Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal ...protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague-Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.
Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We ...investigated the effects of 14-day nicotine exposure (6.32mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays, indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to increase during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use.
•Chronic nicotine exposure increased impulsive choice in LI rats.•Impulsive choice continued to increase during nicotine withdrawal in LI rats.•Chronic nicotine had no effect on impulsive choice in HI or non-selected rats.•Nicotine withdrawal had no effect on impulsive choice in HI or non-selected rats.
Highlights ► Parkinson disease (PD) is a neurodegenerative disorder of unknown etiology. ► The study investigates the effects of antioxidants on rotenone-induced PD in rats. ► Effects of pioglitazone ...and retinoic acid were evaluated. ► The data imply that these agents may be helpful for preventing of PD. ► In this study, pioglitazone seems to be more effective than retinoic acid.
The aim of the present study was to explore the role of N‐methyl‐D‐aspartate receptor (NMDAR) related amino acids in drug‐naive first episode psychosis (FEP) patients. The medication naïve patients ...with FEP (n = 40) and healthy volunteers with no family history of schizophrenia (n = 35) were recruited to the study and followed up for 10 weeks. Liquid chromatography–mass spectrometry method was used to measure plasma levels of the amino acids. The plasma glutamine, glutamic acid, proline, serine, asparagine, and hydroxyproline levels were significantly higher in the FEP patients compared to healthy controls (p values < .0001). The glutamine/glutamic acid ratio in FEP patients was not different from the healthy controls (p > .05). After the antipsychotic treatment, plasma glutamic acid, proline, and hydroxyproline levels were significantly increased (p values < .05) while the asparagine level and glutamine/glutamic acid ratio were decreased (p values < .05). The serine and glutamine levels did not show any differences with the treatment (p > .05). The initial plasma glutamine levels were negatively correlated with the initial Scale for the Assessment of Positive Symptoms (SAPS) score (r = −.45, p = .003). The initial plasma proline levels were negatively correlated with the initial and follow‐up SAPS scores (r = −.51 and −.39, p values < .05). The initial plasma proline and hydroxyproline levels were both negatively correlated with the initial Brief Psychiatric Rating Scale score (r = −.37, p = .017 and r = −.33, p = .033, respectively). Increase in NMDAR‐related amino acid levels during the FEP may be a compensatory response to glutamatergic hypofunction. Their plasma levels were significantly correlated with several psychotic symptoms before and after 10‐week treatment. Antipsychotic treatment has differential effects on the plasma levels of these amino acids.
The present study investigated the NMDAR‐related amino acid levels in peripheral blood of treatment naïve first episode psychosis (FEP) patients. All of the measured amino acids were significantly increased during FEP. The antipsychotic treatment selectively changed these measurements.
The endocannabinoid system is responsible for regulating a spectrum of physiological activities and plays a critical role in the developing brain. During adolescence, the endocannabinoid system is ...particularly sensitive to external insults that may change the brain’s developmental trajectory. Cannabinoid receptor type 2 (CB2R) was initially thought to predominantly function in the peripheral nervous system, but more recent studies have implicated its role in the mesolimbic pathway, a network largely attributed to reward circuitry and reward motivated behavior, which undergoes extensive changes during adolescence. It is therefore important to understand how CB2R modulation during adolescence can impact reward-related behaviors in adulthood. In this study, adolescent male rats (postnatal days 28–41) were exposed to a low or high dose of the CB2R antagonist/inverse agonist SR144528 and Pavlovian autoshaping and instrumental conditional behavioral outcomes were measured in adulthood. SR144528-treated rats had significantly slower acquisition of the autoshaping task, seen by less lever pressing behavior over time
F
(2, 19)
= 5.964,
p
= 0.010. Conversely, there was no effect of adolescent SR144528 exposure on instrumental conditioning. These results suggest that modulation of the CB2R in adolescence differentially impacts reward-learning behaviors in adulthood.
Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.
The effects ...of Nomega-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and a combination of a NO precursor L-arginine and L-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.
Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, L-NAME (15-60 mg/kg) and L-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.
Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of L-NAME blocked the development of sensitization to nicotine; and, L-arginine (1 g/kg) pretreatment reversed this effect of L-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of L-NAME inhibited the expression of sensitization to nicotine on day 18; and, L-arginine (1 g/kg) pretreatment reversed this inhibitory effect of L-NAME.
Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.
The main objective of the present study is to investigate the possible effects of chronic ethanol consumption and ethanol withdrawal on cyclic guanosine 3′, 5′-monophosphate (cGMP) levels in cerebral ...cortex, striatum, hippocampus and hypothalamus of rat brain. Ethanol was given to female Wistar rats (225–270
g) by a liquid diet for 21 days. cGMP levels were measured in respective brain regions using an EIA kit at 7th, 14th and 21st days of ethanol ingestion and at 6th and 24th h of ethanol withdrawal. cGMP levels in cortex, striatum and hippocampus but not hypothalamus were found significantly increased at 14th and 21st days of ethanol consumption. The most prominent increase was observed in striatal tissues (approximately 350%). cGMP levels of striatum and hippocampus were still remaining significantly high at 6th h of ethanol withdrawal. Blood ethanol levels were found as 115.60, 50.0 and 7.0
mg/dl just before and after 6 and 24
h of ethanol withdrawal, respectively and audiogenic seizures also occurred at 6th h of ethanol withdrawal with an incidence of 75% in individual parallel groups. Our results suggest that changes of cGMP levels in cerebral cortex, striatum and hippocampus might participate in the mechanism of ethanol dependence and withdrawal in rats.
Abstract Agmatine is an endogenous substance, synthesized from l -arginine, and it is proposed to be a new neurotransmitter. Preclinical studies indicated that agmatine may have an important role in ...the pathophysiology of schizophrenia. This study was organized to investigate plasma agmatine in patients with schizophrenia and in healthy controls. Eighteen patients with schizophrenia and 19 healthy individuals constituted the subjects. Agmatine levels in the plasma were measured using the HPLC method. The S100B protein level, which is a peripheral biomarker for brain damage, was also measured using the ELISA method. While plasma levels of agmatine in patients with schizophrenia were significantly increased ( p < 0.0001) compared to those of healthy individuals (control), there were no significant changes in the levels of S100B protein ( p = 0.660). An ROC (receiver operating characteristic) curve analysis revealed that measuring plasma agmatine levels as a clinical diagnostic test would significantly differentiate between patients with schizophrenia and those in the control group (predictive value: 0.969; p < 0.0001). The predictive value of S100B measurements was not statistically significant ( p > 0.05). A multiple regression analysis revealed that the age of the patient and the severity of the illness, as indicated by the PANSS score, significantly contributed the plasma agmatine levels in patients with schizophrenia. These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia.
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