Lipoic acid effects on lipid peroxidation level,superoxide dismutase activity and monoamines concentration in rat hippocampus

The purposes of the present work were to verify lipid peroxidation level, superoxide dismutase (SOD) activity and monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9% saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. In LA20 group only there was a significant decrease in lipid peroxidation level. However, no alteration was observed in SOD activity in groups treated with LA. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, DOPAC and HVA levels did not show any significant change. The reduction in lipid peroxidation level and alterations in hippocampal monoamines can be suggested as a possible brain mechanism from this antioxidant. The outcome of the study may have therapeutic implications in the neurodegenerative diseases.     

Vitamin C antioxidant effects in hippocampus of adult Wistar rats after seizures and status epilepticus induced by pilocarpine

Vitamin C (VIT C) is an exogenous antioxidant able to alter the brain oxidative stress. Antioxidant properties have been showed in seizures and status epilepticus (SE) induced by pilocarpine in adult rats. This present study was aimed at was investigating the VIT C effects on latency to first seizure, in percentage of seizures, mortality rate, as well as hippocampal lipid peroxidation levels and catalase activity after seizures and SE. The VIT C effects were investigated after the pretreatment with dose 250mg/kg, i.p., 30min before pilocarpine administration (400mg/kg, s.c., pilocarpine group (P400)). The VIT C increase the latency to first seizure and decrease the mortality rate and lipid peroxidation levels. In P400+VIT C and VIT C groups were observed an increase in hippocampal catalase activity. Our results suggests that the vitamin C can exert antioxidant and anticonvulsive effects in adult rats, suggesting that this vitamin can be able by reduction of lipid peroxidation content and increased of catalase enzymatic activity which cerebral compensatory mechanisms in free radical formation during SE.     

Investigation of oxidative stress involvement in hippocampus in epilepsy model induced by pilocarpine

The relationship between free radical and scavenger enzymes has been found in the epileptic phenomena and reactive oxygen species have been implicated in seizure-induced neurodegeneration. Using the epilepsy model obtained by systemic administration of pilocarpine in rats, we investigated the lipid peroxidation, nitrite content, superoxide dismutase (SOD) and catalase activities in the hippocampus of rats during chronic period. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline-treated animals. The superoxide dismutase and catalase activities increased during the chronic phase. In addition, lipid peroxidation and nitrite levels increased in same period in the hippocampus of animals observed during spontaneous recurrent seizures. Previous studies showed that animals presenting seizures and submitted to 24 h of status epilepticus showed normal levels of superoxide dismutase and increased in catalase activities as well as an increase in hippocampal lipid peroxidation and nitrite concentrations. These results show a direct evidence of lipid peroxidation and nitrite during seizure activity that could be responsible for neuronal damage in the hippocampus of rats, during the establishment of pilocarpine model of epilepsy.     

Choline acetyltransferase and acetylcholinesterase activities are reduced in rat striatum and frontal cortex after pilocarpine-induced seizures

In the present study we investigated the alterations on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in rat striatum and frontal cortex caused by pilocarpine-induced seizures. Wistar rats were treated with 0.9% saline (i.p., control group), with the association of 0.9% saline (i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of saline (pilocarpine group). After the treatments all groups were observed for 1 h. The ChAT and AChE activities were measured using spectrophotometric methods and the results compared to values obtained from saline-treated animals. In pilocarpine group was observed a significantly decreases in ChAT and AChE activities in striatum and frontal cortex of adult rats, when compared to control group. Results showed that during acute phase of seizures striatal and frontal cortex ChAT and AChE activities are diminished. Our findings suggest that seizures caused cognitive dysfunction and decreases of ChAT and AChE activities that might be related, at least in part, to the neurological problems presented by epileptic patients.     

Anticonvulsant effect of phytol in a pilocarpine model in mice

The present study investigated the effects of phytol in pilocarpine-induced seizures. The latency for development of convulsions and mortality rate was recorded in this model using mice. The results revealed that phytol (25, 50 and 75 mg/kg, i.p.) increased latency to first seizure and decreased percentage of these seizures. Moreover, phytol also protected the animals against status epilepticus induced by pilocarpine, and decreased the mortality rate. Mice treated with pilocarpine (n = 24) presented 100% of mortality during the first hour of observation. In turn, phytol-pretreated animals within 30 min before the administration of pilocarpine (400 mg/kg) remained alive during the first hour of observation. On the other hand, 6–8 h after administration of pilocarpine it was observed that 10 (41.66%), 8 (33.33%) and 4 (16.66%) animals died (respectively). Thus, the pretreatment with phytol was able to block mortality rate during the first hour in acute phase of seizures, and significantly reduced this rate in a dose-dependent manner (p < 0.05), suggesting an anticonvulsant effect. In addition, none of the phytol effects was blocked by pre-treatment with flumazenil, an antagonist of benzodiazepine receptors. In conclusion, phytol exhibits anticonvulsant activity by modulating of neurotransmitter systems, but further investigations are in progress to confirm this pharmacological property.     

Lipoic acid effects on monoaminergic system after pilocarpine-induced seizures

Systemic injection of pilocarpine has been shown to induce recurrent seizures and epileptic discharges demonstrated by EEG monitoring. It also has been reported that antioxidants are able to diminish or prevent the occurrence of epileptic discharges induced by pilocarpine through the inhibition of free radical formation and neurotransmitter metabolic alterations. The purpose of this work was to determine the effects of lipoic acid (LA) on the levels of dopamine (DA), serotonin (5-HT), norepinephrine (NE) and subsequent metabolites in the hippocampus of rats after seizure induction by pilocarpine. Seizures dramatically decreased the levels of DA, 5-hydroxyindoleacetic acid (5-HIAA) and NE, whereas significantly increased the levels of neurotransmitter metabolites. The administration of lipoic acid before seizure induction resulted in normalized levels of DA and 5-HA. However, the lipoic acid administration in similar conditions produced a reduction of the metabolites levels when compared with the pilocarpine group. These results suggest that the establishment of acute phase of seizures induced by pilocarpine might be produced by consequent the activation of serotonergic neurons. In addition, the lipoic acid inhibits hyperactivity of this system during the installation of pilocarpine-induced seizures.     

The role of epidermal growth factor in prevention of oxidative injury and apoptosis induced by intestinal ischemia/reperfusion in rats

Intestinal ischemia/reperfusion is a major problem which may lead to multiorgan failure and death. The aim of the study was to evaluate the effects of epidermal growth factor (EGF) on apoptosis, cell proliferation, oxidative stress and the antioxidant system in intestinal injury induced by ischemia/reperfusion in rats and to determine if EGF can ameliorate these toxic effects. Intestinal ischemia/reperfusion injury was produced by causing complete occlusion of the superior mesenteric artery for 60 min followed by a 60-min reperfusion period. Animals received intraperitoneal injections of 150 μg/kg human recombinant EGF 30 min prior to the mesenteric ischemia/reperfusion. Mesenteric ischemia/reperfusion caused degeneration of the intestinal mucosa, inhibition of cell proliferation, stimulation of apoptosis and oxidative stress in the small intestine of rats. In the ischemia/reperfusion group, lipid peroxidation was stimulated accompanied by increased intestinal catalase and glutathione peroxidase activities, however, glutathione levels and superoxide dismutase activities were markedly decreased. EGF treatment to rats with ischemia/reperfusion prevented the ischemia/reperfusion-induced oxidative injury by reducing apoptosis and lipid peroxidation, and by increasing antioxidant enzyme activities. These results demonstrate that EGF has beneficial antiapoptotic and antioxidant effects on intestinal injury induced by ischemia/reperfusion in rats.     

Pharmacological studies of the opioids, mood stabilizer and dopaminergic drugs on pilocarpine-induced seizures and status epilepticus

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Morphine (0.1 and 0.2 mg/kg), SCH 23390 (0.1 and 0.2 mg/kg), haloperidol (5 and 10mg/kg) and lithium (30 and 60 mg/kg) were administered intraperitoneally (i.p.), 30 min before to pilocarpine (400 mg/kg, s.c.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. Morphine and haloperidol had proconvulsant effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures, SE and/or mortality. SCH 23390 protected against seizures, increased the latency to first seizure and reduced the mortality of the animals treated with pilocarpine Theses results suggest that dopamine receptor system receptor subtypes exert opposite functions on the regulation of convulsive activity. The morphine is proconvulsant in lower doses. The opioids in high doses tested exert an action proconvulsant during the establishment of epileptic activity induce by pilocarpine. The lithium no protected the animals against seizures induced by pilocarpine and is used which a model of epilepsy associated with lower doses of pilocarpine in several studies, suggesting absence of the effect anticonvulsants in rodents.     

Carnosine inhibits pentylenetetrazol-induced seizures by histaminergic mechanisms in histidine decarboxylase knock-out mice

In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1 h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that α-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine–histidine–histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.     

Study pharmacologic of the GABAergic and glutamatergic drugs on seizures and status epilepticus induced by pilocarpine in adult Wistar rats

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.     

Subcortical morphological correlates of impaired clock drawing performance

The present study investigates the neurological protective effects of edaravone against global brain ischemia. Gerbils were treated with edaravone (3 mg/kg; i.p.) 30 min before transient forebrain ischemia, which was induced by occluding the bilateral common carotid artery for 5 min. The effects of edaravone were examined by measuring neuronal damage and behavioral deficits. Hexanoyl-lysine adduct (HEL) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), oxidative stress markers, were also examined to assess the anti-oxidative effects of edaravone. Edaravone treatment significantly inhibited both lipid and DNA oxidative damage 72 h after ischemia, and decreased neuronal damage. Edaravone also significantly reduced the locomotor activity deficit 72 h after ischemia and improved memory impairment. These findings suggest that edaravone inhibits oxidative stress and attenuates neuronal damage induced by transient forebrain ischemia in gerbils and which may contribute to improvements in behavioral deficits.     

Cardioprotective effect of Sida rhomboidea. Roxb extract against isoproterenol induced myocardial necrosis in rats

The present study investigates cardioprotective effect of Sida rhomboidea. Roxb (SR) extract on heart weight, plasma lipid profile, plasma marker enzymes, lipid peroxidation, endogenous enzymatic and non-enzymatic antioxidants and membrane bound ATPases against isoproterenol (IP) induced myocardial necrosis (MN) in rats. Rats treated with IP (85 mg/kg, s.c.) recorded significant (p<0.05) increment in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation (LPO) and activity levels of Ca⁺² ATPase whereas there was significant (p<0.05) decrease in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na⁺-K⁺ ATPase and Mg⁺² ATPase. Pre-treatment with SR extract (400 mg/kg per day, p.o.) for 30 consecutive days followed by IP injections on days 29th and 30th, showed significant (p<0.05) decrease in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation, Ca⁺² ATPase and significant increase in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na⁺-K⁺ ATPase and Mg⁺² ATPase compared to IP treated group. Hence, this study is the first scientific report on cardioprotective effect of SR against IP induced MN in rats.     

Edaravone,a free radical scavenger,retards the development of amygdala kindling in rats

This study evaluated the antiepileptogenic effects of edaravone, a newly developed radical scavenger, on the amygdala kindling rats. The afterdischarge duration (ADD), AD threshold (ADT), and seizure severity in animals were measured to study the anticonvulsant effects of edaravone (2 mg/kg or 20 mg/kg i.p. for 7 days) on fully kindled seizures. Furthermore, for the study of antiepileptogenesis effects of the drug (2 mg/kg or 20 mg/kg i.p. for 7 days), not only ADD and seizure severity during kindling but also both the pre- and post-kindling ADT were measured. Edaravone neither induces nor inhibits fully kindled seizures regardless of the dose; however high-dose edaravone (20 mg/kg) retarded kindling development together with shortened ADD and elevated ADT. The present data suggest that high-dose edaravone has an antiepileptogenic drug effect for the prevention of epilepsy. However, other chronic models and clinical trials are needed to confirm the effects of edaravone on the prevention of human epilepsy.     

Further antinociceptive effects of myricitrin in chemical models of overt nociception in mice

The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10–100 mg/kg, i.p.) with ID₅₀ of 12.4 (8.5–18.1) mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E₂ (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100 mg/kg, i.p.) and camphor (7.6 mg/kg, s.c.) in 43 ± 10% and 57 ± 8%, respectively. Myricitrin (30–100 mg/kg, i.p.) and amiloride (100 mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID₅₀ of 22.0 (16.1–30.0) mg/kg and inhibition of 71 ± 6% and 64 ± 5%, respectively. Moreover, myricitrin (10–30 mg/kg, i.p.) and ruthenium red (3 mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 μmol/paw i.pl.) with the mean ID₅₀ of 2.4 (1.5–3.7) mg/kg and inhibition of 95 ± 3% and 51 ± 7%, respectively. In addition, myricitrin administration (30 and 100 mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100 mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs.     

A novel animal model to evaluate the ability of a drug delivery system to promote the passage through the BBB

The purpose of this investigation was to explore the potentiality of a novel animal model to be used for the in vivo evaluation of the ability of a drug delivery system to promote the passage through the blood–brain barrier (BBB) and/or to improve the brain localization of a bioactive compound. A Tween 80^®-coated poly-l-lactid acid nanoparticles was used as a model of colloidal drug delivery system, able to trespass the BBB. Tacrine, administered in LiCl pre-treated rats, induces electrocorticographic seizures and delayed hippocampal damage. The toxic effects of tacrine-loaded poly-l-lactid acid nanoparticles (5 mg/kg), a saline solution of tacrine (5 mg/kg) and an empty colloidal nanoparticle suspension were compared following i.p. administration in LiCl-pre-treated Wistar rats. All the animals treated with tacrine-loaded nanoparticles showed an earlier outcome of CNS adverse symptoms, i.e. epileptic onset, with respect to those animals treated with the free compound (10 min vs. 22 min respectively). In addition, tacrine-loaded nanoparticles administration induced damage of neuronal cells in CA1 field of the hippocampus in all treated animals, while the saline solution of tacrine only in 60% of animals. Empty nanoparticles provided similar results to control (saline-treated) group of animals. In conclusion, the evaluation of time-to-onset of symptoms and the severity of neurodegenerative processes induced by the tacrine–lithium model of epilepsy in the rat, could be used to evaluate preliminarily the capability of a drug delivery system to trespass (or not) the BBB in vivo.     

Effects on antioxidant status of liver following atrazine exposure and its attenuation by vitamin E

In the present investigation, the effect of atrazine on antioxidant enzymes and body weight was studied in male Wistar rats. Atrazine (300 mg/kg bw) was administered by gavage for 7, 14 and 21 days. A significant increase in hepatic lipid peroxidation (LPO) was observed following atrazine administration. Vitamin E treatment (100 mg/kg bw), on the otherhand, attenuated atrazine-induced LPO in liver. In addition, vitamin E treatment restored the GSH content and glucose-6-phosophate dehydrogenase activity that was found to be lowered after atrazine administration. The activities of antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase were significantly increased following atrazine administration and vitamin E treatment could restore these activities. In conclusion, the results of the study demonstrate that atrazine induces oxidative stress in terms of enhanced lipid peroxidation. However, vitamin E treatment ameliorated the effects of atrazine suggesting it as potential antioxidant against atrazine-induced oxidative stress.     

Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: effects of intranigral 2-amino-7-phosphonoheptanoate and N-methyl-D-aspartate

Seizures produced by pilocarpine given i.p. to rats provide an animal model for studying the initiation, spread and generalisation of convulsive activity within the forebrain. Pilocarpine, 380 mg/kg, produces a sequence of behavioural and electroencephalographic alterations indicative of motor limbic seizures and status epilepticus, which is followed by widespread damage to the limbic forebrain resembling that occurring subsequent to prolonged intractable seizures. Microinjections of a selective antagonist at the N-methyl-D-aspartate receptor, (+/-)-2-amino-7-phosphonoheptanoate, into the substantia nigra pars reticulata, bilaterally, protects against the behavioural, electrographic and morphological features of seizures produced by pilocarpine, 380 mg/kg, with an ED50 of 0.0007 mumol (0.0004-0.0011). Microinjections of (+/-)-2-amino-7-phosphonoheptanoate, 0.005 or 0.01 mumol, into the substantia nigra pars compacta or into the dorsal part of mid-anterior striatum do not modify the electrographic and morphological sequelae of pilocarpine, 380 mg/kg. In rats pretreated with microinjections of N-methyl-D-aspartate into the substantia nigra pars reticulata, a non-convulsive dose of pilocarpine, 100 mg/kg, results in recurrent motor limbic seizures and status epilepticus. The ED50 of N-methyl-D-aspartate for the generation of seizures after pilocarpine, 100 mg/kg, is 0.0014 mumol (0.001-0.0019). Electrographic monitoring shows a pattern and sequence of evolution of convulsant activity within the hippocampus and cortex similar to that produced with pilocarpine, 380 mg/kg, alone. Morphological examination of brains from rats treated with N-methyl-D-aspartate in the substantia nigra pars reticulata and subsequently given pilocarpine, 100 mg/kg, which underwent status epilepticus, reveals widespread damage to the amygdala, thalamus, olfactory cortex, substantia nigra, neocortex, and hippocampus. Microinjections of N-methyl-D-aspartate, 0.002 mumol, into either the substantia nigra pars compacta or dorsal striatum, bilaterally, do not augment seizures produced by pilocarpine, 100 mg/kg. The results indicate that the threshold for pilocarpine-induced seizures in rats is modulated by excitatory amino acid neurotransmission within the substantia nigra pars reticulata.     

The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming

The interaction between dopaminergic and cholinergic pathways in the induction of behavioral responses has been previously established. In the brain, M2 receptors are found predominantly in presynaptic cholinergic neurons as autoreceptors, and in dopaminergic neurons as heteroceptors, suggesting a control role of acetylcholine and dopamine release, respectively. Our aim was to investigate the role of M2 receptors on the yawning and genital grooming of rats induced by apomorphine, a dopaminergic receptor agonist, focusing on the interaction between cholinergic and dopaminergic pathways. Initially, the effect of atropine, a non-selective muscarinic antagonist, on yawning and genital grooming induced by apomorphine (100 μg/kg s.c.) was analyzed. Atropine doses of 0.5, 1 and 2 mg/kg i.p. were administered to Wistar rats 30 min before induction of the behavioral responses by apomorphine. Number of yawns and time spent genital grooming were quantified over a 60 min period. Apomorphine-induced yawning was increased by low dose (0.5 mg/kg i.p.) but not by high doses (1 and 2 mg/kg, i.p.) of atropine. Genital grooming was antagonized by 2 mg/kg i.p. of atropine and showed no changes at the other doses tested. Tripitramine, a selective M2 cholinergic antagonist, was used as a tool for distinguishing between M2 and all other muscarinic receptor subtypes in yawning and genital grooming. Tripitramine doses of 0.01, 0.02 and 0.04 μmol/kg i.p. were administered to Wistar rats 30 min before apomorphine (100 μg/kg s.c.). Number of yawns and time spent genital grooming were also quantified over a 60 min period. Tripitramine 0.01 μmol/kg increased all parameters. Higher doses, which possibly block all subtypes of muscarinic receptor, did not modify the response of apomorphine, suggesting a non-selective effect of tripitramine at these doses. Given that low doses of tripitramine increased the behavioral responses induced by apomorphine and that the main distribution of the M2 receptor is presynaptic, we raised the hypothesis that tripitramine may alter cholinergic and/or dopaminergic transmission in brain areas responsible for induction of yawning and genital grooming in rats, possibly by control of acetylcholine and/or dopamine release. In addition, the present study showed the involvement of M2 cholinergic receptors in the complex mechanisms of functional interactions between dopaminergic and cholinergic systems involved in the control of yawning and genital grooming.     

The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food

The assumption of a novel high palatable food (a candied cherry) occurs concomitantly with an increase in the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) by about 45% in the dialysate obtained by intracerebral microdialysis from the shell of the nucleus accumbens of male rats. Such increase was reversed by SR 141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist (0.3 mg/kg i.p. and 1 mg/kg i.p.), which also reduces the assumption of the high palatable food, when given 15 min before exposure to the candied cherry. SR 141716A effects on extracellular dopamine and DOPAC were prevented by WIN 55,212-2 (0.3 mg/kg i.p.) or HU 210 (0.1 mg/kg i.p.) given 15 min before SR 141716A. The present results show for the first time that SR 141716A reduces the increase in extra-cellular dopamine induced by a novel high palatable food in the nucleus accumbens. This confirms that cannabinoid CB1 receptors play a key role in food intake and/or appetite and suggests that the mesolimbic dopaminergic system is involved at least in part, in the effects of cannabinoid receptor agonists and antagonists on food intake and/or appetite.     

Involvement of nitric oxide system in enhancement of morphine-induced conditioned place preference by agmatine in male mice

Agmatine recently has been suggested as a neurotransmitter, is able to interact with various effects of morphine like analgesia and dependence. In this study, the effects of agmatine on rewarding properties of morphine, and the possible involvement of nitric oxide (NO) system has been evaluated in an unbiased conditioned place preference (CPP) paradigm. Agmatine (1, 5 and 10 mg/kg, i.p.) alone induced neither CPP nor conditioned place aversion (CPA). Morphine (0.01, 0.05, 0.1 and 0.5 mg/kg, s.c.), while unable to show CPP or CPA, induced CPP in mice pretreated with agmatine. L-arginine (200 mg/kg, i.p.), a NO precursor, significantly enhanced the effect of agmatine (5 mg/kg) on morphine (0.5 mg/kg)-induced place preference. N^G-nitro-l-arginine methyl ester (l-NAME; 2.5 mg/kg, i.p.), a non specific nitric oxide synthase (NOS) inhibitor, and aminoguanidine (50 and 100 mg/kg, i.p.), a specific inducible NOS inhibitor, significantly reduced the effect of agmatine (5 mg/kg) on morphine (0.5 mg/kg)-induced place preference. These results suggest the possible involvement of inducible nitric oxide system in potentiating effects of agmatine on morphine-induced place preference.