Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats.

Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.

Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide/NMDA pathways.

Besides the clinical applications of penicillamine, some reports show that use of D-penicillamine (D-pen) has been associated with adverse effects such as seizures. So, the purpose of this study was to evaluate the effects of D-pen on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice. It also examined whether N-methyl-D-aspartate (NMDA) receptor/nitrergic system blockage was able to alter the probable effects of D-pen. Different doses of D-pen (0.1, 0.5, 1, 10, 100, 150, and 250 mg/kg) were administered intraperitoneally (i.p.) 90 min prior to induction of seizures. D-Penicillamine at a low dose (0.5 mg/kg, i.p.) had anticonvulsant effects, whereas at a high dose (250 mg/kg, i.p.), it was proconvulsant. Both anti- and proconvulsant effects of D-pen were blocked by a single dose of a nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (10 mg/kg, i.p.), and a single dose of a specific inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (30 mg/kg, i.p.). A selective inhibitor of iNOS, aminoguanidine (100 mg/kg, i.p.), had no effect on these activities. An NMDA receptor antagonist, MK-801 (0.05 mg/kg, i.p.), alters the anti- and proconvulsant effects of D-pen. The results of the present study showed that the nitric oxide system and NMDA receptors may contribute to the biphasic effects of D-pen, which remain to be clarified further.

Hyperactivity Induced By Vapor Inhalation of Nicotine in Male and Female Rats.

Rationale: Preclinical models of electronic nicotine delivery system (ENDS; "e-cigarette") use have been rare, so there is an urgent need to develop experimental approaches to evaluate their effects. Objective: To contrast the impact of inhaled nicotine across sex. Methods: Male and female Wistar rats were exposed to vapor from a propylene glycol vehicle (PG), nicotine (NIC; 1-30 mg/mL in PG), or were injected with NIC (0.1-0.8 mg/kg, s.c.), and then assessed for changes in temperature and activity. The antagonist mecamylamine (2 mg/kg) was administered prior to NIC to verify pharmacological specificity. Plasma levels of nicotine and cotinine were determined after inhalation and injection. Results: Activity increased in females for ~60 minutes after nicotine inhalation, and this was blocked by mecamylamine. A similar magnitude of hyperlocomotion was observed after s.c. administration. Body temperature was reduced after nicotine inhalation by female rats but mecamylamine increased this hypothermia. Increased locomotor activity was observed in male rats if inhalation was extended to 40 minutes or when multiple inhalation epochs were used per session. The temperature of male rats was not altered by nicotine. Plasma nicotine concentrations were slightly lower in male rats than in female rats after 30-minute nicotine vapor inhalation and slightly higher after nicotine injection (1.0 mg/kg, s.c.). Conclusions: Nicotine inhalation increases locomotor activity in male and female rats to a similar or greater extent than by subcutaneous injection. Sex differences were observed, which may be related to lower nicotine plasma levels, lower baseline activity and/or a higher vehicle response in males.

Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice.

Estradiol decline has been associated with depressive-like behavior in female mice and NO has been suggested to play a major role in the pathogenesis of major depression. This study was conducted to investigate the antidepressant-like effects of acute estradiol administration in female ovariectomized (OVX) mice and the possible role of nitric oxide (NO)/cyclic GMP (cGMP) pathway. To this end, bilateral ovariectomy was performed in female mice and different doses of estradiol were injected alone or in combination with non-specific NO synthase (NOS) inhibitor (L-NAME), selective neural NOS (nNOS) inhibitor (7-NI), an NO precursor (L-arginine) or selective phosphodiesterase type 5 inhibitor (sildenafil). The duration of immobility was recorded in the forced swimming test (FST) to assess the depressive behavior. Moreover, hippocampal levels of NO were determined in select groups. 10 days following the procedure, OVX mice showed significantly prolonged immobility time in comparison with the sham group. Estradiol (3, 10, and 30 µg/kg, s.c.), when injected 1 h prior to FST, exerted antidepressant-like effects in OVX mice. Both L-NAME (30 mg/kg, i.p.), and 7-NI (50 mg/kg, i.p.) significantly reduced the immobility times of OVX mice. Administration of a sub-effective dose of L-NAME (10mg/kg), 15 min after a sub-effective dose of estradiol (1 µg/kg, s.c.) had a robust antidepressant-like effect in OVX mice. Also a sub-effective dose of 7-NI (25 mg/kg), 30 min after a sub-effective dose of estradiol (1 µg/kg, s.c.) showed antidepressant-like effect in OVX mice. Both the NO precursor L-arginine (750 mg/kg, i.p.) and the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil (5 mg/kg, i.p.), 30 min before estradiol treatment, prevented the antidepressant-like effect of a potent dose of estradiol (10 µg/kg, s.c.) in OVX mice. The present findings suggest that suppression of the NO synthase/NO/cGMP pathway may be involved in the antidepressant-like effects of estradiol in OVX mice.

Nitric oxide mediates the beneficial effect of chronic naltrexone on cholestasis-induced memory impairment in male rats.

Recent studies suggest an augmentation of endogenous opioids following bile duct ligation (BDL) and their pivotal role in the pathophysiology of cholestasis. In this study, the effect of naltrexone, an opioid receptor antagonist, was determined on cholestasis-induced memory impairment and the possible involvement of nitric oxide (NO) in this effect. Male Albino-Wistar rats were randomized to sham-operated and BDL-operated groups. In each group, animals were treated for up to 28 days with saline; naltrexone (10 mg/kg); naltrexone and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor (3, 10 mg/kg); naltrexone and aminoguanidine, an inducible NOS inhibitor (100 mg/kg); or methylnaltrexone, a peripherally acting opioid receptor antagonist (3 mg/kg, intraperitoneal). Spatial recognition memory was determined in a Y-maze task on the day before surgery and days 7, 14, 21, and 28 after surgery. Memory performance was impaired 14 days after BDL in cholestatic rats and was significantly reversed by chronic treatment with naltrexone at days 14, 21, and 28 after BDL. On day 21 after BDL, chronic L-NAME produced only a nonsignificant decrease in the beneficial effect of naltrexone, whereas on day 28, chronic administration of both L-NAME and aminoguanidine significantly reversed this effect of naltrexone. It is therefore shown in this study that naltrexone improves BDL-induced memory deficit in rats. We conclude that the memory impairment in cholestatic rats might be because of an increase in the level of endogenous opioids and that naltrexone improved the spatial recognition memory by antagonizing opioid receptors. The observation that the procognitive effect of naltrexone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by naltrexone in BDL rats.

Effects of combined THC and heroin vapor inhalation in rats.

RATIONALE: Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. OBJECTIVES: To determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected. METHODS: Groups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50 mg/mL in propylene glycol vehicle; PG), THC (50 mg/mL), or the combination for assessment of effects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay. RESULTS: Heroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague-Dawley rats. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive effects on thermal nociception in both male and female Sprague-Dawley and Wistar rats. CONCLUSIONS: This study shows that additive effects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

Effect of DETA-NONOate and papaverine on vasodilation of human internal mammary artery.

In this study, the relaxatory effect of DETA-NONOate is compared with that of papaverine on isolated human internal mammary artery. We investigated the inhibitory effects of DETA-NONOate and papaverine on phenylephrine-induced contractile response in internal mammary artery segments. The internal mammary artery segments, taken from methodologically matched patients who underwent coronary artery bypass grafting, were prepared, placed in an organ bath, and contracted with phenylephrine (10(-9) to 10(-4) mol/L) to investigate their relaxatory response to DETA-NONOate or papaverine. Phenylephrine dose-response contraction was obtained after 1, 2, and 3 h in segments pre-incubated with DETA-NONOate or papaverine for 30 min. The EC50 that presented for internal mammary artery segments incubated with DETA-NONOate was 3.523 ± 1.2696 × 10(-7) mol/L, and for papaverine was 3.467 ± 1.2145 × 10(-6) mol/L. In segments pre-incubated with DETA-NONOate, the contractile response to phenylephrine was suppressed in the first 2 h post-incubation, compared with control responsive groups (p < 0.05), but this inhibition was revoked after 3 h post-incubation. We showed that DETA-NONOate has a more significant relaxative effect by comparison with papaverine; moreover, continuous and long-lasting nitric oxide production by DETA-NONOate might be of great importance for the outcome from coronary artery bypass grafting, when internal mammary artery is used as a conduit.

Involvement of the nitric oxide pathway in the anticonvulsant effect of tramadol on pentylenetetrazole-induced seizures in mice.

In the present study, the effects of tramadol on pentylenetetrazole (PTZ)-induced seizures and involvement of nitric oxide (NO) were assessed in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. Tramadol was administered intraperitoneally (0.5-50mg/kg) 30 minutes prior to induction of seizures. The effects of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 0.5, 1, 5, and 10mg/kg), the nitric oxide precursor L-arginine (10, 30, and 60 mg/kg), and the nonspecific opioid receptor antagonist naloxone (0.1, 0.5, 1, and 5mg/kg) on the anticonvulsant effect of tramadol were investigated. Administration of tramadol (1mg/kg) increased the threshold for seizures induced with PTZ in a monophasic, dose-independent, and time-dependent manner. Acute administration of L-NAME (5 and 10mg/kg) inhibited the anticonvulsant effect of tramadol (1mg/kg), whereas L-arginine, in the noneffective dose range (30 and 60 mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of tramadol (0.5mg/kg). Naloxone partially and dose-independently antagonized the anticonvulsant effect of tramadol (1mg/kg). These results indicate that the anticonvulsant effect of tramadol is mediated by the nitric oxide pathway and also by classic opioid receptors.

Effect of lithium on secretory factors and growth stimulation by bombesin in rat pancreas and salivary glands.

Lithium, a drug of choice in bipolar affective disorders, also affects the metabolism and cell proliferation in a diverse array of organisms. In this study, we investigated the effect of lithium on bombesin-mediated function in excretion and growth of the pancreas and the salivary glands. The weight, protein content, amylase concentration and salivary flow rate of the pancreas, parotid and the submandibular glands were determined in male Wistar rats after consumption of either water or lithium chloride (600 mg/l) for 14 days and each group received s.c. injection of either saline or bombesin (10 microg/kg) during the last 4 days of experiment. Our results revealed that administration of bombesin in lithium-treated group not only suppressed pancreas and parotid weight augmentation due to bombesin, but also significantly decreased pancreas growth. Chronic lithium consumption significantly inhibited the protein content augmentation due to bombesin in the salivary glands. Getting bombesin, as well as saline in lithium-treated group, resulted in notable decrease in salivary protein content. Protein content of pancreatic gland increased considerably in the bombesin-injected groups either treated with saline or lithium. In conclusion, the stimulatory effect of bombesin on the growth and protein content of the pancreas and the salivary gland was inhibited by lithium. Lithium seems to be a potent inhibitor of growth factors induced by bombesin probably through inhibiting phosphatidylinositol 4,5,bisphosphate hydrolysis.

Vapor inhalation of cannabidiol (CBD) in rats.

RATIONALE: Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE: To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS: Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS: Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.

Effects of nicotine and THC vapor inhalation administered by an electronic nicotine delivery system (ENDS) in male rats.

BACKGROUND: Electronic nicotine delivery systems (ENDS, e-cigarettes) are increasingly used for the self-administration of nicotine by various human populations, including previously nonsmoking adolescents. Studies in preclinical models are necessary to evaluate health impacts of ENDS including the development of nicotine addiction, effects of ENDS vehicles, flavorants and co-administered psychoactive substances such as Δ9-tetrahydrocannabinol (THC). This study was conducted to validate a rat model useful for the study of nicotine effects delivered by inhalation of vapor created by ENDS. METHODS: Male Sprague-Dawley rats (N = 8) were prepared with radio telemetry devices for the reporting of temperature and activity. Experiments subjected rats to inhalation of vapor generated by an electronic nicotine delivery system (ENDS) adapted for rodents. Inhalation conditions included vapor generated by the propylene glycol (PG) vehicle, Nicotine (1, 10, 30 mg/mL in the PG) and THC (12.5, 25 mg/mL). RESULTS: Nicotine inhalation increased spontaneous locomotion and decreased body temperature of rats. Pretreatment with the nicotinic cholinergic receptor antagonist mecamylamine (2 mg/kg, i.p.) prevented stimulant effects of nicotine vapor inhalation and attenuated the hypothermic response. Combined inhalation of nicotine and THC resulted in apparently independent effects which were either additive (hypothermia) or opposed (activity). CONCLUSIONS: These studies provide evidence that ENDS delivery of nicotine via inhalation results in nicotine-typical effects on spontaneous locomotion and thermoregulation in male rats. Effects were blocked by a nicotinic antagonist, demonstrating mechanistic specificity. This system will therefore support additional studies of the contribution of atomizer/wick design, vehicle constituents and/or flavorants to the effects of nicotine administered by ENDS.

Locomotor and reinforcing effects of pentedrone, pentylone and methylone in rats.

The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 °C) was observed for four hours after 10.0 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

RATIONALE: Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. OBJECTIVES: To compare thermoregulatory and locomotor responses to inhaled ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. RESULTS: THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. CONCLUSION: In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

Binge-like acquisition of α-pyrrolidinopentiophenone (α-PVP) self-administration in female rats.

RATIONALE: The synthetic cathinone α-pyrrolidinopentiophenone (α-PVP) has been associated with bizarre public behavior in users. Association of such behavior with extended binges of drug use motivates additional investigation, particularly since a prior study found that half of male rats experience a binge of exceptionally high intake, followed by sustained lower levels of self-administration during the acquisition of intravenous self-administration (IVSA) of a related drug, 3,4-methylenedioxypyrovalerone. OBJECTIVES: The binge-like acquisition pattern is novel for rat IVSA; thus, the present study sought to determine if this effect generalizes to IVSA of α-PVP in female rats. METHODS: Female Wistar rats were trained in IVSA of α-PVP (0.05 mg/kg/inf) in experimental chambers containing an activity wheel. Groups were trained with the wheels fixed (No-Wheel group), fixed for the initial 5 days of acquisition or free to move throughout acquisition (Wheel group). The groups were next subjected to a wheel access switch and then all animals to dose-substitution (0.0125-0.3 mg/kg/inf) with the wheels alternately fixed and free to move. RESULTS: Approximately half of the rats initiated their IVSA pattern with a binge day of exceptionally high levels of drug intake, independent of wheel access condition. Wheel activity was much lower in the No-Wheel group in the wheel switch post-acquisition. Dose-effect curves were similar for wheel access training groups, for binge/no binge phenotypic subgroups and were not altered with wheel access during the dose-substitution. CONCLUSION: This confirms the high reinforcer effectiveness of α-PVP in female rats and the accompanying devaluation of wheel activity as a naturalistic reward.

HIV-1 and cocaine disrupt dopamine reuptake and medium spiny neurons in female rat striatum.

HIV-1 and addictive drugs, such as cocaine (COC), may act in combination to produce serious neurological complications. In the present experiments, striatal brain slices from HIV-1 transgenic (Tg) and F344 control female rats were studied. First, we examined dopamine (DA) reuptake in control, HIV-1, COC-treated (5µM) and HIV-1+COC-treated, striatal slices using fast scan cyclic voltammetry. COC-treated striatal slices from F344 control animals significantly increased DA reuptake time (T80), relative to untreated control slices. In contrast, in HIV-1 Tg striatal slices, DA reuptake time was extended by HIV-1, which was not further altered by COC treatment. Second, analysis of medium spiny neuronal populations from striatal brain slices found that controls treated with cocaine displayed increases in spine length, whereas cocaine treated HIV-1 slices displayed decreased spine length. Taken together, the current study provides evidence for dysfunction of the dopamine transporter (DAT) in mediating DA reuptake in HIV-1 Tg rats and limited responses to acute COC exposure. Collectively, dysfunction of the DAT reuptake and altered dendritic spine morphology of the MSNs, suggest a functional disruption of the dopamine system within the HIV-1 Tg rat.

Protective Effects of Lithium on Sumatriptan-Induced Memory Impairment in Mice.

Lithium is a drug used for the treatment of bipolar disorder. It has several mechanisms of action, and recently it is shown that lithium can antagonize the 5-HT1B/1D serotonin receptors. Sumatriptan is a 5-HT1B/1D receptor agonist used for the treatment of cluster headaches and migraine which might cause memory impairment as a potential side effect. In this study, effects of lithium on sumatriptan-induced memory impairment have been determined in a two-trial recognition Y-maze and passive avoidance tests. Male mice weighing 25-30 g were divided into several groups randomly. In Y-maze test, effects of lithium (1,5,10,20,40,80 mg/kg) and sumatriptan (1,5,10 mg/kg) were assessed on memory acquisition, then lithium (0.1,1,10 mg/kg) and sumatriptan (1,10 mg/kg) were studied in passive avoidance test. Effects of lithium (1mg/kg) on sumatriptan (10 mg/kg)-induced memory impairment were studied in both of tests. The present study demonstrated that sumatriptan impaired memory in Y-maze and passive avoidance tests (P<0.05, P<0.01, respectively). Lithium did not show any significant effect on memory function compared to saline-treated control group in both tests (P>0.05), but significantly reversed sumatriptan-induced memory impairment in Y-maze and passive avoidance tests (P<0.001, P<0.05, respectively). It is concluded that lithium reverses the sumatriptan-induced memory impairment probably through 5-HT1B/1D receptors antagonism.

The modulatory effect of nitric oxide in pro- and anti-convulsive effects of vasopressin in PTZ-induced seizures threshold in mice.

Vasopressin neuropeptides play an important role in the several cognitive, social, and neuroendocrine functions. Also, several studies report the involvement of nitrergic system in the vasopressin functions in central nervous system. This study investigates the effect of Arginine-Vasopressin (AVP) in pentylenetetrazol (PTZ)-induced seizures threshold and the probable role of nitric oxide (NO). AVP is administered intraperitoneally (0.01-20µg/kg, i.p.) 30min before induction of seizures. Administration of AVP (0.1µg/kg) significantly lowered the PTZ-induced seizures threshold. But, administration of AVP (10 and 20µg/kg) increased the seizures threshold, significantly. Pretreatment of SR 49059 (V1a receptor antagonist, 2mg/kg, i.p.) just reversed the pro-convulsant effect of AVP. Meanwhile, SSR 149415 (V1b receptor antagonist, 10mg/kg, i.p.) pretreatment reversed both pro-and anti-convulsant effects of AVP. The nitric oxide precursor, L-arginine (60mg/kg, i.p.) increased pro-convulsant effect of AVP, but did not change anticonvulsant activity. The nitric oxide synthase (NOS) inhibitor L-NAME (10mg/kg, i.p.) reversed both pro- and anti-convulsant effect of AVP. Selective inducible NOS inhibitor, aminoguanidine (100mg/kg, i.p.) just reversed the anti-convulsant effects of AVP. The results of the present study showed nitric oxide system may contribute to the biphasic effects of AVP on PTZ-induced seizures. V1a receptor may modulate only the proconvulsive effect. While, V1b receptors can mediate both the pro- and anti-convulsive effect of AVP.

Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 µg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 µg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 µg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 µg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 µg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 µg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 µg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.

NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice.

PURPOSE: The present study has been undertaken to investigate the possible involvement of the glutamatergic pathway in the beneficial effects of pioglitazone on consolidation and retrieval phases of memory. MATERIALS AND METHODS: The Y-maze task was used to assess short-term spatial recognition memory in animals. Scopolamine (1mg/kg, i.p.) or MK-801 (dizocilpine) (0.03, 0.1 and 0.3mg/kg, i.p.) were administered immediately after the training session to impair memory consolidation or 30min before the retention trial to impair memory retrieval. Pioglitazone (10, 20, 40 and 80mg/kg, p.o.) was administered 2h before the retention session in memory retrieval experiments or immediately after the training session in consolidation experiments. And finally NMDA (N-methyl-d-aspartate) (75mg/kg, i.p) was administered 15min before the administration of pioglitazone. RESULTS: 1) MK-801 (0.3mg/kg) impaired the retrieval of spatial recognition memory. 2) Pioglitazone failed to improve MK-801 induced impairment of retrieval of spatial recognition memory. 3) The 20mg/kg dose of pioglitazone significantly improved memory in mice with scopolamine induced impairment of memory retrieval. 4) Sub-effective dose of MK-801 (0.1mg/kg) was capable of reversing the beneficial effect of pioglitazone on retrieval of memory in scopolamine-treated mice, 5) Administration of NMDA (75mg/kg) and a sub-effective dose of pioglitazone (10mg/kg) reversed the effect of scopolamine and promoted memory retrieval. 6) MK-801 did not affect the consolidation phase of spatial recognition memory. 7) Pioglitazone did not affect scopolamine-induced impairment of memory consolidation. CONCLUSIONS: Sub-effective dose of MK-801 is capable of reversing the protective action of pioglitazone on scopolamine-induced impairment of memory retrieval. Additionally, co-administration of 75mg/kg NMDA and a sub-effective dose of pioglitazone potentiated the effect of pioglitazone on memory retrieval impaired by scopolamine. These results support the idea that pioglitazone plays its memory retrieval enhancement role through the glutamatergic pathway.

Suppression of memory acquisition following co-administration of lithium and atorvastatin through nitric oxide pathway in mice.

PURPOSE: The aim of this study was to investigate the interactive effect of lithium and atorvastatin on cognitive performance and the role of NO as a potential mechanism involved in this interaction. MATERIALS AND METHODS: Memory performance was evaluated in a two-trial recognition Y-maze test and a step-through passive avoidance task in mice. Lithium (5, 10, 20 or 40 mg/kg, i.p.) and atorvastatin (1 mg/kg, p.o.) were administered 1 h before each trial, L-NAME, a non-specific NO synthase inhibitor (3, 10 mg/kg, i.p.); aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor (100 mg/kg); and L-arginine, a NO precursor (750 mg/kg) were administered 30 min before training sessions. The level of plasma NO end-products (NOx) was determined using Griess reagent protocol. RESULTS: 1) Lithium (40 mg/kg) impaired the acquisition of spatial recognition memory; 2) lithium did not affect the retrieval phase of spatial memory; 3) atorvastatin (1 mg/kg) significantly impaired the memory performance, when co-administered with the sub-effective dose of lithium (10 mg/kg), but did not affect the status when administered with lithium (5 mg/kg); 4) L-NAME (10 mg/kg) and aminoguanidine (100 mg/kg) dramatically decreased memory performance in mice received sub-effective doses of both lithium (5 mg/kg) and atorvastatin (1 mg/kg); 5) L-arginine (750 mg/kg) improved the memory acquisition in mice administered lithium (10 mg/kg) and atorvastatin (1 mg/kg); 6) lithium did not affect the cognitive performance in the passive avoidance test. All results were compatible and confirmed with in vitro determination of plasma NOx levels. CONCLUSIONS: Lithium, dose dependently, impaired acquisition phase of spatial recognition memory. Lithium and atorvastatin co-administration impaired spatial recognition memory mediating by nitrergic pathway. In addition to L-arginine, our data from L-NAME and aminoguanidine also support the involvement of NO pathway in this interaction.