Marisa Möller

Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration

Social isolation rearing (SIR) in rats induces behavioral and glutamatergic changes akin to schizophrenia. We studied the effects of 8 weeks SIR on cortico-striatal redox and social and cognitive behaviors in rats. SIR increased superoxide dismutase activity, decreased oxidized:reduced glutathione ratio and increased lipid peroxidation in both brain regions, and induced deficits in prepulse inhibition and social and self-directed interactive behaviors. Both behavioral and cortico-striatal redox disturbances were corrected by clozapine (5 mg/kg/day×11days). Behavioral changes evoked by SIR are associated with cortico-striatal oxidative stress that is reversed by clozapine treatment, providing novel insight into the neurobiology and treatment of schizophrenia.

Development and validation of a single analytical method for the determination of tryptophan, and its kynurenine metabolites in rat plasma

It is highly beneficial to monitor the activity of the kynurenine pathway in a large series of samples with high accuracy and reliability in a single experimental protocol. We have developed a rapid specific solid-phase extraction (SPE)-liquid chromatography-electrospray ionization tandem mass spectrometry method for assaying tryptophan, kynurenine, kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3OHAA), anthranilic acid and quinolinic acid (QA) in rat plasma. We also evaluated picolinic acid (PA) in this method, but it presented with unacceptable validation parameters. The assay involves pre-purification by SPE followed by chromatographic separation by C18 reversed phase chromatography. Mass spectrometric detection was performed using a mass spectrometer in positive and negative electrospray ionization; with a flow rate of 0.2 mL/min and an injection volume of 10 μL. Total run time including sample clean-up was 12 min. The assay method was found to be linear (R² > 0.95) and all the validation parameters were within acceptance range. The developed technique also demonstrated a significant elevation in plasma tryptophan, kynurenine, anthranilic acid and QA, and a significant decrease in KYNA, in rats subjected to post-weaning social isolation rearing, a putative animal model of relevance for depression and schizophrenia. This method can therefore be applied to measure metabolites of the kynurenine pathway in plasma accurately and precisely by LC-MS/MS, thereby helping to realize new opportunities in pharmacological and diagnostic research.

The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl-D-aspartate and D1 receptor binding in rats.

Glutamate and dopamine disturbances are implicated in frontal cortical dysfunction in schizophrenia. Little, however, is known about the nature of dopamine D(1) and N-methyl-D-aspartate (NMDA) receptor interactions in the illness, nor of the extent of their co-involvement in antipsychotic drug response. It is well known that early life adversity may pre-date the development of schizophrenia. Using a neurodevelopmental model of schizophrenia, namely post weaning social isolation rearing (SIR), we studied the effect of SIR (post natal day 21-61) on frontal cortical NMDA and D(1) receptor binding characteristics with/without chronic haloperidol (0.1 mg/kg/day i.p.) or clozapine (5 mg/kg/day i.p.) treatment, undertaken from post-natal day 50-60. SIR increased frontal cortical NMDA-density, with decreased affinity (decreased pK(D)), but reduced D(1) receptor density (without effects on pK(D)). In socially reared animals, clozapine but not haloperidol increased NMDA receptor density without effects on pK(D.) Neither drug markedly affected D(1) receptor density, although clozapine increased D(1) affinity. Increased NMDA density in SIR animals was unaffected by haloperidol, but further increased by clozapine. However, SIR-associated decrease in NMDA affinity remained unaltered despite drug treatment. Reduced D(1) receptor density in SIR animals was exacerbated by haloperidol, but unaltered by clozapine, without changes in pK(D). SIR thus induces opposing effects on frontal cortical NMDA and D(1) radio-receptor binding characteristics, which has direct bearing on the mutual interplay of these receptors in schizophrenia. The ability of SIR to affect NMDA receptor affinity warrants deeper study. Furthermore, at the doses examined, in contrast to haloperidol, clozapine bolsters frontal cortical glutamatergic but stabilizes D(1) dopaminergic pathways in a neurodevelopmental animal model of schizophrenia, possibly explaining the atypical clinical characteristics of this drug.

A Review of Biomarkers in Mood and Psychotic Disorders: A Dissection of Clinical vs. Preclinical Correlates

Despite significant research efforts aimed at understanding the neurobiological underpinnings of mood (depression, bipolar disorder) and psychotic disorders, the diagnosis and evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms as well as psychometric evaluations. Therefore, biological markers aimed at improving the current classification of psychotic and mood-related disorders, and that will enable patients to be stratified on a biological basis into more homogeneous clinically distinct subgroups, are urgently needed. The attainment of this goal can be facilitated by identifying biomarkers that accurately reflect pathophysiologic processes in these disorders. This review postulates that the field of psychotic and mood disorder research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the particular illness and to target the same for more effective disease modifying therapy. This implies that a “one-size fits all” paradigm in the treatment of psychotic and mood disorders is not a viable approach, but that a customized regime based on individual biological abnormalities would pave the way forward to more effective treatment. In reviewing the clinical and preclinical literature, this paper discusses the most highly regarded pathophysiologic processes in mood and psychotic disorders, thereby providing a scaffold for the selection of suitable biomarkers for future studies in this field, to develope biomarker panels, as well as to improve diagnosis and to customize treatment regimens for better therapeutic outcomes.

Late-life effects of chronic methamphetamine exposure during puberty on behaviour and corticostriatal mono-amines in social isolation-reared rats

Chronic methamphetamine (MA) abuse results in an acute psychosis indistinguishable from paranoid schizophrenia. However, less is known of the interaction between MA use and environmental insults, and how this contributes to late-onset psychopathology. Using social isolation rearing (SIR), a neurodevelopmental animal model of schizophrenia, we investigated the association between changes in corticostriatal mono-amines and putative behaviours related to MA-induced psychosis in isolation and group-housed rats following chronic MA or saline exposure. Weaned male offspring of MA-naive female Wistar rats, either group- or isolation-housed from postnatal day (PND) +21, received saline (2 ml/kg s.c. b.i.d.) or an escalating dose of MA (0.2-6 mg/kg s.c. b.i.d.) for 16 days from PND +35 to +50. On PND +78, offspring were tested for deficits in social interactive behaviour (SIB) and prepulse inhibition (PPI) of startle, with frontal cortex and striatum harvested for the assessment of mono-amine concentrations. SIR significantly reduced rearing time, staying together, approaching and anogenital sniffing (outward-directed SIB), but increased self-grooming and locomotor activity (self-directed SIB), and also induced profound deficits in PPI. Pubertal MA exposure in group-housed animals also induced similar alterations in outward- and self-directed SIB and reduced PPI. Combined MA + SIR exposure evoked a similarly intense behavioural response as SIR or MA separately, with no exacerbation evident. Neither treatment separately nor together affected corticostriatal serotonin or noradrenaline levels, although frontal cortical dopamine (DA) levels were significantly increased in SIR and MA + group-housed animals. A trend towards further elevated frontal cortical DA was noted in the MA + SIR treatment group. Striatal DA was unaltered by all treatments. This study provides the first evidence that chronic pubertal MA exposure evokes postpubertal psychosis-like behaviours in rats of similar intensity to that induced by a neurodevelopmental animal model of schizophrenia (SIR). Moreover, the study is unique in that these behavioural changes occur together with associated changes in frontal cortical but not striatal DA, without affecting other mono-amines, and strongly implicates frontal cortical DA changes in the psychotogenic effects of early-life MA exposure or environmental insult. Although MA exposure in animals with a history of environmental insult (i.e. MA + SIR) has similar effects, combined exposure was not additive with regard to behavioural or neurochemical changes. We conclude that a ceiling effect or compensatory mechanisms prevent more pronounced neurobehavioural deficits occurring following MA + SIR treatment, at least under the current study conditions.

Studies into the anxiolytic actions of agomelatine in social isolation reared rats: role of corticosterone and sex

Anxiety disorders are severely disabling, while current pharmacological treatments are complicated by delayed onset, low remission rates and side-effects. Sex is also noted to contribute towards illness severity and treatment response. Agomelatine is a melatonin (MT1/MT2) agonist and serotonin (5-HT2C) antagonist purported to be anxiolytic in clinical and some pre-clinical studies. We undertook a detailed analysis of agomelatine’s anxiolytic activity in a neurodevelopmental model of anxiety, the social isolation reared rat. Rats received sub-chronic treatment with vehicle or agomelatine (40 mg/kg per day intraperitoneally at 16:00 h for 16 days), with behaviour analysed in the open field test, social interaction test and elevated plus maze. The contribution of corticosterone and sex was also studied. Social isolation rearing increased locomotor activity and reduced social interaction in the social interaction test, and was anxiogenic in the elevated plus maze in males and females. Agomelatine reversed these behaviours. Male and female social isolation reared rats developed anxiety-like behaviours to a similar degree, although response to agomelatine was superior in male rats. Social isolation rearing decreased plasma corticosterone in both sexes and tended to higher levels in females, although agomelatine did not affect corticosterone in either sex. Concluding, agomelatine is anxiolytic in SIR rats, although correcting altered corticosterone could not be implicated. Sex-related differences in the response to agomelatine are evident.

Efavirenz exposure, alone and in combination with known drugs of abuse, engenders addictive-like bio-behavioural changes in rats

Efavirenz is abused in a cannabis-containing mixture known as Nyaope. The addictive-like effects of efavirenz (5, 10 and 20 mg/kg) was explored using conditioned place preference (CPP) in rats following sub-acute exposure vs. methamphetamine (MA; 1 mg/kg) and Δ9-tetrahydrocannabinol (THC; 0.75 mg/kg). The most addictive dose of efavirenz was then compared to THC alone and THC plus efavirenz following sub-chronic exposure using multiple behavioural measures, viz. CPP, sucrose preference test (SPT) and locomotor activity. Peripheral superoxide dismutase (SOD), regional brain lipid peroxidation and monoamines were also determined. Sub-acute efavirenz (5 mg/kg) had a significant rewarding effect in the CPP comparable to MA and THC. Sub-chronic efavirenz (5 mg/kg) and THC + efavirenz were equally rewarding using CPP, with increased cortico-striatal dopamine (DA), and increased lipid peroxidation and SOD. Sub-chronic THC did not produce CPP but significantly increased SOD and decreased hippocampal DA. Sub-chronic THC + efavirenz was hedonic in the SPT and superior to THC alone regarding cortico-striatal lipid peroxidation and sucrose preference. THC + efavirenz increased cortico-striatal DA and decreased serotonin (5-HT). Concluding, efavirenz has dose-dependent rewarding effects, increases oxidative stress and alters regional brain monoamines. Efavirenz is hedonic when combined with THC, highlighting its abuse potential when combined with THC.

Defensive coping and essential amino acid markers as possible predictors for structural vascular disease in an African and Caucasian male cohort : The SABPA study

Defensive coping (DefS), oxidative stress, inflammation, and related amino acids (phenylalanine [Phe] and tyrosine [Tyr]) have been implicated in cardiovascular disease. This study assessed whether inflammation, oxidative stress, changes in essential amino acids, and altered coping strategies are correlated with subclinical vascular changes in African (n = 82) and Caucasian (n = 100) men from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. The Coping Strategy Indicator questionnaire identified DefS participants. Ambulatory blood pressure (BP) was monitored for 24 h, whereas carotid intima media thickness (CIMT) and cross-sectional wall area (CSWA) were determined ultrasonically. Essential amino acids were analyzed with a liquid chromatography tandem mass spectrometry method. Oxidative-inflammatory markers were measured by spectrophotometry. African men had poorer health than Caucasian men, including higher alcohol abuse, elevated BP, abdominal obesity, physical inactivity, and elevated inflammation. Phe (p < .001) and Phe/Tyr ratio (p = .006) as well as CIMT (p = .032) were higher in African men. DefS African men had higher levels of Phe (p = .002) and Phe/Tyr (p = .009) compared to DefS Caucasian men; these differences were not observed in non-DefS men. Systolic BP and inflammation (C-reactive protein) were positively associated with left (L-) CSWA, while Phe/Tyr was negatively associated with L-CSWA in DefS African men. African males presented with elevated Phe and Phe/Tyr ratio, catecholamine precursors, worsening during DefS-possibly driven by inflammation and BP contributing to structural vascular abnormalities.