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.

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.

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.

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.

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.

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.

Clozapine inhibits development and expression of nicotine-induced locomotor sensitization in rats.

It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.

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.

Escitalopram increases cortical nitric oxide synthase (NOS) in rat brain during ethanol withdrawal.

The effect of escitalopram on ethanol withdrawal syndrome (EWS) and involvement of nitric oxide system in rats was investigated. Male Wistar rats divided into five experimental groups of eight animals each: (a) control group; (b) EWS (saline) group; (c) escitalopram 2.5 mg group; (d) escitalopram 5mg group and (e) escitalopram 10 mg group. Ethanol dependence was induced in rats by ethanol-containing liquid diet and ethanol withdrawal was precipitated by replacing ethanol free diet. Ethanol receiving rats in individual groups were decapitated on 21st day of ethanol ingestion and at sixth hour of ethanol withdrawal. Brains were removed and dissected. Five regions of the brain were dissected: the frontal cortex, cerebellum, striatum, hippocampus and hypothalamus. Immunohistochemical NOS staining was performed. The NOS staining intensity in cortex and hypothalamus regions were significantly lower in EWS group than control group. During EWS period, in rats given 2.5 and 10 mg/kg escitalopram, the staining intensity in cortex, striatum and hippocampus were found to be 11.492, 8.519 and 11.234, respectively, and was statistically different than the control group. The hippocampal NOS staining intensity was found to be significantly decreased with 2.5 mg/kg escitalopram, whereas the cortex, striatum and hippocampal staining intensity were increased significantly with 5 mg/kg. In 10 mg/kg escitalopram group, staining properties were not different than those of the control group. Our results suggest that NOS decreases during ethanol withdrawal in cortex and hypothalamus of rat brain and treatment with escitalopram reverses the enzyme density in cortex but not hypothalamus.

Effects of olanzapine on ethanol withdrawal syndrome in rats.

The present study was designed to investigate the effects of olanzapine, a serotonin-dopamine antagonistic atypical antipsychotic agent, on ethanol withdrawal syndrome in rats. Adult male Wistar rats were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. After 2nd, 4th and 6th h of ethanol withdrawal, rats were observed for 5 min, afterwards withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, tremor, wet dog shakes, abnormal posture and abnormal gait were recorded or rated. Olanzapine (0.5, 1 and 2 mg/kg) and saline were injected to the rats intraperitoneally 30 min before ethanol withdrawal assessment. A second series of injections was also given 30 min before the 6th-h-observation, and subjects were then tested for audiogenic seizures. Olanzapine (2 mg/kg) produced significant inhibitory effects on stereotyped behaviors and wet dog shakes at the 6th h of ethanol withdrawal. Contrary, the same dose caused some increases in the intensity of posture and gait impairments at the 2nd h of ethanol withdrawal. In addition, that dose was found to be ineffective on agitation, tremor, tail stiffness and audiogenic seizures. Our results suggest that acute olanzapine treatment has beneficial effects on stereotyped behavior and wet dog shakes, but it also has some adverse effects on posture and gait during ethanol withdrawal in rats. Overall, olanzapine does not seem to be an adequate and suitable drug in controlling of ethanol withdrawal syndrome.

Stimulus properties of venlafaxine in a conditioned taste aversion procedure.

Conditioned stimulus properties of venlafaxine are still unknown. In the present study, the discriminative stimulus properties of venlafaxine by using a conditioned taste aversion procedure were investigated. Swiss Webster mice were allowed to reach water from 2 pipettes for 20 min (09:00-11:30 h), plus 30 min (15:30-16:00 h), daily. During the 4 days, the test drugs [fluoxetine, escitalopram, tianeptine, reboxetine, and Nomega-nitro-L-arginine methyl ester (L-NAME)] were injected to mice at least 1 h after they had first water session. On day 5, they consumed glucose solution (5% w/v) and immediately injected with conditioning drug (venlafaxine 32 mg/kg). On day 8, mice were allowed to make a choice between water and glucose solution. The amount of glucose consumption as a percentage of total fluid intakes was calculated for each animal. Significant reduction in glucose choice was defined as conditioned taste aversion. Venlafaxine (32 mg/kg) induced a robust conditioned taste aversion in mice. Pre-exposure to tianeptine (2.5-10 mg/kg), fluoxetine (10 mg/kg), escitalopram (32 mg/kg), and reboxetine (5 mg/kg) substituted for venlafaxine by preventing the conditioned taste aversion induced by venlafaxine. L-NAME did not substitute for venlafaxine. Substitution of venlafaxine by fluoxetine, tianeptine, escitalopram, and reboxetine provides further evidence that both 5-HT and noradrenaline reuptake inhibition may play an important role in the stimulus effect of venlafaxine.

Effects of clozapine on ethanol withdrawal syndrome in rats.

AIMS: Co-morbid substance use in schizophrenic patients is common, and an important factor affects the outcome of disease. On the other hand, drug dependence is a predictive factor for psychosis. Alcohol is one of the most frequently abused psychoactive substances and may contribute psychotic symptoms in several conditions, such as withdrawal syndrome. The present study was designed to investigate the effects of clozapine on ethanol withdrawal syndrome (EWS) in rats. METHODS: Adult male Wistar rats were used in the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 14 days. An isocaloric liquid diet without containing ethanol was also given to control rats. Clozapine (2.5, 5 and 10 mg/kg) and its vehicle (0.1% acetic acid) were injected to rats subcutaneously at the 1.5th and 5.5th hours of ethanol withdrawal. At 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min and withdrawal signs that included locomotor hyperactivity, agitation, tremor, tail stiffness, stereotyped behaviour and wet dog shakes were recorded or rated. Following the observations at 6th hour, subjects were tested for audiogenic seizures. RESULTS: Clozapine significantly and dose-dependently inhibited the EWS-induced locomotor hyperactivity, wet dog shake, stereotyped behaviour, tremor and tail stiffness. However, it did not produce any significant effect on agitation and audiogenic seizures. Doses of clozapine used in the present study did not produce any significant change on locomotor activities of naïve rats. CONCLUSIONS: Our results suggest that clozapine had some significant beneficial effects on EWS in rats. Thus, this drug may be helpful for controlling some withdrawal signs in ethanol-dependent patients.

Effects of tianeptine on onset time of pentylenetetrazole-induced seizures in mice: possible role of adenosine A1 receptors.

Depression is a common psychiatric problem in epileptic patients. Thus, it is important that an antidepressant agent has anticonvulsant activity. This study was organized to investigate the effects of tianeptine, an atypical antidepressant, on pentylenetetrazole (PTZ)-induced seizure in mice. A possible contribution of adenosine receptors was also evaluated. Adult male Swiss-Webster mice (25-35 g) were subjects. PTZ (80 mg/kg, i.p.) was injected to mice 30 min after tianeptine (2.5-80 mg/kg, i.p.) or saline administration. The onset times of 'first myoclonic jerk' (FMJ) and 'generalized clonic seizures' (GCS) were recorded. Duration of 600 s was taken as a cutoff time in calculation of the onset time of the seizures. To evaluate the contribution of adenosine receptors in the effect of tianeptine, a nonspecific adenosine receptor antagonist caffeine, a specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A2A receptor antagonist 8-(3-chlorostyryl) caffeine (CSC) or their vehicles were administered to the mice 15 min before tianeptine (80 mg/kg) or saline treatments. Tianeptine (40 and 80 mg/kg) pretreatment significantly delayed the onset time of FMJ and GCS. Caffeine (10-60 mg/kg, i.p.) dose-dependently blocked the retarding effect of tianeptine (80 mg/kg) on the onset times of FMJ and GCS. DPCPX (20 mg/kg) but not CSC (1-8 mg/kg) blocked the effect of tianeptine (80 mg/kg) on FMJ. Our results suggest that tianeptine delayed the onset time of PTZ-induced seizures via adenosine A1 receptors in mice. Thus, this drug may be a useful choice for epileptic patients with depression.

Nicotine antagonizes caffeine- but not pentylenetetrazole-induced anxiogenic effect in mice.

RATIONALE: Nicotine and caffeine are widely consumed licit psychoactive drugs worldwide. Epidemiological studies showed that they were generally used concurrently. Although some studies in experimental animals indicate clear pharmacological interactions between them, no studies have shown a specific interaction on anxiety responses. OBJECTIVES: The present study investigates the effects of nicotine on anxiety induced by caffeine and another anxiogenic drug, pentylenetetrazole, in mice. The elevated plus-maze (EPM) test was used to evaluate the effects of drugs on anxiety. METHODS: Adult male Swiss Webster mice (25-32 g) were given nicotine (0.05-0.25 mg/kg s.c.) or saline 10 min before caffeine (70 mg/kg i.p.) or pentylenetetrazole (15 and 30 mg/kg i.p.) injections. After 15 min, mice were evaluated for their open- and closed-arm time and entries on the EPM for a 10-min session. Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test. RESULTS: Nicotine (0.05-0.25 mg/kg) itself did not produce any significant effect in the EPM test, whereas caffeine (70 mg/kg) and pentylenetetrazole (30 mg/kg) produced an anxiogenic effect, apparent with decreases in open-arm time and entry. Nicotine (0.25 mg/kg) pretreatment blocked the caffeine- but not pentylenetetrazole-induced anxiety. Administration of each drug and their combinations did not produce any effect on locomotor activity. CONCLUSIONS: Our results suggest that the antagonistic effect of nicotine on caffeine-induced anxiety is specific to caffeine, instead of a non-specific anxiolytic effect. Thus, it may extend the current findings on the interaction between nicotine and caffeine.

Discriminative stimulus properties of tianeptine.

RATIONALE: In view of the difficulties in using antidepressant agents as training drugs in drug discrimination research, it was reasoned that tianeptine, because of its short duration of action and its lack of toxicity associated with long-term administration, would be well-suited to establish a discriminative stimulus cue in rats and, hence, a valuable tool in the investigation of the neural basis of depression. OBJECTIVES: A drug discrimination procedure was used to determine whether tianeptine was associated with a specific discriminative stimulus effect, and substitution tests were conducted to determine whether this effect was mediated by serotonergic mechanisms. METHOD: Rats were trained to discriminate 10 mg/kg tianeptine from saline and were tested with fluoxetine, a selective serotonin (5-HT) reuptake inhibitor; venlafaxine, a 5-HT/noradrenaline reuptake inhibitor; 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist; and caffeine, a nonselective antagonist of adenosine receptors. RESULTS: Tianeptine induced a specific, robust, and sustained discriminative stimulus in rats. Fluoxetine and 8-OH-DPAT partially substituted for tianeptine by producing >50% of tianeptine-appropriate lever responding. In contrast, venlafaxine and caffeine induced responding on a saline-associated lever. CONCLUSION: The discriminative stimulus effect of tianeptine is mediated by serotonergic mechanisms, but what is surprising is that this mechanism seems to be, at least partially, enhanced by serotonergic transmission.

Effects of escitalopram on ethanol withdrawal syndrome in rats.

The present study was designed to investigate the effects of escitalopram, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (266-278 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Escitalopram (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the second and sixth hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes, tremors and audiogenic seizures were recorded or rated. A second series of injections was given 30 min before sixth hour of withdrawal test. Effects of escitalopram on the locomotor activities of the naïve (no ethanol-dependent) rats were also evaluated. Escitalopram (5 mg/kg) reduced the increased stereotyped behaviors at the sixth hour of ethanol withdrawal. It inhibited tremors at the second hour of ethanol withdrawal at doses of 5 and 10 mg/kg. Escitalopram (2.5 and 5 mg/kg) also produced some significant attenuations in the incidence of wet dog shakes at the second and sixth hours of the observation period. It was found ineffective on locomotor hyperactivity, agitation and audiogenic seizures. Escitalopram (2.5 and 5 mg/kg) did not cause any significant effect on locomotor activities of the naïve rats. Our results suggest that acute escitalopram treatment has some limited beneficial effects on ethanol withdrawal syndrome in rats.

Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats.

Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.

Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats.

The effects of tianeptine and fluoxetine on pentylenetetrazole (PTZ)-induced seizures in rats were investigated. Female Wistar rats (172-278 g) were used in the study. Tianeptine (1.25, 2.5, 5, 10 and 20 mg/kg) and fluoxetine (2.5, 5, 10 and 20 mg/kg) or saline were injected to rats intraperitoneally 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ administrations, latency and intensity of the PTZ-induced seizures was recorded and scored, respectively. Fluoxetine (2.5-20 mg/kg) did not produce any significant difference in latency and intensity of the PTZ-induced seizures. Although tianeptine (1.25-20 mg/kg) also did not affect the latency time, it produced significant attenuations in the intensity of the seizures. Tianeptine did not cause any significant change in the locomotor activity of the rats. The results of this preliminary study suggest that tianeptine but not fluoxetine has some inhibitory effects on PTZ-induced seizures in rats.