Carnosine, a precursor of histidine, ameliorates pentylenetetrazole-induced kindled seizures in rat

Carnosine (beta-alanyl-l-histidine) has been characterized as a putative neurotransmitter. However, so far, understanding of the role of carnosine in the brain is very limited. The objective of this study was to examine the effects of carnosine on the development of pentylenetetrazol (PTZ) kindling seizures and protection against the PTZ kindled seizures in rats. Chemical kindling was elicited by repeated intraperitoneal injection of PTZ (35 mg/kg) once every 48 h until the occurrence of Stage 4-5 seizures, and the seizure activity of kindling was recorded for 30 min. In an acute PTZ challenge study, 60 mg/kg PTZ was used to induce kindled seizure. Injection of carnosine (200, 500 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latencies for myoclonic jerks, in a dose- and time-dependent manner. In the seizure development process, 500 mg/kg carnosine also significantly delayed the onset of PTZ kindled seizures. In addition, carnosine significantly reversed decreased histamine levels induced by PTZ kindled seizure in the hippocampus. These results indicate that carnosine can protect against PTZ-induced seizures in both the development of kindling and the challenge process in rats. The results suggest that carnosine might be an endogenous anticonvulsant factor in the brain and can be used as a new antiepileptic drug in future.     

Effects of carnosine on amygdaloid-kindled seizures in Sprague-Dawley rats

The effects of carnosine (beta-alanyl-L-histidine) on amygdaloid-kindled seizures were investigated in rats. I.p. injection of carnosine (500, 1000, 1500 mg/kg, i.p.) significantly decreased seizure stage, afterdischarge duration and generalized seizure duration, and significantly prolonged generalized seizure latency of amygdaloid-kindled seizures, in a dose-dependent, and time-related manner. The protective effect of carnosine (1500 mg/kg) was completely antagonized by histamine H1-antagonists pyrilamine (2, 5 mg/kg, i.p.) and diphenhydramine (5, 10 mg/kg, i.p.), but not by histamine H2-antagonist zolantidine even at a high dose of 10 mg/kg. Carnosine (1500 mg/kg, i.p.) caused a significant increase of carnosine and histidine levels in the hypothalamus, thalamus, hippocampus, amygdala and cortex, as well as histamine levels in the hippocampus and amygdala. I.c.v. injection of alpha-fluoromethylhistidine (50 microg, i.c.v.), a selective and irreversible histidine decarboxylase inhibitor, only partially reversed the inhibition of amygdaloid-kindled seizures induced by carnosine. In addition, carnosine significantly decreased glutamate contents in the amygdala and hippocampus. These results indicate that carnosine could protect against amygdaloid-kindled seizures in rats, and its action may be due to the activation of histamine postsynaptic H1-receptors via two different mechanisms, one being carnosine's direct action, and the other being indirectly mediated by histaminergic pathway. The study suggests that carnosine may be an endogenous anticonvulsant factor in the brain and could be used as a new antiepileptic drug in the future.     

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.     

Morphine induces conditioned place preference behavior in histidine decarboxylase knockout mice

Pharmacological and lesion studies have shown that histamine exerts inhibitory effects on morphine-induced reward-seeking behavior. The present study was designed to further investigate the involvement of endogenous histamine in morphine-induced reward-seeking behavior using histidine decarboxylase gene knockout (HDC-KO) mice. Conditioned place preference (CPP) was present in both wild-type (WT) and HDC-KO mice treated with 5 or 10 mg/kg morphine. HDC-KO mice showed stronger morphine-induced CPP as compared with WT mice. Meanwhile, morphine significantly increased dopamine level in the VTA and NAc, especially in HDC-KO mice. However, the extinction of CPP is similar between WT and HDC-KO mice. Moreover, naloxone-precipitated withdrawal jumping was markedly decreased in HDC-KO mice. These results indicate that endogenous histamine inhibits the development, but not the extinction, of morphine-induced CPP and reduces morphine withdrawal sign, probably through modulating dopaminergic activity in the brain.     

The stimulatory effects of caffeine with oseltamivir (Tamiflu) on light–dark behavior and open-field behavior in mice

Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu^®) have emerged as a major issue in influenza patients taking the drug. Here, we investigated the mechanisms underlying the effects of oseltamivir on the behavior of mice using light–dark and open-field preference tests. Oseltamivir (75 and 150 mg/kg, intraperitoneally (i.p.)) alone affected neither time spent in the open area in the light–dark preference test nor ambulation in the open-field test at 2 h post-injection. However, a non-selective adenosine A₁/A₂ receptor antagonist, caffeine (10 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased time spent in the open area in the light–dark preference test. This enhancement was not inhibited by a benzodiazepine receptor antagonist, flumazenil (10–20 mg/kg, subcutaneously (s.c.)). Enhancement of ambulation in the open-field test was also observed when caffeine (10 mg/kg, i.p.) was combined with oseltamivir (150 mg/kg, i.p.). This enhancement was inhibited by a dopamine D₂ receptor antagonist, haloperidol (0.1 mg/kg, s.c.). Furthermore, an adenosine A₂ receptor antagonist, SCH58261 (3 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased ambulation in the open-field test, while an adenosine A₁ receptor antagonist, DPCPX (1–3 mg/kg, i.p.) did not. These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems. Our findings suggest that due to the interaction between central blockade of adenosine A₂ receptors by caffeine, and oseltamivir-induced behavioral changes, patients being treated with oseltamivir should be closely monitored.     

Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference

We have demonstrated previously that mice expressing a constitutive deletion of the kainate receptor subunit GluR5 (GluR5 KO) do not differ from wildtype (WT) littermates of a congenic C57BL/6 background with regard to both the development of morphine physical dependence as measured by naloxone-precipitated withdrawal signs and to morphine reward as revealed by the expression of conditioned place preference (CPP). However, unlike WT, GluR5 KO mice fail to develop antinociceptive tolerance following repeated systemic morphine administration. In this report, we examined the impact of GluR5 deletion on cocaine-mediated CPP and locomotor sensitization. Expression of CPP was evident in WT mice following repeated daily administration of 20 mg/kg (but not 10 mg/kg) i.p. cocaine. Interestingly, GluR5 KO mice exhibited enhanced cocaine preference as compared with WT mice at both 10 and 20 mg/kg doses. In addition, while GluR5 KO mice did not differ from WT with respect to baseline locomotor activity, mutant mice demonstrated increased locomotor hyperactivity versus WT mice after repeated injection of 15 mg/kg i.p. cocaine. Collectively, these data indicate that GluR5 appears to negatively modulate some psychostimulant and rewarding properties of cocaine, as demonstrated by heightened sensitization and salience in mutant mice.     

Effect of systemic administration of adenosine on brain adenosine levels in pentylenetetrazol-induced seizure threshold in mice

Adenosine is one of the inhibitory neuromodulators in the brain. The present study was carried out to elucidate the effect of adenosine on the pentylenetetrazol (PTZ)-induced seizure threshold in mice. Further, the study also correlated the brain adenosine levels in PTZ-induced seizure threshold. PTZ (0.5%, w/v) was infused through lateral tail vein of mouse at a constant rate of 0.3 ml/min until various stages of convulsions were observed. Minimal dose of PTZ (mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extensor) of PTZ convulsions were noted as an index of seizure threshold. Intravenous infusion of PTZ resulted in a significant decrease in brain adenosine levels. Systemic administration of adenosine (100 and 200 mg/kg, i.p.), 30 min before PTZ infusion, produced a dose-dependent elevation of PTZ-seizure threshold and also enhanced brain adenosine levels as compared to vehicle treated group. The behavioral and neurochemical observations demonstrated a relationship between adenosine levels in the brain and the PTZ seizure threshold in mice.     

Palmitone prevents pentylenetetrazole-caused neuronal damage in the CA3 hippocampal region of prepubertal rats

Palmitone is a secondary metabolite of polyketide origin extracted from leaves of Annona diversifolia Saff. (Annonaceae). We found that palmitone possesses anticonvulsant properties against penicillin-, 4-AP-, and pentylenetetrazole (PTZ)-caused seizure in adult animals. Some convulsants as PTZ cause neuronal damage in different brain regions such as the CA3 hippocampal region. Our objective was to evaluate if palmitone protects against PTZ-caused seizures and hippocampal neuronal damage in prepubertal rats. We used 32 prepubertal Wistar rats (30–35 days old) divided into four groups of 8 animals; group I was the control group, group II received a single PTZ dose of 50 mg/kg ip, group III received a single palmitone dose of 50 mg/kg ip, and group IV received a palmitone dose of 50 mg/kg ip plus a PTZ dose of 50 mg/kg ip. Ten days after administration, the animals were killed using pentobarbital anesthesia (35 mg/kg). The brains were removed and were embedded in paraffin. Coronal cuts of 7 μm were obtained from −2.8 to −3.3 from Bregma. Each section was stained with cresyl violet-eosin. We evaluated the number of normal and abnormal neurons in the CA3 hippocampal region in a 10,000 μm² section. It was observed that palmitone did not prevent the PTZ-caused seizure but palmitone prevents the PTZ-caused neuronal damage in the CA3 hippocampal region.     

Posttraining administration of pentylenetetrazol dissociates gabapentin effects on memory consolidation from that on memory retrieval process in mice

Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced retention of an inhibitory avoidance task when given 20 min after training, as indicated by retention performance 48 h later. The immediate post-training administration of pentylenetetrazol (PTZ, 45 mg/kg, i.p.) impaired retention performance. The amnesic effects of the convulsant drug PTZ were not influenced by GBP at any level of doses. However, GBP 100 mg/kg, but not 10 mg/kg, delayed the latency to first clonic body seizures and decreased the duration of convulsion induced by PTZ. The enhancing effect of GBP on retention was not prevented by the opiate receptor antagonist, naltrexone (0.01 mg/kg, i.p.), which completely prevented the impairment of retention caused by PTZ. Further, naltrexone did not modify the convulsions induced by PTZ. In mice pretreated with naltrexone and that received PTZ, the administration of GBP again, enhanced retention performance during the retention test. Since previous results indicate that the amnesic action of PTZ are due to an effect on memory retrieval, the present results provide additional pharmacological evidence suggesting that GBP influenced memory consolidation and not memory retrieval of an inhibitory avoidance task in mice.     

Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100 mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50 mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a serotonin 5-HT_1A receptor antagonist), cyproheptadine (3 mg/kg, i.p., a serotonin 5-HT₂ receptor antagonist), prazosin (62.5 μg/kg, i.p., an α₁-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist) or propranolol (5 mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression.     

Paradoxical facilitation of pentylenetetrazole-induced convulsion susceptibility in mice lacking neuronal nitric oxide synthase

The major aim of this study was to elucidate the relationship between nitric oxide (NO) and generalized epilepsy. Mice lacking the neuronal nitric oxide synthase (nNOS) gene (nNOS^−/−) were used in this study to determine the relationship between nNOS α and NO in pentylentetrazole (PTZ)-induced convulsions. nNOS^−/− mice exhibited severe convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg i.p.) and convulsive doses were lethal in all of the mice (60 mg/kg i.p.) following tonic convulsions.     

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.     

Effects of the fruit essential oil of Cuminum cyminum Linn. (Apiaceae) on acquisition and expression of morphine tolerance and dependence in mice

The problem of morphine tolerance and dependence is a universal phenomenon threatening social health everywhere the world. The major objective of this paper was to investigate the effects of fruit essential oil (FEO) of Cuminum cyminum on acquisition and expression of morphine tolerance and dependence in mice. Animals were rendered dependent on morphine using the well-established method in which was morphine (50, 50, 75 mg/kg; s.c.) injected three times daily for 3 days. In experimental groups, administration of FEO (0.001, 0.01, 0.1, 0.5, 1 and 2%; 5 ml/kg; i.p.) or Tween-80 (5 ml/kg; i.p.) was performed 60 min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by tail-flick before and after administration of a single dose of morphine (50 mg/kg; s.c.) in test day (4th day). Morphine dependence was also evaluated by counting the number of jumps after injection of naloxone (5 mg/kg; i.p.) on the test day. The results showed that Cumin FEO, only at the dose of 2%, significantly attenuated the development of morphine tolerance (P < 0.01) and dependence (P < 0.05) while it could be significantly effective on expression of morphine tolerance (1 and 2%) and dependence (0.5, 1 and 2%) in a dose-dependent manner. Solely Cumin FEO injection (0.001–2%) did not show any analgesic effect. In conclusion, the essential oil of Cuminum cyminum seems to ameliorate the morphine tolerance and dependence in mice.     

Therapeutic potential of α2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders

We examined the effects of JP-1302 (a selective α_2C antagonist), BRL-44408 (a selective α_2A antagonist) and yohimbine (a non-selective α₂ antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of α₂ adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1–1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center–perimeter residence time in the open-field test. BRL-44408 (1–10 mg/kg, s.c.) and yohimbine (0.3–3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with α_2A antagonism. The present study shows for the first time that blockade of α_2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.     

The evaluation of effects of lipoic acid on the lipid peroxidation,nitrite formation and antioxidant enzymes in the hippocampus of rats after pilocarpine-induced seizures

It has been suggested that pilocarpine-induced seizures is mediated by increases in oxidative stress. Current researches have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures in cellular level. The objective of the present study was to evaluate the neuroprotective effects of lipoic acid (LA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 6 h. 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 and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite level. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the superoxide dismutase and catalase activities in hippocampus of rats after seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that strong protective effect could be achieved using lipoic acid as an antioxidant.     

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.     

Anticonvulsant effect of celecoxib on pentylenetetrazole-induced convulsion: Modulation by NO pathway

This study aimed to examine whether celecoxib influences clonic seizure thresholds through modulation of nitric oxidergic (NO) pathway. The effect of celecoxib (1-5 mg per kg, p.o.) was investigated on clonic seizures induced by pentylenetetrazole (PTZ, 50 and 80 mg per kg, i.p.) in male Swiss mice. The interaction of celecoxib-induced effects with NO pathway was examined using a NO synthase (NOS) inhibitor, N(G)-omega-nitro-L-arginine methyl ester (L-NAME, 20 and 50 mg per kg, i.p.) and a NOS substrate, L-arginine (100 and 200 mg per kg, i.p.). The criteria for the development of seizure activity were the possibility for appearance of generalized clonus and prolongation of latency to the onset of convulsions following administration of 50 and 80 mg per kg of PTZ, respectively. Pretreatment with celecoxib (2.5 and 5 mg per kg) or L-NAME (50 mg per kg) induced anticonvulsant effect on the PTZ-induced clonic seizures. L-arginine at the dose of 200 mg per kg had proconvulsant effect. A sub-effective dose of celecoxib (1 mg per kg) induced an additive anticonvulsant effect when co-administered with L-NAME (20 mg per kg). Although L-arginine (100 mg per kg) per se did not influence PTZ-induced convulsion, it could attenuate the anticonvulsant effect of celecoxib (5 mg per kg). Our results indicate that celecoxib induces an anticonvulsant effect on clonic seizure threshold that may involve NO pathway.     

Central 5-HT3 receptor-induced hypothermia in mice: Interstrain differences and comparison with hypothermia mediated via 5-HT1A receptor

The selective agonist of serotonin 5-HT₃ receptor 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) administered intracerebroventricularly (40, 80 or 160 nmol) produced long-lasting dose-dependent hypothermic response in AKR/2J mice. m-CPBG (160 nmol i.c.v.) induced profound hypothermia (delta t = −4 °C) that lasted up to 7 h. m-CPBG (40 nmol i.c.v.)-induced hypothermia was attenuated by 5-HT₃ receptor antagonist ondansetron pretreatment. At the same time, intraperitoneal administration of m-CPBG in a wide range of doses (0.5, 1.0, 5.0 or 10.0 mg/kg) did not affect the body temperature. These findings indicate: (1) the implication of central, rather than peripheral 5-HT₃ receptor in the thermoregulation; (2) the inability of m-CPBG to cross blood–brain barrier in mice. The comparison of brain 5-HT₃-induced hypothermic reaction in six inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J) was performed and two highly sensitive to m-CPBG strains (CBA/Lac and C57BL/6) were found. In the same six mouse strains the functional activity of 5-HT_1A receptor was studied. The comparison of hypothermic reactions produced by 5-HT_1A receptor agonist 8-OH-DPAT (1.0 mg/kg i.p.) and m-CPBG revealed significant correlation between 5-HT₃ and 5-HT_1A-induced hypothermia in five out of six investigated mouse strains. 5-HT_1A receptor antagonist p-MPPI pretreatment (1 mg/kg i.p.) diminished hypothermia produced by centrally administered m-CPBG (40 nmol i.c.v.). The data suggest the cross-talk between 5-HT_1A and 5-HT₃ receptors in the mechanism of 5-HT-related hypothermia.     

Carnosine ameliorates morphine-induced conditioned place preference in rats

The histidine-containing dipeptide, carnosine (β-alanyl-l-histidine), is present in high concentrations in mammalian brain of mammals. There are many theories about its biological functions, such as anti-inflammatory agent, free radical scavenger, and protein glycosylation inhibitor, however, the role of carnosine in morphine addiction is less understood. Therefore, the objectives of this study were to determine the effects of carnosine on the development of morphine-induced conditioned place preference (CPP) and investigate its possible mechanism of action in Sprague-Dawley rats. Intraperitioneal (i.p.) injection of carnosine (200, 500, 1000 mg/kg) significantly inhibited the development of morphine-induced CPP in a dose-dependent manner. Although carnosine had no appreciable effect on the levels of histamine in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), it significantly decreased glutamate level in the VTA, dopamine levels in the NAc and PFC, and DOPAC level in the NAc of morphine-treated rats. These results indicate that carnosine inhibits morphine-induced CPP in rats, and its action may be due to modulation of dopaminergic and glutaminergic activity. The study suggests that carnosine has potential as a new anti-addictive drug.     

Protective effect of stilbenes containing extract-fraction from Cajanus cajan L. on Aβ25–35-induced cognitive deficits in mice

Cajanus cajan (L.) is a traditional Chinese herb medicine which contains a lot of potential active components. In the present study, we identified the effects of the stilbenes containing extract-fraction from C. cajan L. (sECC) on Aβ_25–35-induced cognitive deficits, oxidative stress and cholinergic dysfunction in mice. Mice were treated with sECC (100 and 200 mg/kg/d) for 1-week, and then received a single intracerebroventricular (i.c.v.) injection of Aβ_25–35 (5 μg/mice). Behavioral changes and neuron apoptosis in mice were evaluated using Morris water maze and TUNEL tests. Furthermore, superoxide dismutase (SOD), choline acetyl transferase (ChAT) and acetylcholine esterase (AchE) activity in hippocampus and cortex were analyzed by spectrophotometric method. The data showed that consumption of sECC (200 mg/kg) significantly ameliorated the cognitive deficits and neuron apoptosis caused by i.c.v. injection of Aβ_25–35. At the same time, the decreased SOD and ChAT activity in hippocampus and cortex were markedly increased by sECC (200 mg/kg). sECC has no effect on AchE activity in hippocampus and cortex. These findings suggest that sECC may be a potential candidate for the development of therapeutic agents to manage cognitive impairment associated with Alzheimer's disease (AD) through increasing the activity of ChAT and anti-oxidative mechanism.