Sex differences in the neural and behavioral effects of acute high-dose edible cannabis consumption in rats.

The consumption of D9-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). Sprague-Dawley rats (6 males, 7 females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24-h after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition, and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 h. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and anti-nociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 h post-ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC. Significance Statement The effects of high-dose edible cannabis on behaviour and neural circuitry are poorly understood. We found that the effects of acute high-dose edible cannabis consumption, which include decreased gamma power, hypothermia, hypolocomotion, analgesia, and learning and information processing impairments, are time- and sex-dependent. Moreover, these effects begin 2 h after AHDECC and last for at least 24 h, suggesting that treatments should target this time window in order to be effective.

The Relationship Between Cannabis, Cognition, and Schizophrenia: It's Complicated.

The consequences of cannabis use, especially in the context of schizophrenia, have gained increased importance with the legalization of cannabis in North America and across the globe. Cannabis use has multifaceted impacts on cognition in schizophrenia patients and healthy subjects. Healthy subjects, particularly those who initiated cannabis use at earlier ages and used high-potency cannabis for longer durations, exhibited poorer cognition mainly in working memory and attention. Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes. However, cannabis-using patients have better overall cognitive performance compared to patients who were not cannabis users. Interestingly, these effects were only apparent in lifetime cannabis users, but not in current (or within last 6 months) users. Moreover, higher frequency and earlier age of cannabis use initiation (i.e., before 17 years of age) were associated with better cognitive performance, although they had an earlier illness onset. Three possible hypotheses seem to come forward to explain this paradox. First, some components of cannabis may have antipsychotic or cognitive-enhancing properties. Secondly, chronic cannabis use may alter endocannabinoid signaling in the brain which could be a protective factor for developing psychosis or cognitive impairments. A third explanation could be their representation of a phenotypically distinct patient group with more intact cognitive functioning and less neurodevelopmental pathology. Multiple factors need to be considered to understand the complex relationship between cannabis, cognitive function, and schizophrenia. In short, age at initiation, duration and rate of cannabis use, abstinence duration, co-use of substances and alcohol, prescribed medications, relative cannabinoid composition and potency of cannabis, presence of genetic and environmental vulnerability factors are prominent contributors to the variability in outcomes. Animal studies support the disruptive effects of Δ9-tetrahydrocannabinol (THC) administration during adolescence on attention and memory performance. They provide insights about interaction of cannabinoid receptors with other neurotransmitter systems, such as GABA and glutamate, and other regulatory molecules, such as PSD95 and synaptophysin. Cannabidiol (CBD), on the other hand, can improve cognitive deficits seen in neurodevelopmental and chemically-induced animal models of schizophrenia. Future studies focusing on bridging the translational gaps between human and animal studies, through the use of translationally relevant methods of exposure (e.g., vaping), consistent behavioral assessments, and congruent circuit interrogations (e.g., imaging) will help to further clarify this complex picture.

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.

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.

Discordant Effects of Cannabinoid 2 Receptor Antagonism/Inverse Agonism During Adolescence on Pavlovian and Instrumental Reward Learning in Adult Male Rats.

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.

The boundaries between survival and nonsurvival at COVID-19: Experience of tertiary care pandemic hospital.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is an emerging, fast-spreading, highly mortal and worldwide infectious disease. The pulmonary system was defined as the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mortality concept of this disease presented with more severe and systemic disease. The present study investigated the relationship between the patient characteristics at the initial hospital administration and fatality in COVID-19 patients. METHODS: In this retrospective and comparative cohort study, all the 767 hospitalised COVID-19 patients, treated between 18 March and 15 May 2020 in the Covid Clinics of Gulhane Training and Research Hospital in Ankara, Turkey, were evaluated. RESULTS: The fatality rate was significantly increased in patients with any comorbid disease except asthma. The initial laboratory test results indicated highly significant differences according to the patient's outcome. A multifactor logistic regression analysis was performed to calculate the adjusted odds ratios for predicting patient outcomes. Being older than 60 years increased the death risk with an adjusted OR of 7.2 (95% CI: 2.23-23.51; P = .001). The presence of a cancer and the extended duration of intensive care unit treatment were other significant risk factors for nonsurvival. Azithromycin treatment was determined as significantly reduced the death ratio in these patients (P = .002). CONCLUSION: It was revealed that being older than 60 years, presence of a cancer and extended duration of ICU treatment were the major risk factors for predicting fatality rate in hospitalised COVID-19 patients.

Alteration in NMDAR-related amino acids in first episode psychosis.

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.

l-Arginine metabolism before and after 10 weeks of antipsychotic treatment in first-episode psychotic patients.

Agmatine is an endogenous NMDA (N-methyl-d-aspartate) antagonist which is synthesized from l-Arginine and described as a novel neurotransmitter. Agmatine is considered to play an important role for the development of schizophrenia. The aim of the present study is to explore the role of agmatine and l-arginine metabolism in medication-naive first-episode psychosis (FEP). We conducted a case control study in medication-naive patients with FEP (n = 40). The healthy volunteers with no family history of schizophrenia (n = 35) matched for age, gender and education level were selected as a control group. The patients were recruited to the study and followed up for 10 weeks. The plasma l-arginine, l-citrulline, l-ornithine and agmatine levels were measured using modified liquid chromatography/mass spectrometry. The plasma levels of l-arginine, l-citrulline and agmatine (p < 0.0001), but not l-ornithine and agmatinase (p > 0.05), were significantly increased during baseline analysis. After 10 weeks of treatment, plasma l-arginine and l-citrulline levels were still significantly increased (p < 0.05) while l-ornithine and agmatinase levels remained unchanged (p > 0.05). Conversely, plasma agmatine levels were significantly decreased after the treatment (p < 0.0001). Positive and negative predictive values of agmatine used for evaluating the diagnostic accuracy were 95.1% and 97.1%, respectively (p < 000.1). This is the first study of arginine metabolism and agmatine in medication-naive first-episode patients and provides evidence of increased levels of an endogenous NMDA antagonist which decreases following antipsychotic treatment.

Social interaction of rats is related with baseline prepulse inhibition level.

The symptoms of schizophrenia are evaluated in three general categories: positive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model positive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by using a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively assigned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was assigned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a significant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were significantly lower, and the average distance between rat pairs was significantly longer than HI rats. In the EPM test LI and HI rats showed similar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.

Varenicline disrupts prepulse inhibition only in high-inhibitory rats.

Varenicline, a widely used smoking cessation drug, has partial agonistic activity at α4ß2 nicotinic receptors, and full agonistic activity at α7 nicotinic receptors. Thus it may interact with cognitive processes and may alleviate some of the cognitive disturbances observed in psychotic illnesses such as schizophrenia. We aimed to test the effects of varenicline on sensorimotor gating functioning, which is crucial for normal cognitive processes, especially for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. Prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning. First, the effects of varenicline and nicotine on rats having high or low baseline PPI levels were evaluated; then, varenicline was applied prior to apomorphine (0.5 mg/kg), and MK-801 (0.15 mg/kg), which are used as comparative models of PPI disruption. Varenicline (0.5-3 mg/kg) did not change PPI when given alone in naïve animals. When rats were selected according to their baseline PPI values, varenicline (1 mg/kg) significantly decreased PPI in high-inhibitory (HI) but not in low-inhibitory (LI) rats. Nicotine (1 mg/kg; tartrate salt) produced a similar activity in LI and HI groups. In combination experiments, varenicline did not reverse either apomorphine or the MK-801-induced disruption of PPI. These results demonstrate that the effects of both varenicline and nicotine on sensorimotor gating are influenced by the baseline PPI levels. Moreover, varenicline has no effect on apomorphine or the MK-801-induced disruption of PPI.

Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats.

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.

Increased plasma agmatine levels in patients with schizophrenia.

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.

Effects of pioglitazone and retinoic acid in a rotenone model of Parkinson's disease.

Parkinson's disease (PD) is a late-onset, progressive and neurodegenerative disorder of unknown etiology. Besides the other therapeutic approaches, new drug options in pharmacotherapy of PD are important. The aim of the present study was to investigate the effects of pioglitazone and retinoic acid, antioxidant and neuroprotective agents, on rotenone-induced model of PD in rats. Adult male Wistar rats (260-373 g) were subjects. Rotenone (2.5mg/kg, sc) was injected to rats for 70 days. At the end of rotenone administration, rats were treated with pioglitazone (10mg/kg, ip) and retinoic acid (1mg/kg, ip) or vehicles for 15 days. Then, rats were tested for evaluation of Parkinson signs by measurement of locomotor activity. In addition, dopamine levels were detected in striatum, hippocampus and hypothalamus in individual groups of control, rotenone and pioglitazone or retinoic acid-treated rats. Rotenone significantly reduced locomotor activity of the rats. It also significantly reduced dopamine levels in striatum and hippocampus, but not hypothalamus. Pioglitazone and retinoic acid reversed in reduction of locomotor activity significantly. Pioglitazone, but not retinoic acid, significantly reversed the reduced striatal dopamine level. Both drugs were ineffective on reduced levels of dopamine in hippocampus. Our results suggest that pioglitazone and retinoic acid have some beneficial effects on rotenone-induced model of PD in rats. Pioglitazone seems to be more effective than retinoic acid. These agents may be helpful for preventing or controlling of some signs of PD.

Agmatine blocks ethanol-induced locomotor hyperactivity in male mice.

Ethanol-induced locomotor activity is associated to rewarding effects of ethanol and ethanol dependence. Agmatine is a novel endogenous ligand at α2-adrenoceptors, imidazoline and N-methyl-d-aspartate (NMDA) receptors, as well as a nitric oxide synthase (NOS) inhibitor. There is no evidence presented for the relationship between the acute locomotor stimulating effect of ethanol and agmatine. Thus, the present study investigated the effects of agmatine on acute ethanol-induced locomotor hyperactivity in mice. Adult male Swiss-Webster mice (26-36g) were used as subjects. Locomotor activity of the mice was recorded for 30min immediately following intraperitoneal administration of ethanol (0.5, 1 and 2g/kg) or saline (n=8 for each group). Agmatine (5, 10 and 20mg/kg) or saline was administered intraperitoneally to another four individual groups (n=8 for each group) of the mice 20min before the ethanol injection. In these groups, locomotor activity was also recorded immediately following ethanol (0.5g/kg) injection for 30min. Ethanol (0.5g/kg) produced some significant increases in locomotor activity of the mice. Agmatine (5-20mg/kg) significantly blocked the ethanol (0.5g/kg)-induced locomotor hyperactivity. These doses of agmatine did not affect the locomotor activity in naive mice when they were administered alone. Our results suggest that agmatine has an important role in ethanol-induced locomotor hyperactivity in mice. There may be a relationship between the addictive psychostimulant effects of the ethanol and central agmatinergic system.

Impact of baseline prepulse inhibition on nicotine-induced locomotor sensitization in rats.

The rats having high locomotor reactivity to a novel environment (LRNE) are known to be more vulnerable to develop locomotor sensitization, which reflects the initial neuroplastic changes in brain systems related to addictive behaviours. The present study aimed to investigate whether sensorimotor gating level, measured by prepulse inhibition (PPI) of acoustic startle reflex, also reflects vulnerability for nicotine sensitization. A batch of rats was assigned into three groups according to their baseline PPI values. The highest 1/3 and the lowest 1/3 proportions were selected and defined as high-inhibitory (HI) and low-inhibitory (LI) groups. LRNE was measured in the rats, then they were treated with nicotine (1 mg/kg, tartrate salt, subcutaneously) or saline and locomotor activity (LMA) was immediately recorded for 15 min. This procedure was performed daily for 5 successive days. After a 3-day drug-free period, all rats were challenged with nicotine (1 mg/kg) on 9th day and with saline on 12th day. Same sensitization protocol was applied in another batch of rats, except assigning them into the high-responder (HR) and low-responder (LR) groups according to LRNE levels. There was no significant difference between HI and LI rats in LRNE. Although the acute effect of nicotine on LMA was higher in HI rats, a locomotor sensitization developed and expressed only in LI rats. In the following experiments, nicotine stimulated LMA both in HR and LR rats, but induced and expressed locomotor sensitization only in HR rats. The present study shows that acute locomotor stimulant effect and locomotor sensitization developing effects of nicotine are associated with the baseline PPI and LRNE levels. But these two factors are independent from each other.

Effects of sildenafil and tadalafil on ischemia/reperfusion injury in fetal rat brain.

OBJECTIVE: The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, sildenafil and tadalafil, in ischemia/reperfusion (I/R)-induced oxidative injury in fetal rat brain. METHODS: Timed pregnant adult Wistar rats were randomly assigned to the following groups (n = 6 for each group): saline + none I/R (1), saline + I/R (2), sildenafil + none I/R (3); sildenafil + I/R (4), tadalafil + none I/R (5) and tadalafil + I/R (6). Fetal ischemia was induced by clamping the utero-ovarian artery bilaterally. Fetuses were delivered and 268 fetal rats were decapitated. Malondialdehyde (MDA) levels and, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed in fetal brain tissue homogenates by spectrophotometric methods. RESULTS: In saline + I/R group, MDA levels were increased and, SOD and GSH-Px activities were decreased significantly comparing with saline + none I/R group. Both tadalafil and sildenafil treatment decreased the MDA levels significantly in ischemia/reperfusion groups, whereas this effect was significantly more potent with tadalafil. SOD levels were significantly decreased in all groups after I/R. Tadalafil seems to be more effective than sildenafil by means of increasing GSH-Px activity significantly after I/R. CONCLUSION: Our results indicate some beneficial effects of PDE5 inhibitory drugs, especially tadalafil, on oxidative I/R injury in fetal rat brains.

Effects of risperidone on development and expression of nicotine-induced locomotor sensitization in rats.

It has been shown that atypical antipsychotics significantly reduce smoking and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of risperidone, especially on nicotine abuse is limited. We aimed to test the effects of risperidone in an animal model of nicotine-induced locomotor sensitization, which represents initial neuroadaptations and continued behavioral changes in nicotine-type dependence. To investigate the effect of risperidone on the development of nicotine-induced locomotor sensitization, rats were pretreated with risperidone (0.025 and 0.050 mg kg⁻¹) 30 min before the nicotine (0.5 mg kg⁻¹, base) treatment, and locomotor activity was recorded for 30 min. This procedure was repeated every day for eight sessions. After a 6-day drug-free period, rats were challenged with nicotine (0.5 mg kg⁻¹). To reveal the effect of risperidone on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 6-day drug-free period, rats were pretreated with risperidone (0.025 and 0.050 mg kg⁻¹) or vehicle 30 min before the nicotine (0.5 mg kg⁻¹) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Risperidone pretreatment (0.050 mg kg⁻¹) blocked the expression but not the development of nicotine-induced locomotor sensitization in rats. Our results suggest that risperidone blocks the continuation of nicotine-type addictive behavior, but it is ineffective on early adaptations in the initiation of nicotine addiction. Thus, this drug may have a limited beneficial effect in treatment of nicotine dependence.

Effects of risperidone, quetiapine and ziprasidone on ethanol withdrawal syndrome in rats.

Comorbid substance use in schizophrenic patients is common, and substance dependence is a predictive factor for psychosis. The present study was designed to investigate the effects of risperidone, quetiapine and ziprasidone, atypical antipsychotic drugs, on ethanol withdrawal syndrome (EWS) in rats. Adult male Wistar rats were used in the study. Ethanol (7.2%, v/v) was given to rats via a liquid diet for 21 days. An isocaloric liquid diet without ethanol was given to control rats. Risperidone (1 and 2 mg/kg), quetiapine (8 and 16 mg/kg), ziprasidone (0.5 and 1 mg/kg) and vehicle were injected into rats intraperitoneally at 1.5 and 5.5 h of ethanol withdrawal. At the 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, stereotyped behaviors, abnormal gait and posture, tail stiffness and agitation were recorded or rated. Following the observations at the 6th hour, the rats were tested for audiogenic seizures. All three drugs had some significant inhibitory effects on EWS-induced behavioral signs beginning at the 2nd hour of withdrawal. The drugs also significantly reduced the incidence of audiogenic seizures. Overall, risperidone and quetiapine seemed to be more effective than ziprasidone in ameliorating the withdrawal signs. Doses of the drugs used in the present study did not produce any significant changes in locomotor activities of naïve rats. Our results suggest that risperidone, quetiapine and ziprasidone had beneficial effects on EWS in rats. Thus, these drugs may be helpful for controlling withdrawal signs in ethanol-dependent patients.

The relationship between baseline prepulse inhibition levels and ethanol withdrawal severity in rats.

Baseline prepulse inhibition (PPI) of the acoustic startle reflex is thought to reflect the functioning of the sensorimotor gating system in the brain. The current literature indicates that similar neurotransmitter systems may play roles both in the regulation of PPI and in the development of ethanol withdrawal syndrome (EWS). The aim of the present study was to test if individual baseline PPI levels have any relationship to the behavioral and neurochemical consequences of EWS in rats. A batch of rats (n=30) was sorted according to baseline PPI levels and classified as either high-inhibitory (HI) or low-inhibitory (LI) rats (n=10 in each group). Ethanol was administered in a liquid diet for 21 days. On the 22nd day, ethanol was removed from the diet, and EWS was induced. At the 2nd, 4th, and 6th hours of EWS, locomotor activity and behavioral symptoms were evaluated. Brain tissue concentrations of dopamine, serotonin and noradrenaline in hippocampus, cortex, and striatum were measured after the 6th hour of EWS testing. Another batch of rats (n=30) was classified using the same procedure and fed with regular diet. On the 22nd day, rats were decapitated and neurochemical measurements were repeated. HI and LI rats consumed similar amounts of ethanol. However, EWS signs such as stereotyped behaviors, wet-dog shakes, and tremor were more intense in LI rats compared to their HI counterparts. Audiogenic seizures occurred in both groups in a similar manner. Although the catecholamine concentrations in the brains of both groups were parallel under baseline conditions, dopamine levels increased in the cortex of LI and in the striatum of HI rats, whereas striatum serotonin levels decreased only in LI rats after the 6th hour of EWS. In conclusion, the data suggest that the behavioral symptoms and neurochemical changes observed in EWS may be associated with baseline PPI levels.

Sex-related effects of agmatine on caffeine-induced locomotor activity in Swiss Webster mice.

In mammalian brain, agmatine is an endogenous amine that is synthesized through the decarboxylation of l-arginine by arginine decarboxylase. It has been proposed as a new neurotransmitter and/or neuromodulator. It was shown that agmatine had some beneficial effects in animal models of opioid and alcohol addiction. Locomotor stimulant properties of drugs such as ethanol, caffeine, nicotine and amphetamine have been linked to their addictive properties. The present study investigates the effects of agmatine on caffeine-induced locomotor activity both in male and female mice. Adult Swiss Webster mice were used in the study. Locomotor activity was measured for 30min immediately following caffeine (2.5, 5, 10 and 20mg/kg, i.p.) or saline treatments. Agmatine (5, 10 and 20mg/kg, i.p.) were injected 20min before caffeine (2.5 and 5mg/kg, i.p.) administration. In both sexes, agmatine (5-20mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of caffeine. Caffeine (5mg/kg) induced a significant increase in locomotor activity of both male and female mice. There was no significant difference in the locomotor-activating effects of caffeine between male and female mice. Agmatine blocked the caffeine (5mg/kg)-induced locomotor stimulation dose dependently in male but not female mice. Agmatine had not any effect on the lower dose (2.5mg/kg) of caffeine in both sexes. These results suggest that agmatine has sex-related inhibitory effects on caffeine-induced locomotor activity in Swiss Webster mice, and male mice are more sensitive than the females to the effect of agmatine.

Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model.

Increased serum insulin levels and reduced peripheral insulin activities seen in insulin resistance syndrome are associated with age-dependent cognitive impairment and Sporadic Alzheimer's Disease (SAD), suggesting a disturbance in the insulin signalling system in the brain and possibly being one of the causes of dementia. Therefore, the streptozotocin (STZ)-induced animal may be an appropriate model for the investigation of SAD and related dementia. This study was designed to investigate the beneficial effect of Curcumin (CUR), a neuroprotective agent, on intracerebroventricular (ICV) STZ-induced cognitive impairment in rats. For this purpose, adult male Wistar rats were bilaterally ICV injected with STZ (3 mg/kg). An artificial cerebrospinal fluid (aCSF) was given to the control group (SHAM) instead of STZ on days 1 and 3. Learning and memory performance were assessed using the "passive avoidance task" and the "Morris water maze test". After confirmation of acquisition impairment with these tests, the STZ group was divided into two subgroups: STZ + vehicle (Vh) and STZ + CUR. The rats in the SHAM and STZ + Vh groups were administered intraperitoneally with 0.5 ml Vh and the rats in the STZ + CUR group were treated intraperitoneally with CUR (300 mg kg(-1) day(-1) in Vh) for 10 days starting from the 25th day after STZ injection. The Morris water maze test was reapplied on the 35th day after STZ injection and all of the rats were sacrificed on day 36 for quantitation of IGF-1 and for histopathological evaluation. Rats in the STZ + CUR group were found to have a higher performance in cognitive tests than rats in the STZ + Vh group (P < 0.01). In parallel with the cognitive tests, IGF-1 levels were decreased in all of the STZ-injected groups (1.78 +/- 0.34) compared to the SHAM group (3.46 +/- 0.41). In contrast, CUR treatment significantly increased IGF-1 levels (P < 0.001). The degree of neuronal loss decreased after CUR treatment compared to the SHAM group (P < 0.02). These results clearly indicate that CUR treatment is effective in reducing the cognitive impairment caused by STZ in rats, and may be a potential therapeutic agent for altering neurodegeneration in SAD.