were inadequately considered., Conclusion: The potential direct bioactivity of GMB-derived indolic and phenolic molecules on primate CNS remains largely unknown. The field requires additional strategies to identify and prioritize screening of the most promising small molecules that enter the CNS., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: The gut microbiome (GMB) generates numerous small chemicals that can be absorbed by the host and variously biotransformed, incorporated, or excreted. The resulting metabolome can provide information about the state of the GMB, of the host, and of their relationship. Exploiting this information in the service of biomarker development is contingent on knowing the GMB-sensitivity of the individual chemicals comprising the metabolome. In this regard, human studies have lagged far behind animal studies. Accordingly, we tested the hypothesis that serum levels of chemicals unequivocally demonstrated to be GMB-sensitive in rodent models would also be affected in a clinical patient sample treated with broad spectrum antibiotics., Methods: We collected serum samples from 20 hospitalized patients before, during, and after treatment with broad-spectrum antibiotics. We also collected samples from 5 control patients admitted to the hospital but not prescribed antibiotics. We submitted the samples for a non-targeted metabolomic analysis and then focused on chemicals known to be affected both by germ-free status and by antibiotic treatment in the mouse and/or rat., Results: Putative identification was obtained for 499 chemicals in human serum. An aggregate analysis did not show any time x treatment interactions. However, our literature search identified 10 serum chemicals affected both by germ-free status and antibiotic treatment in the mouse or rat. Six of those chemicals were measured in our patient samples and additionally met criteria for inclusion in a focused analysis. Serum levels of 5 chemicals (p-cresol sulfate, phenol sulfate, hippurate, indole propionate, and indoxyl sulfate) declined significantly in our group of antibiotic-treated patients but did not change in our patient control group., Conclusions: Broad-spectrum antibiotic treatment in patients lowered serum levels of selected chemicals previously demonstrated to be GMB-sensitive in rodent models. Interestingly, all those chemicals are known to be uremic solutes that can be derived from aromatic amino acids (L-phenylalanine, L-tyrosine, or L-tryptophan) by anaerobic bacteria, particularly Clostridial species. We conclude that judiciously selected serum chemicals can reliably detect antibiotic-induced suppression of the GMB in man and thus facilitate further metabolome-based biomarker development., Competing Interests: Curtis J. Donskey has received research funding from Clorox, Pfizer, and PDI. He also serves as an associate editor for Pathogens and Immunity. All other authors report no relevant conflicts of interest., (Copyright © Pathogens and Immunity 2020.)

Background: The gut microbiome (GMB) generates numerous chemicals that are absorbed systemically and excreted in urine. Antibiotics can disrupt the GMB ecosystem and weaken its resistance to colonization by enteric pathogens such as Clostridium difficile . If the changes in GMB composition and metabolism are sufficiently large, they can be reflected in the urinary metabo-lome. Characterizing these changes could provide a potentially valuable biomarker of the status of the GMB. While preliminary studies suggest such a possibility, the high level of data variance presents a challenge to translational applications. Since many GMB-generated chemicals are derived from the biotransformation of plant-derived dietary polyphenols, administering an oral precursor challenge should amplify GMB-dependent changes in urinary metabolites., Methods: A course of antibiotics (clindamycin, piperacillin/tazobactam, or aztreonam) was administered SC daily (days 1 and 2) to mice receiving polyphenol-rich green tea in drinking water. Urine was collected at baseline as well as days 3, 7, and 11. Levels of pyrogallol and pyrocatechol, two phenolic molecules unequivocally GMB-dependent in humans but that had not been similarly examined in mice, were quantified., Results: In confirmation of our hypothesis, differential changes in murine urinary pyrogallol levels identified the treatments (clindamycin, piperacillin/tazobactam) previously associated with a weakening of colonization resistance to Clostridium difficile . The changes in pyrocatechol levels did not withstand corrections for multiple comparisons., Conclusions: In the mouse, urinary pyrogallol and, in all likelihood, pyrocatechol levels, are GMB-dependent and, in combination with precursor challenge, deserve further consideration as potential metabolomic biomarkers for the health and dysbiotic vulnerability of the GMB., Competing Interests: Curtis J. Donskey has received research funding from Clorox, GOJO, Pfizer, Avery Dennison, PDI, and Boehringer Laboratories. He also serves as an associate editor for Pathogens and Immunity. All other authors report no relevant conflicts of interest., (© Pathogens and Immunity 2019.)

Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges. Some SPMs have multiple structural isomers and most have conjugates. Without specialized approaches, SPMs can be incorrectly assigned or inaccurately quantified. In addition, SPM levels can be affected by dietary polyphenol or protein consumption and by various medications and diseases. Nonetheless, heterotypical excretion of various SPMs in association with schizophrenia or autism continues to be reported in independent samples. Recent studies in human cerebrospinal fluid demonstrate the presence of many SPMs A large number of these are bioactive in experimental models. Whether such mechanisms are relevant to the human brain in health or disease is not known. Systematic metabolomic and microbiome studies of well-characterized populations, an appreciation of multiple confounds, and implementation of standardized approaches across platforms and sites are needed to delineate the potential utility of the phenolic interactome in neuropsychiatry.

Aim: Co-metabolism between a human host and the gastrointestinal microbiota generates many small phenolic molecules such as 3-hydroxy-3-(3-hydroxyphenyl)propanoic acid (3,3-HPHPA), which are reported to be elevated in schizophrenia and autism. Characterization of these chemicals, however, has been limited by analytic challenges., Methodology/results: We applied HPLC to separate and quantify over 50 analytes, including multiple structural isomers of 3,3-HPHPA in human cerebrospinal fluid, serum and urine. Confirmation of identity was provided by NMR, by MS and other detection methods. The highly selective methods support rapid quantification of multiple metabolites and exhibit superior chromatographic behavior., Conclusion: An improved ultra-HPLC-MS/MS and structural approaches can accurately quantify 3,3-HPHPA and related analytes in human biological matrices.

We previously found that L-tyrosine (L-TYR) but not D-TYR administered by reverse dialysis elevated catecholamine synthesis in vivo in medial prefrontal cortex (MPFC) and striatum of the rat (Brodnik et al., 2012). We now report L-TYR effects on extracellular levels of catecholamines and their metabolites. In MPFC, reverse dialysis of L-TYR elevated in vivo levels of dihydroxyphenylacetic acid (DOPAC) (L-TYR 250-1000 μM), homovanillic acid (HVA) (L-TYR 1000 μM) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (L-TYR 500-1000 μM). In striatum L-TYR 250 μM elevated DOPAC. We also examined L-TYR effects on extracellular dopamine (DA) and norepinephrine (NE) levels during two 30 min pulses (P2 and P1) of K+ (37.5 mM) separated by t = 2.0 h. L-TYR significantly elevated the ratio P2/P1 for DA (L-TYR 125 μM) and NE (L-TYR 125-250 μM) in MPFC but lowered P2/P1 for DA (L-TYR 250 μM) in striatum. Finally, we measured DA levels in brain slices using ex-vivo voltammetry. Perfusion with L-TYR (12.5-50 μM) dose-dependently elevated stimulated DA levels in striatum. In all the above studies, D-TYR had no effect. We conclude that acute increases within the physiological range of L-TYR levels can increase catecholamine metabolism and efflux in MPFC and striatum. Chronically, such repeated increases in L-TYR availability could induce adaptive changes in catecholamine transmission while amplifying the metabolic cost of catecholamine synthesis and degradation. This has implications for neuropsychiatric conditions in which neurotoxicity and/or disordered L-TYR transport have been implicated., (Published by Elsevier Ltd.)

In rodents, transport of large neutral amino acids (LNAAs) across the blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier is mediated by high affinity carriers. Net brain LNAA levels are thought to be determined mainly by this competitive transport from plasma. Since the affinity for LNAA transport at the BBB in primates is considerably higher than in rodents, brain influx and by extension LNAA brain levels, should be even more dependent on competitive transport. Given that LNAA levels in CSF and brain interstitial fluid are usually similar, we analyzed serum and CSF of fasted subjects (n=24) undergoing spinal anesthesia and calculated brain influx and transporter occupancy using a conventional model of transport. Despite predicted near-full transporter saturation (99.7%), correlations between CSF levels and brain influx were modest, limited to tyrosine (r=0.60, p<0.002) and tryptophan (r=0.50, p<0.01) and comparable to correlations between CSF and serum levels. We also analyzed serum and CSF in (n=5) fasted vervet monkeys. Tyrosine and phenylalanine levels in CSF were positively correlated with those in serum, but correlations with calculated brain influx, which takes competition into account, were weaker or absent. We conclude that in primates i) baseline CSF LNAA levels do not confirm competitive transport, ii) brain LNAA levels should not be estimated on the basis of serum indices alone. This has implications for amino acid challenge studies and for neuropsychiatric disorders associated with dysregulated LNAA transport in which quantitative information about brain LNAA levels is needed., (Published by Elsevier B.V.)

Objective: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting., Method: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed., Results: Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms., Conclusion: In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Schizophrenia is associated with altered tyrosine transport across plasma membranes. This is typically demonstrated by measuring the uptake of radiolabeled tyrosine in cultured human fibroblasts. Our primary goal was to determine whether tyrosine uptake could be characterized using unlabeled tyrosine. A secondary goal was to assess the effect of antipsychotic drugs added during the incubation., Method: Epithelium-derived fibroblast cultures were generated from patients with schizophrenia (n=6) and age-matched controls (n=6). Cells between cycles 8-12 were exposed to an amino acid free medium for 60min and then for 1min to media containing tyrosine (0.008-1.0mM). Amino acid levels were measured and Michaelis-Menten parameters determined. Uptake of tyrosine (0.5mM) was also measured in control cells after antipsychotic drugs were introduced during the depletion or uptake phases., Results: Tyrosine uptake was sodium-independent. The maximal transport velocity (Vmax) was significantly lower in patients with schizophrenia than in controls (p<0.01). The transporter affinity (Km) did not differ between the groups. Tyrosine uptake was differentially affected (p<0.001) by inclusion of 10(-4)M haloperidol, chlorpromazine or clozapine during different periods of incubation., Conclusion: Dysregulated tyrosine kinetics in schizophrenia can be readily studied without the use of radiolabeled tracers. The data also indicate that tyrosine uptake may be subject to complex pharmacological effects., (© 2013.)

Rationale: Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe., Objectives: The objective of this study was to determine whether the subthreshold stimulation of presynaptic DA receptors would potentiate tyrosine depletion-induced effects on extracellular DA levels in the medial prefrontal cortex (MPFC) and striatum of the rat., Methods: We administered quinpirole, a predominantly DA type 2 (D2R) receptor agonist, into the MPFC and striatum by reverse dialysis. A tyrosine- and phenylalanine-free neutral amino acid mixture [NAA(-)] IP was used to lower brain tyrosine levels. DA levels in the microdialysate were measured by HPLC with electrochemical detection., Results: Quinpirole dose-dependently lowered DA levels in MPFC as well as in the striatum. NAA(-) alone transiently lowered DA levels (80 % baseline) in the striatum, but had no effect in MPFC. The co-administration of NAA(-) and a subthreshold concentration of quinpirole (6.25 nM) lowered DA levels (50 % baseline) in both the MPFC and striatum. This effect was blocked by the mixed D2R/D3R antagonist haloperidol at IP doses that on their own did not affect DA levels (10.0 nmol/kg in the MPFC and 0.10 nmol/kg in the striatum)., Conclusions: Pharmacological stimulation of inhibitory D2R receptors during tyrosine depletion markedly lowers the extracellular DA levels in the MPFC and striatum. The data suggest that combining tyrosine depletion with a low dose of a DA agonist should robustly lower brain regional DA levels in man.

In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus. A tyrosine- and phenylalanine-free neutral amino acid mixture was used to lower brain tyrosine levels in rats undergoing in vivo microdialysis. In one group, NSD-1015 was included in perfusate to permit measurement of DOPA levels. In a second group, NSD-1015 was not included in perfusate so that catecholamine levels could be assayed. Tyrosine depletion significantly lowered DOPA levels in the NSD-1015 treated group and lowered DOPAC but not dopamine or noradrenaline levels in the group not exposed to NSD-1015. We conclude that while catecholamine synthesis in the ventral hippocampus declines when tyrosine availability is lowered, under basal conditions, compensatory mechanisms are able to maintain stable extracellular catecholamine levels., (Published by Elsevier B.V.)

Tyrosine hydroxylation is considered to be the rate-limiting step in catecholamine synthesis. It is also assumed that under usual conditions, tyrosine 3-monooxygenase (EC 1.14.16.2) (tyrosine hydroxylase - TH) is close to full saturation with its l-tyrosine substrate and hence that raising the availability of l-tyrosine does not substantially increase 3,4-dihydroxyphenylalanine (DOPA) synthesis. We evaluated this in vivo by reverse dialysis of the aromatic-l-amino-acid decarboxylase (EC 4.1.1.28) inhibitor NSD-1015 (20μM) and selected concentrations of l- or d-tyrosine. In striatum, extracellular DOPA levels increased linearly (maximum 250% control) as l-tyrosine concentrations were raised from 0-1000μM. In medial prefrontal cortex, DOPA levels reached a maximum (300% control) at l-tyrosine 62.5-125μM but still remained significantly elevated (200% control) at higher l-tyrosine concentrations (250-500μM). At the l-tyrosine concentrations tested, DOPA levels were never below those of controls. d-tyrosine (62.5μM) did not affect DOPA levels. The degree to which the elevation of DOPA levels represents a net increase in tyrosine hydroxylation as opposed to heteroexchange of l-TYR for intracellular DOPA remains to be determined. However, one interpretation of the data is that under usual in vivo conditions brain TH may not be near full saturation with l-tyrosine and that mechanisms other than tyrosine hydroxylation may be more important in the acute regulation of brain catecholamine synthesis than previously appreciated. This would have implications for the pathophysiology and treatment of neuropsychiatric conditions in which dysregulation of DA transmission and l-tyrosine transport have been implicated., (Published by Elsevier Ltd.)

Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl(2)) 3.0mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl(2) 3.0mEq/kg IP also augmented haloperidol (0.19mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood-brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Experimental limitations may preclude direct measurement of large neutral amino acid (LNAA) levels in brain tissue. Some data suggest that serum or cerebrospinal fluid (CSF) may provide an index of LNAA brain levels. We examined this in a series of experiments in rats, administering tyrosine, phenylalanine or valine IP 60min prior to harvesting of blood, CSF or brain tissue or during in vivo microdialysis of the brain. Serum indices of the administered LNAA generally showed a significant (r>0.8) correlation with brain tissue levels but the linear relationships varied significantly across brain regions, the LNAA and its dose. Increases in levels of an administered LNAA were consistently greater in CSF than in brain tissue. In contrast, changes in LNAA levels in brain tissue and in vivo microdialysate were generally comparable. We confirm that changes in serum and CSF LNAA levels can support limited, qualitative inferences about changes in brain tissue LNAA levels; quantitative inferences should not be drawn without prior validation under relevant experimental conditions., (Published by Elsevier B.V.)

Gamma-butyrolactone (GBL) elevates striatal and prefrontal cortex dopamine levels; only the striatal dopamine levels are elevated by increased dopamine synthesis. If increased dopamine synthesis is necessary in order for dopamine levels to be affected by tyrosine availability, then GBL-induced prefrontal cortex dopamine levels should be tyrosine insensitive. Rats received either vehicle, tyrosine (50 or 200 mg/kg i.p.) or a tyrosine-depleting mixture prior to GBL 750 mg/kg i.p.. GBL-induced dopamine levels in prefrontal cortex were lowered by tyrosine depletion. GBL-induced striatal dopamine levels were not affected. Hence, increased dopamine synthesis may not be necessary in order for tyrosine availability to affect pharmacologically elevated prefrontal cortex dopamine levels.

The relationship between tyrosine availability and high potassium (K+) induced dopamine (DA) and norepinephrine (NE) efflux was examined in striatum using in vivo microdialysis. High K+ (80 mM) was included in perfusate for two 30 min periods, 2.5 h apart. After the first high-K+ perfusion, a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA(-)) was administered (IP) to lower brain tyrosine. Tyrosine (0, 25, 50 or 100 mg/kg IP) was administered 30 min prior to the second high-K+ perfusion. The ratio of catecholamine efflux during the two perfusions (P2/P1) was compared between groups. LNAA(-) significantly lowered P2/P1 for both DA and NE. Tyrosine 25-50 mg/kg blocked the LNAA(-) effect. We conclude that catecholamine efflux during prolonged depolarization is tyrosine dependent. Analyses of LNAA levels suggest that availability of tyrosine for tyrosine hydroxylation may be modulated by competition between LNAAs within brain extracellular fluid.

The relationship between limited tyrosine availability, DA (dopamine) synthesis and DA levels in the medial prefrontal cortex (MPFC) of the rat was examined by in vivo microdialysis. We administered a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA-) IP to lower brain tyrosine, and the norepinephrine transporter inhibitor desipramine (DMI) 10 mg/kg IP to raise MPFC DA levels without affecting DA synthesis. For examination of DOPA levels, NSD-1015 20 microM was included in perfusate. Neither NSD-1015 nor DMI affected tyrosine levels. LNAA- lowered tyrosine levels by 45%, and lowered DOPA levels as well; this was not additionally affected by concurrent DMI 10 mg/kg IP. In parallel studies DMI markedly increased extracellular levels of DA (420% baseline) and norepinephrine (NE) (864% baseline). LNAA- had no effect on baseline levels of DA or NE but robustly lowered DMI-induced DA (176% baseline) as well as NE (237% baseline) levels. Even when DMI (20 microM) was administered in perfusate, LNAA- still lowered DMI-induced DA and NE levels. We conclude that while baseline mesocortical DA synthesis is indeed dependent on tyrosine availability, the MPFC maintains normal extracellular DA and NA levels in the face of moderately lower DA synthesis. During other than baseline conditions, however, tyrosine depletion can lower ECF DA and NE levels in MPFC. These data offer a potential mechanism linking dysregulation of tyrosine transport and cognitive deficits in schizophrenia.

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015. In additional groups, we also measured DA, tyrosine and large neutral amino acids in striatal microdialysate, as well as in tissue from striatum and medial prefrontal cortex (MPFC). gamma-butyrolactone (GBL) (750 mg/kg i.p.) increased DOPA levels in striatal microdialysate, increased tissue DA levels in the MPFC and striatum, but lowered tissue tyrosine levels only in striatum. In striatal microdialysate, GBL markedly lowered DA levels; tyrosine levels were only marginally lower. Haloperidol (HAL) (1.0 mg/kg s.c.)+/-amfonelic acid (AFA) (5 mg/kg i.p.) increased striatal DOPA accumulation, increased striatal DA efflux, lowered striatal tissue tyrosine levels, but did not affect microdialysate tyrosine levels. There were no consistent changes in levels of other large neutral amino acids. We conclude that increased tyrosine hydroxylation can significantly deplete the endogenous pool of tyrosine. Under such conditions, near normal extracellular tyrosine levels are maintained despite lower tissue levels. The data are consistent with a net transfer of tyrosine from non-DAergic cells to DA terminals in support of DA synthesis.

We previously reported that depletion of brain tyrosine attenuated the acute clozapine (CLZ)-induced increase in medial prefrontal cortex (MPFC) dopamine (DA) levels. This effect was now examined after chronic CLZ treatment. Male rats received CLZ (10 mg kg(-1) day(-1)) in drinking water for 21 days. On day 18, a cannula was stereotaxically implanted over the MPFC. A microdialysis probe was inserted on day 20. On day 21 after a stable baseline was reached, rats received an acute injection of vehicle (VEH) or a tyrosine- and phenylalanine-free mixture of neutral amino acid [NAA(-)] (total 1 g kg(-1), i.p., two injections, 1 h apart) followed by CLZ (10 mg kg(-1), i.p.) or VEH. Basal tyrosine or norepinephrine (NE) levels were not different between the groups, but basal DA was higher in the group treated chronically with CLZ (p<0.05). Acute CLZ (10 mg kg(-1), i.p.) increased MPFC DA and NE levels to 370% and 510% of baseline, respectively, and similarly in rats chronically pretreated with CLZ or VEH. NAA(-) did not affect basal MPFC DA or NE levels but significantly attenuated acute CLZ-induced DA (220% of baseline) and NE (330% of baseline) levels (p<0.01) in rats pretreated chronically with CLZ or with VEH. These data demonstrate that even after chronic CLZ administration, the acute CLZ-induced increases in MPFC DA and NE levels depend on the availability of brain tyrosine. Judicious manipulation of brain tyrosine levels may provide a useful probe as well as a mechanism for enhancing psychotropic drug actions.

Using in vivo microdialysis, we examined whether tyrosine administration would potentiate the desipramine (DMI)-induced elevation of medial prefrontal cortex (MPFC) dopamine (DA) levels. DMI (10 or 20 mg/kg IP) increased MPFC DA levels but not DOPA accumulation. Tyrosine (12.5-100 mug/ml) administered by reverse microdialysis did not affect DMI-induced MPFC DA levels. The data support our hypothesis that DA synthesis must be significantly increased in order for administered tyrosine to increase extracellular DA levels.

Rationale: Tyrosine availability can affect indices of dopamine (DA) release in activated central DA systems. There are, however, inconsistencies between studies. One possibility is that the relationship between tyrosine availability and DA release is non-linear., Objectives: This study aimed to determine how tyrosine depletion as well as a range of administered tyrosine concentrations affect antipsychotic drug-induced extracellular DA levels in the MPFC or striatum., Methods: A guide cannula was implanted over the medial prefrontal cortex or striatum of adult male rats. After a 24-h recovery period, a microdialysis probe was inserted. Microdialysate collection began on the following day. Some rats received vehicle or a tyrosine- and phenylalanine-free neutral amino acid solution NAA(-) (IP) prior to clozapine (CLZ 10 mg/kg IP). Others received vehicle, CLZ (10 mg/kg IP) or haloperidol (HAL) (1 mg/kg IP) while the probe was perfused with artificial cerebrospinal fluid containing tyrosine 0-200 mug/ml., Results: NAA(-) reduced tyrosine levels in MPFC dialysate by 35%. This reduction did not affect basal MPFC DA levels but attenuated the peak of CLZ-induced MPFC DA levels. The NAA(-) effect could be reversed by administration of tyrosine. Infused tyrosine 12.5-200 mug/ml did not affect basal DA levels either in MPFC or striatum. Within the MPFC, tyrosine 50.0 mug/ml significantly increased CLZ-induced DA levels. Within the striatum, tyrosine 25.0 mug/ml significantly increased while 150.0 mug/ml significantly decreased HAL-induced DA levels., Conclusions: Basal extracellular levels of DA in the MPFC and striatum are not affected by wide changes in tyrosine availability. However, modestly increased brain tyrosine levels can augment CLZ-induced MPFC and HAL-induced DA levels. Very high tyrosine concentrations attenuate HAL-induced striatal DA levels. These data may explain inconsistencies in the literature and suggest that tyrosine availability could be exploited to modulate psychotropic drug-induced DA levels in the brain.

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.

It has been reported that tyrosine administration augments clozapine-induced dopamine (DA) release in the medial prefrontal cortex (MPFC). To characterize this effect and exclude possible confounds, we conducted a series of studies in which microdialysate collection started 24 h after probe implantation, a time at which most collected DA is thought to be impulse mediated. Tyrosine (25 or 50 mg/kg IP) administered 30 min after clozapine (10 mg/kg IP) augmented clozapine-induced MPFC but not striatal DA release. While tyrosine potentiation was also evident in both fasted animals and those with free access to food, the effective doses of tyrosine varied. We confirm that tyrosine administration can potentiate clozapine-induced MPFC DA release but note that the effect is not evident across all doses and conditions.

Rationale: There are conflicting reports as to whether alterations in tyrosine levels affect functional indices of striatal dopamine (DA) transmission. Since the DA antagonist haloperidol (HAL) increases striatal DA release and induces catalepsy through its actions on striatal DA systems, it provides a useful paradigm to assess both neurochemical and behavioral effects of lowering brain tyrosine levels., Objectives: To determine how brain tyrosine depletion affects HAL-induced catalepsy and striatal DA release in awake, freely moving rats., Methods: In male rats, a control or tyrosine- and phenylalanine-free neutral amino acid solution NAA(-) (IP) was administered 30-60 min prior to HAL (IP). In one cohort, striatal microdialysate was assayed for DA levels. In a parallel cohort, catalepsy was measured using the bar test., Results: NAA (-) reduced striatal tyrosine levels by 60%. The latter did not affect basal striatal DA release, but consistently delayed the attainment of maximal HAL-induced (0.19 mg/kg and 0.25 mg/kg SC) striatal DA release; the latter was abolished by administration of tyrosine. NAA(-) also potentiated HAL-induced catalepsy., Conclusions: Acute brain tyrosine depletion attenuates HAL-induced striatal DA release and potentiates haloperidol-induced catalepsy. Both effects can be reversed by administration of tyrosine. Overall, the data indicate that tyrosine depletion affects both neurochemical and behavioral indices of striatal DA release.

Rationale: While it is generally believed that administration of the dopamine precursor levodopa ( L-dopa) exacerbates symptoms of schizophrenia, numerous reports suggest that adjunctive L-dopa may be beneficial. This body of literature has not been critically reviewed., Objectives: On the basis of published studies, to determine whether L-dopa administered concomitantly with antipsychotic drugs provides a beneficial response in patients with schizophrenia., Methods: This review examined 30 studies involving 716 patients. Due to wide methodological variability and limited statistical information, only five studies encompassing 160 patients could be included in a meta-analysis. The others were evaluated qualitatively., Results: When L-dopa was added to antipsychotic drugs, the overall improvement was moderate ( d=0.71) and highly significant ( P<0.0001). There were 16 other studies in which L-dopa was added to antipsychotic drugs, but which did not meet criteria for inclusion in the meta-analysis. In these, worsening occurred in less than 20% of patients; the percentage of improved patients varied widely but had a central tendency around 50%., Conclusions: . In patients already on antipsychotic drugs, the addition of L-dopa can be beneficial. Dopamine agonists merit further consideration as adjuncts to antipsychotic drugs in the treatment of schizophrenia.

Objective: To assess the pharmacokinetics and tolerability of quetiapine in elderly patients with selected psychotic disorders., Study Design: This was a multicentre, open-label, 27-day, rising multiple-dose trial. Descriptive statistics summarised plasma quetiapine concentrations and pharmacokinetic parameters by trial day. A two-way analysis of variance was used to evaluate all pharmacokinetic parameters, and 90% confidence intervals of the mean differences were calculated., Methods: Antipsychotic drugs taken prior to the study period were discontinued on day 1. Quetiapine treatment began on day 3. Doses were increased stepwise, starting at 25mg three times daily and reaching 250mg three times daily by day 21., Patients: Twelve patients (age 63-85 years) with schizophrenia, schizoaffective disorder or bipolar disorder., Main Outcome Measures and Results: Key assessments included quetiapine plasma concentrations, and neurological and safety evaluations. Under steady-state conditions, the 100 and 250mg doses of quetiapine were not significantly different in terms of dose-normalised area under the plasma concentration-time curve within an 8-hour dose administration interval, or in dose-normalised minimum plasma concentration (C(min)) at the end of a dose administration interval. The morning C(min) values for the seven discrete dose amounts evaluated also increased linearly with dose. The apparent oral clearance, volume of distribution and half-life did not change as a function of dose. There were no serious adverse events. The most common adverse events were postural hypotension (n = 6), dizziness (n = 5) and somnolence (n = 4)., Conclusions: While quetiapine was well tolerated at doses up to 250mg three times daily, the potential for reduced clearance, as well as the adverse effects of postural hypotension and dizziness, indicated that quetiapine should be introduced at lower doses and titrated at a relatively slower rate in patients > or =65 years.

Tyrosine uptake has been reported to differ across brain regions. However, such studies have typically been conducted over brief intervals and in anesthetized rats; anesthesia itself affects amino acid transport across the blood-brain barrier. To address these concerns, serum, brain tissue and in vivo microdialysate tyrosine levels were compared for 0-3 h after administration of tyrosine [0.138-1.10 mmol/kg intraperitoneally (i.p.)] to groups of awake rats. Serum and brain tissue tyrosine levels increased linearly with respect to dose. Basal tissue tyrosine levels varied significantly across brain regions [medial prefrontal cortex (MPFC), striatum, hypothalamus, and cerebellum], but the rate of tyrosine uptake was similar for hypothalamus, striatum and MPFC. For brain regions in which tyrosine levels in both microdialysate and tissue were assayed, namely MPFC and striatum, there was a high degree of correlation between tyrosine levels in tissue and in microdialysate. Increasing brain tyrosine levels had no effect on DA levels in MPFC microdialysate. We conclude that (i) regional differences in the response of dopamine neurons to systemic tyrosine administration cannot be attributed to pharmacokinetic factors; (ii) in vivo microdialysate provides an excellent index over time and across a wide range of tyrosine doses, of brain tissue tyrosine levels; and (iii) increases in brain tyrosine levels do not affect basal DA release in the MPFC.

The beta-carboline FG-7142 exerts many stress-like effects in the adult rat, including the inhibition of locomotor exploration. However, comparable effects in immature animals have not been reported. Stress-like effects of FG-7142 are mediated via its inverse agonist actions on gamma-aminobutyric acid (GABA) receptors. GABA systems change considerably with development and GABA agonists such as diazepam have opposite behavioral actions in immature and adult rats. Accordingly, we compared FG-7142 effects on locomotor exploration in postweanling and adult rats. Postweanling male rats (24 days) and adult rats (90 days) received a single injection of vehicle or FG-7142 (15 mg/kg i.p.) and 15 min later were placed in photocell monitors for 1 h. Although postweanling animals traveled a smaller distance overall than adults, FG-7142 inhibited locomotor exploration to a similar degree in both groups. We conclude that FG-7142 exerts stress-like effects in postweanling rats and may be considered for use as a model of childhood stress.

The generalizability of research data depends on the degree to which the studied sample represents the larger population of interest. By influencing the likelihood of research participation, socio-demographic and clinical factors could bias a sample. To evaluate this, we retrospectively identified 155 consecutive admissions over an 18-month period to a general acute male psychiatry inpatient unit in a Veterans Affairs Hospital on which all competent patients were offered the opportunity to participate in low-risk clinical research. Male inpatients who did (N=70) and did not consent (N=85) were compared on 17 variables. Patients who consented to research were somewhat younger (M(difference)=4.6 year) and were significantly more likely to carry a diagnosis of schizophrenia. The groups did not differ in financial resources, living situation or alcohol/drug abuse. We conclude that at least in this setting, general socio-demographic and clinical variables were not major influences on sample selection.

Within 1 year of severe trauma to the left anterior temporal lobe and minor injury to the frontal lobes, a 35-year-old individual developed classic positive and negative symptoms of schizophrenia. His antipsychotic drug-induced parkinsonism was greater on the left side, suggesting increased left striatal dopaminergic transmission. The authors propose that even in adulthood, significant and selective disruption of fronto-temporal connectivity is sufficient to produce a phenocopy of schizophrenia.

Background: Weight gain is a common side effect of clozapine treatment and may expose patients to obesity-associated health risks. We proposed that concomitant treatment with an appetite suppressant such as phenylpropanolamine (PPA) would lead to a decrease in appetite and therefore loss of weight., Method: This was a 12-week, double-blind, randomized, placebo-controlled trial of PPA, 75 mg/day, in outpatients with treatment-refractory schizophrenia (DSM-IV) who were stable on clozapine treatment for at least 4 months and had gained > 10% of their baseline body weight since starting clozapine. Patients were evaluated for adverse effects and weighed weekly. A Positive and Negative Syndrome Scale (PANSS) assessment, a short dietary quiz, and blood indices were completed monthly., Results: Sixteen patients were equally randomly assigned to receive PPA or placebo. The groups did not differ in mean age, baseline weight, dose of clozapine, baseline PANSS scores, or the percent of weight gained since the start of clozapine. There was no significant effect of treatment on weight (t = 0.219, df = 10, p = .831). There was no significant change in either the total PANSS scores (t = -0.755, df = 10, p = .468), the positive or negative symptom cluster scores, or any of the remaining variables., Conclusion: Phenylpropanolamine 75 mg/day was well tolerated but was not effective in reversing established weight gain associated with clozapine treatment in stable outpatients with schizophrenia.

Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC). Whether tyrosine concentrations can also affect MPFC extracellular DA concentrations, measured in vivo, is not known. Since clozapine preferentially activates mesocortical DA neurons, we posited that tyrosine administration to a clozapine-pretreated rat would enhance the clozapine-induced augmentation of MPFC extracellular DA concentrations. Tyrosine alone (25-50mg/kg IP) did not affect mesocortical or striatal extracellular DA concentrations measured by in vivo microdialysis. Given 30 minutes after clozapine (10 mg/kg), tyrosine (50 mg/kg) significantly prolonged the clozapine-induced increase in MPFC extracellular DA concentrations but had no effect in the striatum. In contrast, tyrosine (50 mg/kg) significantly prolonged the haloperidol (1 mg/kg) induced increase in striatal extracellular DA concentrations but had no effect in the MPFC. These data constitute the first in vivo evidence that administration of tyrosine can selectively potentiate the clozapine-evoked increase in mesocortical extracellular DA concentrations.

A high-performance liquid chromatographic method for measuring neutral amino acids in rat sera, brain tissues, and perfusates was developed by using o-phthalaldehyde sulfite as a pre-column derivatization reagent. With the present method, it was possible to separate the neutral amino acids within a single run in 25 min, while the acidic amino acids were eluted near or at the solvent front. The recovery was above 88.8% with a relative standard deviation (RSD) below 4.2%. The within- and between-day assay reproducibility for the determination of rat serum amino acids showed RSDs below 1.35 and 7.61%, respectively. In the present study, the neutral amino acids were assayed with high sensitivity, accuracy and good reproducibility in a relatively short time and on a small sample size.

A method for selectively activating the dopaminergic field of the prefrontal cortex would be highly useful for studies of mesocortical dopamine systems. When a rat ('witness' rat) is exposed to a rat that is undergoing footshock, prefrontocortical dopamine metabolism is selectively increased in the witness rat. Since the anxiogenic beta-carboline FG 7142 mimics many of the effects of footshock, we hypothesized that exposure of a witness-rat to a rat treated with FG 7142 would also increase dopamine metabolism in the prefrontal cortex. We found that while as expected, FG 7142 itself increased prefrontal cortex dopamine metabolism, there was no significant change in dopamine metabolism in the witness rat. Thus exposure to a rat treated with FG 7142 does not selectively activate the mesocortical dopamine system.

Increased sulcal widening in the prefrontal cortex of patients with schizophrenia may be associated with a poor treatment response to clozapine. To further evaluate this, we examined data from patients treated with clozapine in our center. Patients with the greatest degree of improvement (n=26) and those with no improvement (n=10) were compared. Computerized tomography (CT) scans were rated blindly on a visual scale of prefrontal sulcal widening. Patients with the greatest degree of functional improvement had significantly less prefrontal sulcal widening than those whose symptoms remained unchanged. There was no relationship between clozapine response and general sulcal widening. These data support the link between the superior therapeutic efficacy of clozapine and the integrity of the prefrontal cortex.

Despite multiple lines of investigation the effect of neuroleptics on glutamate-mediated neurotransmission remains controversial. To study the effects of typical and atypical neuroleptics on selected parameters of glutamate-mediated neurotransmission, male Sprague-Dawley rats were randomly assigned to a 21-day oral treatment course with vehicle, haloperidol (HDL), or clozapine (CLZ). Coronal slices of rat brain were then incubated with tritiated ligands to measure NMDA, AMPA, and kainate receptor, and glutamate reuptake site density. Regions of interest included the frontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, and the nucleus accumbens. CLZ increased the density of AMPA receptors significantly in the frontal and anterior cingulate cortices compared with normal controls. In the dorsal and ventral striatum, and nucleus accumbens as a whole, CLZ-treated rats had a higher AMPA receptor density compared with both the HDL- and vehicle-treated controls. Additionally, within the nucleus accumbens, CLZ-treated rats had a higher density of AMPA receptors compared with the HDL group in the core, and at trend level in the shell. There was a group by region interaction for NMDA receptor density, primarily reflecting the tendency of HDL treated rats to have high receptor densities in the frontal and anterior cingulate cortices. Kainate receptors and glutamate reuptake site densities did not differ significantly across groups. These results suggest a critical role for glutamate in the mediation of atypical antipsychotic drug action in anatomically-specific regions, and further encourage the investigation of glutamate neurotransmitter systems in schizophrenia.

We previously reported significant differences in force control (FC) function between schizophrenics treated with typical antipsychotic drugs (APD) and those treated with clozapine. Clozapine treatment was associated with an attenuation of the capacity for fine motor control. We now report that a test-retest study with 41 treatment-refractory patients confirms our earlier finding; the FC deficit is due primarily to clozapine treatment. An additional comparison was made with 10 patients who were administered the FC test repeatedly through the initial clozapine titration interval of 6-8 weeks. The results suggest that two distinct clozapine effects can be distinguished, an initial transient stage characterized by 'drowsiness' and a subsequent stage with dose-dependent emerging myoclonic features.

Sertraline and other SSRIs have a relatively favorable side-effect profile and are widely prescribed. We report the emergence of psychotic symptoms during treatment with sertraline in four patients. Three of these patients had a history of psychotic illness and were on antipsychotic medication, when sertraline was added. The psychotic symptoms emerged within 3 days-7 weeks of starting sertraline and resolved on its discontinuation. We wish to alert clinicians to the possibility that sertraline may provoke or exacerbate positive psychotic symptoms, particularly in patients on neuroleptics, with a previous history of psychosis.

Background: Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis., Method: We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus., Results: The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms., Conclusion: Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.

Background: Treatment with the atypical antipsychotic drug clozapine appears to be associated with an increased incidence of urinary incontinence (UI). We posited that the potent anti-alpha-adrenergic effects of clozapine were involved, and hence that an alpha-adrenergic agonist would reduce UI. We tested this hypothesis by using ephedrine, an approved alpha-adrenergic agonist., Method: Fifty-seven inpatients with schizophrenia or schizoaffective disorder (DSM-IV) who met the Kane criteria for being treatment refractory were treated with clozapine (75-900 mg/day). Patients who developed UI were then openly treated with ephedrine in increasing doses until UI was attenuated or a dose of 150 mg/day was attained., Results: Seventeen patients developed UI as evidenced by either urine-stained sheets/clothing or direct patient reports. In 2 cases, the UI was sufficiently severe that adult diapers had to be used. Comparison of patients who developed UI and those who did not showed that UI was associated with female gender and with concomitant treatment with typical antipsychotic drugs. One patient was treated with a behavioral program, but the remaining 16 patients were treated with ephedrine. Ephedrine treatment was very effective, with 15/16 patients showing improvement within 24 hours after reaching maximum ephedrine dosage. Twelve of 16 (including the 2 most severe) eventually had a complete remission of their UI. In the remaining 4 patients, 3 had a reduction in the frequency of UI and 1 showed no response. These benefits have been maintained over the course of 12 months of subsequent treatment for several patients. There were no side effects associated with the use of ephedrine nor were there any changes in neuropsychiatric status., Conclusion: Ephedrine appears to be a safe and effective treatment clozapine-associated UI. By inference, it is likely that clozapine may cause UI via its anti-alpha-adrenergic properties.

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.

It is well established that clozapine is less likely than typical antipsychotic drugs to cause clinically discernible extrapyramidal side-effects. There is a paucity of data, however, on clozapine's motor effects. In this report we compare normal controls to groups of chronic schizophrenic patients treated with either typical antipsychotic drugs or with clozapine. Motor function was measured with a target-matching task, a test relying on submaximal sustained force control. Results indicated that patients on clozapine performed with significantly lower accuracy (greater variability) of force control. Even though the clozapine patients were treatment resistant to typical antipsychotic drugs, and many had a history of tardive dyskinesia, we postulate that the observed deficit is likely due to clozapine treatment rather than to earlier treatments or other factors. The observed force control deficit may be the result of an increase in myoclonus and a generally lower level of overall motor activity.

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.

Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system, and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 micrograms) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage, and provide further support for the fidelity of this animal model of schizophrenia.

Effects of prefrontal cortical or hippocampal excitotoxic lesions on behavioral parameters related to dopaminergic transmission in the basal ganglia were investigated in the rat. We examined haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors after ibotenic acid lesions of the medial prefrontal cortex (MPFC), dorsal (DH), or ventral hippocampus (VH) in adult rats. Haloperidol-induced (1 mg/kg) catalepsy was decreased in rats with either MPFC or VH but not DH lesions. While both DH and VH lesioned animals demonstrated a reduction in apomorphine-induced (0.75 mg/kg) stereotypic behaviors, the VH lesioned animals also showed an enhancement of locomotor activity. MPFC lesioned rats tended towards potentiation of stereotypic behaviors and reduced locomotion after apomorphine administration. These data indicate that loss of prefrontal cortical or hippocampal modulation leads to an enhancement of DA transmission within the basal ganglia, though the pattern of augmentation depends on the area lesioned.

Ten patients, who underwent computerized tomography (CT) study during evaluation for first episode schizophreniform psychosis were restudied an average of 7 years later. Of the 10 patients, 7 were found to carry a diagnosis of schizophrenia at follow-up. In this subgroup, there was no significant change in the mean ventricular brain ratio measure of cerebral ventricular size between the index and follow-up scans. These findings are consistent with the hypothesis that ventricular enlargement is present at the onset of schizophrenia and does not progress with duration of illness or treatment.