George E. Jaskiw

Postpubertal Emergence of Hyperresponsiveness to Stress and to Amphetamine after Neonatal Excitotoxic Hippocampal Damage: A Potential Animal Model of Schizophrenia

The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implications of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.

Dopamine and schizophrenia—a cortically corrective perspective

Abstract The traditional dopamine hypothesis holds that excessive striatal/limbic dopamine-mediated transmission is causally related to the pathophysiology of schizophenia. However, schizophrenia is not cured by dopamine blocking drugs and is associated with relatively few replicable, direct indices of dopamine-mediated dysregulation. In comparison, the evidence supporting limbic and neocortical abnormalities in schizophrenia is robust. In light of what is known about these cortical abnormalities and about brain development and connectivity, the overall research data point to an early pathological process affecting temporal-limbic and/or prefrontal cortices which becomes clinically manifested later in life. To the extent that dopamine dysregulation may be a factor in the expression of some schizophrenic symptoms, it probably represents a secondary, ‘downstream’ effect of the cortical abnormalities. A number of possible mechanisms are described that might explain the relationship between cortical abnormalities and dopamine dysregulation in schizophrenia.

Pharmacokinetics of systemically administered tyrosine: a comparison of serum, brain tissue and in vivo microdialysate levels in the rat.

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.

Improved method for the measurement of large neutral amino acids in biological matrices.

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 meta-analysis of the response to chronic l-dopa in patients with schizophrenia: therapeutic and heuristic implications

RationaleWhile 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.ObjectivesOn the basis of published studies, to determine whether l-dopa administered concomitantly with antipsychotic drugs provides a beneficial response in patients with schizophrenia.MethodsThis 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.ResultsWhen 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%.ConclusionsIn 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.

Pharmacokinetics of Quetiapine in Elderly Patients with Selected Psychotic Disorders

ObjectiveTo assess the pharmacokinetics and tolerability of quetiapine in elderly patients with selected psychotic disorders.Study designThis 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.MethodsAntipsychotic 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 resultsKey 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 (Cmin) at the end of a dose administration interval. The morning Cmin 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).ConclusionsWhile 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 ≥65 years.

Tyrosine Augments Acute Clozapine- but not Haloperidol-Induced Dopamine Release in the Medial Prefrontal Cortex of the Rat: An in vivo Microdialysis Study

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.

Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

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.

Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels

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.

OUTCOME OF CLOZAPINE THERAPY FOR ELDERLY PATIENTS WITH REFRACTORY PRIMARY PSYCHOSIS

Objective. The objective was to analyze outcome of clozapine therapy in elderly patients with treatment refractory primary psychosis.