Role of nitric oxide in the acquisition and expression of apomorphine- or morphine-induced locomotor sensitization

In the present study, the effects of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on apomorphine- or morphine-induced locomotor sensitization in male albino mice were investigated. Our data showed that subcutaneous (s.c.) injection of apomorphine (2-10 mg/kg) or morphine sulphate (5-50 mg/kg) significantly increased locomotor behaviour in a dose-dependent manner. Intraperitoneal (i.p.) administration of L-arginine (100 mg/kg) increased locomotor activity, whereas L-NAME (20 mg/kg) decreased it. L-Arginine and L-NAME increased and decreased apomorphine- or morphine-induced locomotions, respectively. The locomotor behavioural response was enhanced in mice pretreated with apomorphine (2 mg/kg, daily x3 days) or morphine (10 mg/kg, daily x3 days) alone, indicating that sensitization had developed. Administration of L-arginine 30 min before each of three daily doses of apomorphine or morphine increased the development of sensitization, while administration of L-NAME 30 min before each of three daily doses of apomorphine or morphine decreased the acquisition of sensitization induced by apomorphine or morphine. Administration of L-arginine significantly increased and L-NAME significantly and dose-dependently decreased the expression of both apomorphine- and morphine-induced sensitization. The results indicate that NO may be involved in the acquisition and expression of apomorphine- or morphine-induced sensitization.     

Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats

The present study investigated the effect of morphine sensitization on the impairment of spatial memory retrieval induced by acute morphine in adult male rats. Spatial memory was assessed by 2-day Morris water maze task which included training and test day. On the training day, rats were trained by a single training session of 8 trials. On the test day, a probe trial consisting of 60s free swim period without a platform and the visible test were administered. Morphine sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days without drug treatment before training. The results indicated that acute administration of morphine (7.5mg/kg, s.c.) before testing impaired spatial memory on the test day. Pre-test morphine-induced amnesia decreased in morphine-sensitized (15 and 20mg/kg, s.c.) rats. Improvement in spatial memory retrieval in morphine-sensitized rats was inhibited by once daily administration of naloxone (1 and 2mg/kg, s.c.) 30 min prior to the injection of morphine for three days. The results suggest that morphine sensitization reverses the impairment of spatial memory retrieval induced by acute morphine and it is implied that mu-opioid receptors may play an important role in this effect.     

Effects of nitric oxide on morphine self-administration in rat

Previous studies have reported that morphine exerts its effects in part through the release of nitric oxide (NO). In the present study, the effects of acute and chronic administration of the NO precursor, L-arginine and NO synthase (NOS) inhibitor, L-nitro-amino-methyl-ester (L-NAME) on morphine self-administration in rats were investigated. The animals were initially trained to press a lever using food as reinforcer. Rats were surgically prepared with a chronic Silastic catheter implanted in the external jugular vein. Five days after surgery, they were trained to press a lever for drug self-administration. The present data indicate that L-arginine (0.05, 0.1, and 0.15 mg/kg/injection) but not L-NAME (0.05, 0.1, and 0.15 mg/kg/injection) induced self-administration behavior and increased locomotion. The response induced by L-arginine (0.1 mg/kg/injection) was reduced by pretreatment with L-NAME (5, 10, and 15 mg/kg ip). Both the acute (5, 10, and 15 mg/kg ip) and the chronic (200 mg/kg ip; twice daily for 4 days) administration of L-arginine reduced morphine self-administration. However, acute (5, 10, and 20 mg/kg ip) and chronic (50 mg/kg ip; twice daily for 4 days) administration of L-NAME increased morphine self-administration significantly. It can be concluded that NO may have a role in morphine self-administration.     

Role of nitric oxide in the rat hippocampal CA1 area on morphine-induced conditioned place preference

Effects of intrahippocampal CA1 injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Animals received subcutaneous (s.c.) injections of saline (1.0 ml/kg) or morphine (0.5-7.5 mg/kg) once daily for 3 days to induce conditioned place preference. The administration of L-arginine (0.3, 1.0, and 3.0 microg/rat), but not L-NAME (0.3, 1.0, and 3.0, microg/rat), prior to administration of morphine (5.0 mg/kg) during acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference, but the interaction between the response to morphine and/or L-arginine was not statistically significant. The response to L-arginine was blocked by L-NAME pre-administration. L-Arginine or L-NAME by itself did not induce conditioned place preference. The administration of L-arginine but not L-NAME, 1 min before conditioned place preference testing, increased the expression of morphine-induced conditioned place preference. Pre-administration of L-NAME blocked the L-arginine response. It is concluded that NO in the rat hippocampal CA1 area may be involved in morphine-induced conditioned place preference.     

Morphine state-dependent learning: sensitization and interactions with dopamine receptors

In the present study, the effects of morphine sensitization on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pretraining administration of morphine (0.5, 2.5 and 5 mg/kg) dose dependently decreased the learning of a one-trial passive avoidance task. Pretest administration of morphine (0.5, 2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under pretraining morphine influence. Pretraining or pretest administration of naloxone (0.25, 0.5 and 1 mg/kg) reversed both responses to morphine (5 mg/kg). Amnesia induced by pretraining morphine was significantly reversed in morphine-sensitized mice which had previously received once daily injections of morphine [20 and 30 mg/kg, subcutaneously (s.c.)] for 3 days. Morphine sensitization tended to reverse but did not significantly affect morphine state-dependent memory. The inhibition of morphine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5, 1 and 2 mg/kg) 30 min prior to injection of morphine (20 mg/kg/day x 3 days). Three-days administration of 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine HCL (SKF 38393; 8, 16 and 32 mg/kg) or SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCL (0.01, 0.05 and 0.1 mg/kg) before morphine (for 3 days) and during morphine-sensitization, decreased and increased, the amnesia induced by pretraining morphine, respectively. Similar administration of quinpirole (0.5, 1 and 2 mg/kg) or sulpiride (25, 50 and 100 mg/kg) before morphine also decreased and increased the amnesia induced by pretraining morphine, respectively. The results suggest that morphine sensitization affects the impairment of memory formation, but not the facilitation of retrieval induced by morphine and thus it is postulated that dopamine receptors may play an important role in this effect.     

Involvement of nucleus accumbens in L-arginine-induced conditioned place preference in rats

In the present study, the effects of intraperitoneal, intra-accumbal and intra-ventral tegmental area administration of L-arginine and N(G)-nitro-L-arginine methyl-ester (L-NAME) on conditioned place preference behavior were studied. Intraperitoneal (i.p.; 0.5, 1 and 5 mg/kg) and intra-accumbal (intra-NAc; 0.3, 1 and 3 microg/rat), but not intra-ventral tegmental area (intra-VTA; 0.3, 1 and 3 microg/rat) administrations of L-arginine produced a significant place conditioning. Similar injections of L-NAME did not produce any response. However, intraperitoneal pretreatment of the animals with L-NAME (5, 10 and 20 mg/kg), 30 min before L-arginine administration, significantly abolished the acquisition of place conditioning induced by either intraperitoneal or intra-accumbal injection of L-arginine. Moreover, injection of L-NAME (5, 10 and 20 mg/kg) on the test day did not alter the L-arginine response. The results may indicate that L-arginine induces conditioned place preference via an increase in nitric oxide (NO) in the nucleus accumbens.     

The effect of <Emphasis Type="SmallCaps">l</Emphasis>-NAME and <Emphasis Type="SmallCaps">l</Emphasis>-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice

Rationale. Morphine and nitric oxide (NO) have important functional interactions in different neural processes, and both modulate learning and memory although their interaction in cognitive performance has not been elucidated. Objective. To examine the effect of the NO synthase (NOS) inhibitor N^G-nitro-l-arginine methyl ester (l-NAME) and NOS substrate l-arginine on morphine-induced impairment of memory formation and the state-dependent retrieval of a passive avoidance task learned under morphine influence. Methods. All drugs were administered intraperitoneally, and a one-trial step-down paradigm was used for the assessment of memory in adult male NMRI mice. Morphine was administered 30 min before training to induce impairment of memory formation and 30 min before test to induce state-dependent retrieval of the memory acquired under pre-training morphine influence. l-NAME or l-arginine was administered either 5 min after training or 45 min before the test. Results. Pre-training morphine induced impairment of memory formation that was reversible by pre-test morphine but not saline. Post-training administration of l-arginine (200 mg/kg) and l-NAME (3, 10 and 30 mg/kg), respectively, facilitated and impaired the memory consolidation, but their pre-test injections did not affect retention. However, post-training l-arginine at per se non-effective doses of 20 mg/kg and 60 mg/kg reversed the morphine-induced impairment of memory formation. Pre-test administration of l-NAME (3 mg/kg and 10 mg/kg) could restore the memory impairment induced by pre-training morphine, and this effect was blocked by concomitant pre-test l-arginine (60 mg/kg). Concomitant administration of low doses of l-NAME (1 mg/kg) and morphine (0.5 mg/kg) pre-test also revealed an additive effect in restoring the morphine state of memory. Conclusion. These results suggest that the impairment of memory formation and the facilitation of retrieval induced by morphine involves decreased synthesis/release of NO and can be counteracted by NOS substrate. Electronic Publication     

Nitric oxide modulates state dependency induced by lithium in an inhibitory avoidance task in mice

The effect of intracerebroventricular (i.c.v.) injections of L-arginine, a nitric oxide (NO) precursor and L-NAME, an inhibitor of NO synthase, on retrieval of state-dependent memory induced by LiCl (lithium) was investigated. A one-trial step-down inhibitory avoidance task was used for memory assessment in adult male NMRI mice. Intraperitoneal administration of lithium (10 mg/kg), immediately after training, impaired memory on the test day. Pretest administration of different doses of lithium (5, 10 and 20 mg/kg) reversed the impairment of memory caused by posttraining lithium (10 mg/kg). In addition, pretest administration of L-arginine (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) or L-NAME (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) also reversed amnesia induced by posttraining lithium. Furthermore, pretest coadministration with lithium of a dose of L-arginine (0.0001 microg/mouse, i.c.v.) or L-NAME (0.0001 microg/mouse, i.c.v.) that had no effects when administered alone, increased the effect of lithium on retrieval of inhibitory avoidance memory. The results suggest that NO may have a modulatory role on state-dependent retrieval of inhibitory avoidance memory induced by lithium.     

Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes

In the present study, the effects of intra-nucleus accumbens injection of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-accumbens administration of L-arginine (0.03 and 0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference, while intra-accumbens administration of L-NAME (0.3, 0.1 and 1 microg/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response to different doses of L-arginine was decreased by L-NAME (0.03 microg/rat). L-Arginine and L-NAME by themselves did not elicit any effect on place conditioning. Intra-accumbens administration of L-arginine but not L-NAME significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. The attenuation of already established morphine-induced place preference on the test day by L-arginine was inhibited by L-NAME. The results indicate that NO may be involved in the acquisition and expression of morphine-induced place preference.     

The effects of simultaneous administration of alpha(2) -adrenergic agents with L-NAME or L-arginine on the development and expression of morphine dependence in mice

Both alpha(2)-adrenoceptors and the L-arginine/nitric oxide (NO) pathway have been implicated in the modulation of morphine dependence. This study examined the effects of simultaneous administration of the alpha(2)-adrenoceptor agonist clonidine or the antagonist yohimbine together with the NO precursor L-arginine or the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the induction and expression of morphine dependence as assessed by naloxone-precipitated withdrawal jumping and diarrhoea. Male NMRI mice weighing 20-30 g were used. In the induction phase, clonidine (0.01-0.1 mg/kg) intensified and yohimbine (0.5-2 mg/kg) attenuated the degree of morphine dependence. Yohimbine reversed the effect of clonidine. L-NAME (5 and 10 mg/kg) did not affect the development of morphine dependence, but significantly potentiated the effects of both subeffective (0.01 mg/kg) and effective (0.03 mg/kg) doses of clonidine. L-Arginine did not alter morphine dependence but inhibited the effect of clonidine. The effects of yohimbine in the induction phase were attenuated by L-NAME, but were not significantly affected by L-arginine. In the expression phase, clonidine attenuated and yohimbine intensified the signs of dependence. The effect of clonidine was inhibited by yohimbine. In the expression phase, L-NAME attenuated the withdrawal syndrome at 10 mg/kg and showed potentiation with clonidine in suppressing withdrawal signs. L-Arginine did not alter morphine dependence, but at 20 mg/kg inhibited and at 100 mg/kg potentiated the attenuating effect of clonidine on the expression of withdrawal syndrome. The effect of yohimbine on the expression phase was also attenuated by L-NAME, but was not significantly affected by L-arginine. In conclusion, alpha(2)-adrenergic and NO pathways seem to be functionally linked in the modulation of opioid dependence.     

Nitric oxide within the ventral tegmental area is involved in mediating morphine reward

In the present study, the effects of intra-ventral tegmental area injection of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-ventral tegmental area administration of a low dose of L-arginine (0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference; however, a higher dose of L-arginine (0.1 microg/rat) reduced the morphine response. Intra-ventral tegmental area administration of L-NAME (0.03 and 0.1 microg/rat) decreased the acquisition of morphine (7.5 mg/kg)-induced place preference. The response to different doses of L-arginine was decreased by L-NAME (0.03 microg/rat). L-Arginine and L-NAME by themselves did not elicit any effect on place conditioning; however, intra-ventral tegmental area administration of L-arginine (0.01-0.1 microg/rat) and a higher dose of L-NAME (0.1 microg/rat) significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. The attenuation of already established morphine-induced place preference on the test day by L-arginine was inhibited by L-NAME (0.03 microg/rat). The results indicate that NO may be involved in the acquisition and expression of morphine-induced place preference.     

The effect of cyclosporin A on morphine tolerance and dependence: involvement of L-arginine/nitric oxide pathway

Cyclosporin A is known to decrease nitric oxide (NO) production in nervous tissues. The effects of systemic cyclosporine A on the induction and expression of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/nitric oxide pathway in these effects were assessed in mice. Cyclosporin A (20 mg/kg), N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg) and a combination of the two at lower and per se non-effective doses (5 and 3 mg/kg, respectively) showed a similar pattern of action, inhibiting the induction of tolerance to morphine-induced antinociception and increasing the antinociception threshold in the expression phase of morphine tolerance. These agents also inhibited the expression of morphine dependence as assessed by naloxone-precipitated withdrawal signs, while having no effect on the induction of morphine dependence. L-Arginine, at a per se non-effective dose (60 mg/kg), inhibited the effects of Cyclosporin A. Moreover, acute administration of Cyclosporin A (20 mg/kg) or L-NAME (10 mg/kg) enhanced the antinociception induced by acute administration of morphine (5 mg/kg), while chronic pretreatment with Cyclosporin A (20 mg/kg) or L-NAME (10 mg/kg) for 2 days (twice daily) did not affect morphine-induced antinociception. The inducible nitric oxide synthase inhibitor, aminoguanidine (100 mg/kg), did not alter morphine antinociception, tolerance or dependence. In conclusion, decreasing NO production through constitutive nitric oxide synthase may be a mechanism through which cyclosporin A differentially modulates morphine tolerance, dependence and antinociception.     

The role of nitric oxide within the nucleus accumbens on the acquisition and expression of morphine-induced place preference in morphine sensitized rats

In the present study, the effects of intra-accumbal administration of L-arginine, a nitric oxide precursor, and N(G)-nitro-L-arginine methyl-ester (L-NAME), a nitric oxide synthase inhibitor, on the acquisition and expression of morphine-induced place conditioning in morphine-sensitized rats were studied. Subcutaneous (s.c.) administration of morphine (2.5, 5 and 7.5 mg/kg) induced conditioned place preference. Repeated pretreatment of morphine (5 mg/kg, i.p.) followed by 5 days without drug treatment, increased conditioning response induced by morphine (0.25, 0.5 and 0.75 mg/kg). Intra-accumbal (intra-nucleus accumbens; 1 microg/rat) administration of L-arginine (0.3, 1 and 3 microg/rat) significantly increased or reduced the acquisition of morphine place conditioning in non-sensitized and sensitized rats respectively. However, the drug reduced expression of place conditioning by morphine in sensitized animals. Intra-nucleus accumbens injections of L-NAME (0.3, 1 and 3 microg/rat) reduced the acquisition and expression of morphine place conditioning in the sensitized animals. The results indicate that nitric oxide (NO) within the nucleus accumbens is involved in the acquisition and expression of morphine place conditioning in morphine-sensitized rats.     

Influence of nitric oxide on morphine-induced conditioned place preference in the rat central amygdala

Effects of intra-central amygdala injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a NO synthase (NOS) inhibitor, on morphine-induced conditioned place preference in rats were investigated by using an unbiased 3-day schedule of place conditioning design. Animals receiving once daily injections of morphine (0.5-7.5 mg/kg, subcutaneously, s.c.) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5.0 mg/kg of the opioid. Co-administration of morphine (5.0 mg/kg) with L-arginine (0.3, 1.0 and 3.0 microg/rat), but not with L-NAME (0.3, 1.0 and 3.0 microg/rat), during the acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference. The response to L-arginine was blocked by L-NAME preadministration. L-arginine and L-NAME by themselves did not induce conditioned place preference. When L-arginine or L-NAME at 0.3-3.0 microg/rat was administered 1 min before conditioned place preference testing, L-arginine but not L-NAME caused an increase in the expression of morphine-induced conditioned place preference, the effect that was blocked by L-NAME preadministration. A dose of L-arginine (0.3 microg/rat), but not L-NAME, during expression of morphine-induced conditioned place preference produced an increase in locomotion compared with that in the control group. It may be concluded that an increase in the NO levels in the central amygdala may have an effect on the acquisition and expression of morphine-induced conditioned place preference.     

Inhibition of morphine-induced amnesia in morphine-sensitized mice: involvement of dorsal hippocampal GABAergic receptors

In the present study, the effects of bilateral injections of the GABAergic receptor agents into the dorsal hippocampal CA1 regions (intra-CA1) on morphine-induced amnesia were examined in morphine sensitized-mice. Pre-training subcutaneous (s.c.) administration of morphine (5 mg/kg) suppressed the learning of a one-trial passive avoidance task. Amnesia induced by pre-training morphine was significantly reversed in mice which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, which may be due to behavioral sensitization. Intra-CA1 injections of GABAA receptor agonist, muscimol (0.125, 0.25, 0.5 and 1 microg/mouse) or the GABAB receptor agonist, baclofen (1, 1.5 and 2 microg/mouse) prior to injection of morphine (20 mg/kg per dayx3 days) decreased the reversion of morphine-induced amnesia in morphine sensitized-mice. Daily intra-CA1 injections of muscimol or baclofen plus saline for 3 days did not alter memory formation. Furthermore, during development of sensitization, the combination of GABAA receptor antagonist, bicuculline (0.25, 0.5, 1 and 2 microg/mouse) with an ineffective dose of morphine (5 mg/kg, s.c.) reversed the amnesia induced by pre-training morphine. However, the same treatment with GABAB receptor antagonist, CGP35348 (2.5-40 microg/mouse) had no effect on the morphine response. On the other hand, daily intra-CA1 injections of bicuculline or CGP35348 alone for 3 days did not alter the amnesia induced by pre-training injection of morphine. The results suggest that morphine sensitization reverses the impairment of memory induced by morphine and that GABAergic receptors of the dorsal hippocampus may play an important role in this effect.     

Comparison of simultaneous administration of lithium with L-NAME or L-arginine on morphine withdrawal syndrome in mice

Due to the claim that chronic administration of lithium or L-N(G)-nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor reduces morphine withdrawal syndrome, the effects of chronic administration of lithium, L-NAME, or L-arginine (L-Arg), a precursor of NO, alone or co-administration of lithium with L-Arg or L-NAME, on naloxone-precipitated withdrawal syndrome and physical dependence development to morphine in mice chronically treated with morphine, were evaluated. Morphine dependency was induced by the intraperitoneal injection (i.p.) of morphine (10 mg/kg), once daily for 7 days. Physical dependence to morphine was observed by precipitating an abstinence syndrome with naloxone (2 mg/kg, i.p.). Chronic administration of L-NAME (10 mg/kg, i.p., once daily, for 7 days after 10 days of receiving only tap water and food prior to naloxone), decreased all withdrawal signs significantly, while L-Arg (200 mg/kg, as above) increased only some withdrawal signs significantly in morphine-dependent mice. Chronic administration of lithium (600 mg/kg, in drinking water) alone or co-administration of lithium (as above) with L-NAME (10 mg/kg) or L-Arg (200 mg/kg, i.p., once daily) for 7 days after 10 days of receiving only lithium (as above) and food, decreased all withdrawal signs and physical dependence significantly in morphine-dependent mice. The results obtained indicate that co-administration of L-NAME with lithium increases the effect of lithium or L-NAME alone, on withdrawal signs, but this increase is not significantly different as compared to chronic lithium or L-NAME administration alone; while co-administration of L-Arg with lithium decreases the effects of lithium on withdrawal signs and this decrease is not significant as compared to chronic lithium administration alone. These findings indicate that nitric oxide may be involved in modulation of naloxone-induced withdrawal syndrome, and treatment with lithium could have some effect on this system. Copyright 2000 John Wiley & Sons, Ltd.     

Anxiolytic effects of acute morphine can be modulated by nitric oxide systems

This study was performed to investigate whether nitric oxide (NO) precursor (L-arginine), NO donor (S-nitroso-N-acetylpenicillamine, SNAP) and NO synthase inhibitors [N(G)-nitro-L-arginine-methylester (L-NAME) and N(G)-nitro-L-arginine (L-NOARG)] modulate morphine-induced anxiolytic effects in the plus-maze. L-Arginine (100, 200 and 300 mg kg(-1), i.p.) and SNAP (4, 8 and 10 mg kg(-1), i.p.) reduced the anxiolytic effect of morphine (20 mg kg(-1), s.c.). L-NAME (10, 20 and 40 mg/kg, i.p.) and L-NOARG (10, 15 and 20 mg kg(-1), i.p.) enhanced the anxiolytic effects of morphine (20 mg kg(-1), s.c.). On the other hand, L-arginine and SNAP increased the morphine-induced locomotor activity. L-NAME decreased the morphine-induced locomotor activity, but L-NOARG did not modify the morphine-induced locomotor activity. Therefore, these results suggest that the anxiolytic effects of morphine can be modulated by NO systems.     

Evidence for an involvement of nitric oxide and gamma aminobutyric acid in the anticonvulsant action of L-arginine on picrotoxin-induced convulsions in rats

Five, 30, and 60 min pretreatment of 1000 mg/kg and not 500 mg/kg of L-arginine inhibited convulsions induced by picrotoxin. The concentrations of nitric oxide (NO) and gamma aminobutyric acid (GABA) were increased in the brain 5, 30, and 60 min after administration of 1000 mg/kg and not 500 mg/kg of L-arginine. A much higher dose of L-arginine (2000 mg/kg), 30 min after administration, produced a lesser anticonvulsant and NO and GABA increasing actions as compared to that produced by 1000 mg/kg of L-arginine. The same dose of L-arginine, 60 min after administration, decreased the concentrations of both NO and GABA and increased the convulsion frequency of picrotoxin. An NO decreasing dose of nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME) decreased brain GABA concentration and increased the convulsant action of picrotoxin. Further, L-NAME pretreatment prevented L-arginine (1000 mg/kg) from producing anticonvulsant and NO and GABA increasing effects. An interpretation of these results suggests that NO synthesized from systemically administered L-arginine inhibits convulsions by increasing the concentration of GABA in the brain. However, the effects of L-arginine are reversible, if it is administered at a higher dose (2000 mg/kg) 60 min prior to the test. It is concluded that L-arginine produces anticonvulsant or proconvulsant action depending upon the dose and time of its administration-related changes in the concentrations of NO and GABA in the brain.     

Nitric oxide involvement in consolidation, but not retrieval phase of cognitive performance enhanced by atorvastatin in mice

Atorvastatin, a widely-used medication in treatment of hypercholesterolemia, has shown some benefits in treating cognition impairment in Alzheimer's disease. In this study, effects of atorvastatin on spatial recognition memory and the involvement of nitric oxide (NO) has been determined on consolidation and retrieval of memory in a two-trial recognition Y-maze test. Memory was impaired using scopolamine (1mg/kg, i.p.); atorvastatin (1, 5mg/kg, p.o.) was administered, either in presence or in absence of a non-specific NO synthase inhibitor, L-NAME (3, 10mg/kg, i.p.); a specific inducible NO synthase inhibitor, aminoguanidine (100mg/kg, i.p.); and a NO precursor, L-arginine (750 mg/kg, i.p.). Results: 1) atorvastatin (5mg/kg) significantly improved memory performance in a dose-dependent manner on consolidation and retrieval stage of memory in scopolamine-treated mice; 2) the beneficial effects of atorvastatin on memory consolidation was significantly reversed by L-NAME (10mg/kg) and aminoguanidine; 3) L-arginine slightly potentiated the effects of sub-effective dose of atorvastatin (1mg/kg) on memory consolidation; 4) either L-NAME (up to 10mg/kg), or aminoguanidine did not affect the memory improvement by atorvastatin on retrieval stage; 5) the effects of sub-effective dose of atorvastatin (1mg/kg) on retrieval of memory were not potentiated by L-arginine. The present study demonstrates that atorvastatin improves both consolidation and retrieval phases of memory. This effect is affected by NO synthase inhibitors and NO precursor, L-arginine, only in memory consolidation phase, but not in retrieval phase. It is concluded that NO might be involved in consolidation of spatial memory improvement by atorvastatin.     

Mediation of nitric oxide in inhibitory effect of morphine against electroshock-induced convulsions in mice

Nitric oxide (NO) and morphine have been coupled in many physiological as well as pathological processes. The present study examined the involvement of the L-arginine/NO pathway in the anticonvulsant properties of systemic morphine (2-30 mg/kg) against electroshock seizures (ECS) in mice. Morphine decreased the intensity of maximal electroshock seizures (MES) and increased the threshold for ECS. Neither the NOS substrate L-arginine (30, 60, and 100 mg/kg), the reversible nonspecific NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 3, 10, and 30 mg/kg), the irreversible specific inducible NOS inhibitor aminoguanidine (20, 50, and 100 mg/kg), nor the opioid receptor antagonist naloxone (0.1, 0.3, and 1 mg/kg) did alter per se the ECS threshold or the intensity of MES at doses used. However, both naloxone and L-NAME, but not aminoguanidine, inhibited the anticonvulsant effects of morphine (30 mg/kg) against ECS, while L-arginine potentiated the anticonvulsant effects of lower doses of morphine (2 or 10 mg/kg). Low doses of naloxone (0.1 or 0.3 mg/kg) or L-NAME (3 mg/kg), which did not alter morphine effect per se, showed additive anticonvulsant effects against MES. Thus, the L-arginine/NO pathway seems to play a role in the anticonvulsant properties of morphine against ECS and this mediation involves the constitutive, but not the inducible, form of nitric oxide synthase.