Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioural sensitization in rats?

Intermittent morphine pretreatment (10 mg/kg/day for 14 days) induced long-lasting (one month post-treatment) sensitization to the locomotor effects of morphine and amphetamine in rats. Co-administration of the non-competitive NMDA-receptor antagonist dizocilpine (MK-801) (0.1 mg/kg) with morphine did not prevent the development of long-term behavioural sensitization. However, this dose of MK-801 did cause long-term sensitization to its own locomotor effects. Co-administration of 0.25 mg/kg MK-801 with morphine caused death in 60% of the animals. In the animals that survived MK-801 plus morphine pretreatment, neither short-term (3 days) nor long-term morphine-induced sensitization was observed. MK-801 alone (0.25 mg/kg/day for 14 days) induced short-term cross-sensitization to morphine. Thus, the development of long-term morphine-induced locomotor sensitization could only be prevented by a dose of MK-801 that yields a lethal combination with morphine. In addition, MK-801 induced sensitization to its own locomotor effects and cross-sensitization to morphine. These findings seriously question whether MK-801 can be used to study the development of morphine-induced behavioural sensitization.     

Discrete quinolinic acid lesions of the rat prelimbic medial prefrontal cortex affect cocaine- and MK-801-, but not morphine- and amphetamine-induced reward and psychomotor activation as measured with the place preference conditioning paradigm

As a part of the mesocorticolimbic system, the medial prefrontal cortex (mPFC) is thought to participate in the regulation of locomotor activity, motivation and reward. The mPFC consists of at least three different subareas. In previous lesion studies examining this region usually large parts of the mPFC were destroyed, with little discrimination between the different subareas. Therefore, this study was designed to selectively lesion the prelimbic area of the mPFC using a relatively low dose of quinolinic acid. In a conditioned place preference (CPP) experiment, lesioned and control animals were treated with cocaine (15 mg/kg), amphetamine (4 mg/kg), morphine (10 mg/kg) or MK-801 (0.3 mg/kg) to induce CPP. The lesion blocked the development of CPP only in animals receiving cocaine, but not in animals receiving amphetamine or morphine. MK-801 failed to produce a CPP in both lesioned and unlesioned animals. During the conditioning experiment, the acute locomotor response to the different drugs was also measured. Only the response (in terms of locomotion and rearing) to cocaine and MK-801 was reduced to a significant extent by the lesion, while the response to amphetamine and morphine was not affected. Also, the lesions did not cause any changes in the spontaneous activity of the animals when tested without drug. These results show that even small lesions of the prelimbic subarea of the mPFC are sufficient to produce behavioral effects. However, these are apparent only when the animals are challenged with cocaine or MK-801, but not with amphetamine or morphine, or when drug-free. This suggests that the mPFC might have a special role in mediating cocaine and MK-801 effects.     

Cloning and sequencing of cDNA of the hepatitis E virus genome--application to diagnosis

Food restriction has been shown to enhance the behavioral sensitivity to addictive drugs. The biological factors involved in this effect are largely unknown. Since food restriction, among other factors, increases corticosterone secretion, the role of this hormone in the effects of food restriction on the response to psychostimulants and opioids was investigated. The effects of food restriction on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal axis; (ii) animals in which food restriction-induced corticosterone secretion was suppressed by adrenalectomy, but which received exogenous corticosterone from a subcutaneous implant, which slowly releases corticosterone, producing a stable plasma level within the normal physiological range over a period of 20 days. It was found that food restriction enhanced sensitivity to the psychomotor effects of amphetamine (1 mg/kg i.p.) and morphine (1 mg/kg i.p.) in animals with an intact hypothalamo-pituitary-adrenal axis, but not in animals in which endogenous corticosterone secretion was eliminated. These results suggest that corticosterone secretion may be one of the mechanisms by which food restriction amplifies the behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.     

Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice

Previously established dose-response curves indicated that modafinil 20-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5-150 micrograms/kg i.p. suppressed the stimulant effect of (+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5-30 micrograms/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [3H]dopamine, modafinil 10(-5) M did not increase the spontaneous [3H]dopamine release whereas (+)amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.     

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice

1. The present study examined a comparison of the effect of DEX on psychomotor stimulant effects of cocaine and amphetamine in mice by using the locomotor activity test. 2. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0-10 mg/kg/i.p.) did not modify the activity of control mice. 3. DEX pretreatment decreased the stimulating effects induced both by cocaine and amphetamine but no consistent dose-related effects were observed. 4. The results suggest that DEX may play an important role on the stimulating effects of cocaine and amphetamine and that it may be of some utility in the clinical management of psychostimulants abuse.     

Antiemetic effects of morphine on motion- and drug-induced emesis in Suncus murinus

Emetic and antiemetic effects of morphine were investigated in Suncus murinus. Subcutaneous (up to 30 mg/kg) or intracerebroventricular administration (50 micrograms) of morphine failed to cause emesis. However, pretreatment with morphine (s.c.) prevented the emesis induced by nicotine (10 mg/kg, i.p.), copper sulfate (40 mg/kg, p.o.), cisplatin (20 mg/kg, i.p.) and motion stimulus. These results suggest that morphine has only antiemetic potency and may block a common mechanism for the emetic reflex of suncus, because the antiemetic effects of the drug were exerted irrespective of the stimulus.     

Selective absorption of radio frequency energy due to collective motion of charged domains: case of lysozyme crystal

The role of the N-methyl-D-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine+MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.     

The aminoacceptor stem of the yeast tRNA(Lys) contains determinants of mitochondrial import selectivity

The effect of quinine, a cinchona alkaloid, was studied on gastrointestinal transit in mice. Intraperitoneal (i.p.) administration of quinine inhibited the intestinal propulsion of a charcoal suspension at a dose of 100 mg/kg, comparing favorably with 5 mg/kg morphine. In an attempt to probe into the mechanism underlying this inhibition, a possible modulation by minoxidil (1 mg/kg, p.o.) and glibenclamide (1 mg/kg, p.o.), the drugs that, respectively, open and close ATP-sensitive K+ channels was tested on gastrointestinal transit in animals treated or not with quinine or morphine. While minoxidil produced no significant change of normal transit, glibenclamide significantly increased it. However, both drugs blocked the quinine-induced reduction in gastrointestinal transit. In contrast, the inhibitory effect of morphine on gastrointestinal transit was not modified by either drug. The effects of quinine as well as of morphine on gastrointestinal transit were significantly antagonized by naloxone (2 mg/kg, s.c.), a mu-opioid receptor antagonist but not by yohimbine (1 mg/kg, i.p.), an alpha2-adrenoceptor antagonist. Furthermore, quinine at a lower dose (25 mg/kg) that showed no per se effect on gastrointestinal transit, significantly potentiated the response to 2.5 mg/kg morphine. Although the role of ATP-sensitive K+ channels in the action of quinine and morphine was not clarified by the present results, a possible involvement of endogenous opioid(s) in the quinine-induced inhibition of gastrointestinal transit can be suggested.     

Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

Sigma ligand S14905 and locomotor activity in mice

The binding and locomotor profile of a new sigma ligand, S14905, (isobutyl-N-(1-indan-2yl-piperid-4-yl)N-methyl carbamate, furamate) was studied. The binding data revealed that S14905 has a high affinity for sigma receptors and very low affinity for both dopamine D1 and D2 receptors. We have demonstrated that this sigma ligand prevents the locomotor stimulation induced by morphine (32 and 64 mg/kg), cocaine (16 mg/kg), amphetamine (4 mg/kg) and adrafinil (32 mg/kg) at doses lower than those required to depress spontaneous locomotor activity. The antagonism observed in the present study seems to be more specific of morphine induced hyperlocomotion. The high affinity of this compound for sigma receptors makes it a good choice to study the role of this receptor in the CNS. In addition, S14905 does not directly block dopamine receptors but may modulate them in some manner, and would thus warrant further study as a potential atypical antipsychotic agent, and an antagonist for the hyperactivity induced by opiate drug.     

Activation of CTP:phosphocholine cytidylyltransferase by hypochlorite-oxidized phosphatidylcholines

The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.     

AMPA-receptors are involved in the expression of amphetamine-induced behavioural sensitisation, but not in the expression of amphetamine-induced conditioned activity in mice

We investigated the role of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) in the expression of amphetamine-induced behavioural sensitisation and amphetamine-induced conditioned activity in mice. Repeated weekly administration of amphetamine (0.375 mg/kg) for 7 weeks led to an increased locomotor response when challenged with amphetamine 1 week later. NBQX attenuated this increased response at doses (3 and 30 mg/kg) which had no effect on the acute locomotor response to amphetamine. In a separate experiment, mice given amphetamine (1 mg/kg) in a distinctive environment, showed an increased locomotor response within this environment following a subsequent saline administration. NBQX (5-20 mg/kg) had no effect on the expression of this conditioned response. These results suggest that AMPA receptors are involved in the expression of amphetamine-induced behavioural sensitisation in mice, and that this involvement is limited to either the neurobiological effects of amphetamine or the effects of amphetamine on conditioned associations, rather than drug environment conditioned associations.     

Correlates of change in depressive symptomatology among gay men with AIDS

The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, i.p.) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, i.p.). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2-4 days) and once, long (9-12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, i.p.) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions.     

Partial characterization of an immortalized human trophoblast cell-line, TCL-1, which possesses a CSF-1 autocrine loop

High doses of morphine produce a state of behavioural inactivity and muscular rigidity. This type of 'catalepsy' is clearly different from the state which is produced by the administration of neuroleptics, e.g. haloperidol. While haloperidol-induced catalepsy can easily be antagonised by NMDA receptor antagonists, there has been a report that the non-competitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801) potentiates morphine-induced catalepsy. The aim of this study was to further examine the role of glutamate receptors in the mediation of morphine-induced catalepsy. To this end we coadministered morphine (20, 40, 60 mg/kg i.p.) with MK-801 (0.1 and 0.3 mg/kg i.p.), the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentoic acid (CGP 37849) (2 and 6 mg/kg i.p.), or 1-(4-aminophenyl)-4-methyl-7,8-methylen-dioxy-5H-2,3- benzodiazepine (GYKI 52466) (2 and 4 mg/kg), an antagonist of the AMPA type of glutamate receptors, respectively. The degree of catalepsy was assessed using two different methods, the 'bar/podium/grid' test which is commonly used to measure neuroleptic-induced catalepsy, and a test for the presence or absence of righting reflexes after turning the animals into a supine position. It was found that in the 'bar/podium/grid' test coadministration of both NMDA receptor antagonists significantly and dose-dependently augmented morphine-induced catalepsy. The results using the AMPA receptor antagonist were less clear since the lower dose of GYKI 52466 tended to attenuate the morphine effect whereas the higher dose augmented morphine-induced catalepsy in some cases. While placing the animals on the bar and on the podium produced essentially the same results, the grid was found to be inapplicable for the measurement of morphine-induced catalepsy since the animals did not cling to the grid and fell off almost immediately after being released from the experimenter's hand. With respect to the righting reflexes it was found that the number of animals not showing these responses increased when MK-801 or CGP 37849 was coadministered with morphine. In contrast, most of the animals treated with GYKI 52466 and morphine displayed intact righting reflexes. It is concluded that glutamatergic transmission plays an important role in the mediation of morphine-induced catalepsy, though different to that of haloperidol-induced catalepsy, and that NMDA and AMPA receptors are differentially involved in different aspects of the associated behavioural state.     

Osteoporotic fractures: background and prevention strategies

To assess the effects of the novel sigma ligand JO 1994 on behavioural, histological and autoradiographical changes following global ischaemia, the Mongolian gerbil was used. Three experiments were carried out and in each case ischaemia was induced by bilateral carotid occlusion (BCO) for 5 min. In the first experiment we examined the effects of JO 1994 administered at doses of 0.25, 0.5 and 1 mg/kg i.p. 1 h before 5 min BCO on histological parameters 96 h after surgery. In the second experiment the effects of JO 1994 administered at doses of 2.5, 5, 10 and 20 mg/kg i.p. 1 h before 5 min BCO on locomotor activity 24, 48 and 72 h after surgery and on histological parameters 96 h after surgery was examined. In the third experiment the effects of JO 1994 (2.5 and 5 mg/kg i.p.), BMY 14802 (1 and 10 mg/kg i.p.) and MK-801 (2.5 mg/kg i.p.) administered 30 min, 6, 24, 48, 72, 96 and 120 h post-surgery on the densities of M1 and M2 muscarinic receptors in 35 brain regions, 7 days after surgery was examined. Results indicated that 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. JO 1994 attenuated this hyperactivity. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min BCO animals 96 h after surgery. The low doses of JO 1994 (0.25, 0.5 and 1 mg/kg) had no effect on the ischaemia-induced cell death. However JO 1994 (2.5, 5, 10 and 20 mg/kg i.p.) protected against the neuronal death of cells in the CA1 layer (P < 0.01-0.03). There was a large loss of M1 and M2 receptors in the CA1 regions of the hippocampus. MK-801, BMY 14802 and JO 1994 provided significant (P < 0.01) protection against this ischaemia-induced receptor loss.     

Does dizocilpine (MK-801) selectively block the enhanced responsiveness to repeated amphetamine administration?

In order to examine the hypothesis that N-methyl-{d}-aspartate (NMDA) receptors are selectively involved in the development of stimulant sensitization, we characterized the interaction between acute and chronic dizocilpine (MK-801)?+?amphetamine using a detailed behavioral analysis, including concurrent assessment of the locomotor and stereotypy components of the stimulant response and continuous monitoring of all the various phases of the emergent sensitization. The results showed that MK-801 (0.125 mg/kg) significantly affected the acute response to amphetamine (0.5, 1.75, 4.0 mg/kg), increasing or decreasing locomotor activity depending on dose. Repeated administration of MK-801?+?amphetamine resulted in a suppression of stereotyped behaviors and a potentiated locomotor sensitization. These findings suggest that rather than blocking the development of sensitization, MK-801 pretreatment may produce a unique behavioral augmentation that is apparent during coadministration and that persists for up to 48 hr in the response to amphetamine challenge. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine

Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.     

The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats

(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, (MK-801) a potent noncompetitive antagonist of central NMDA receptors, has been hypothesized to have rewarding properties indicative of abuse potential. To test this hypothesis, the effects of MK-801 on the acquisition of a conditioned place preference and on locomotor activity were assessed and compared with d-amphetamine. Both MK-801 (0.03 and 0.1 mg/kg, SC) and d-amphetamine (1.0 mg/kg, SC) administration resulted in the acquisition of a conditioned place preference. However, while both amphetamine and the higher dose of MK-801 produced a behavioral activation during the training period the lower dose of MK-801 did not. These results suggest that MK-801, at doses that produce behavioral activation and below, is rewarding and therefore may have abuse potential.     

Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty

We have shown recently that the psychomotor activating effects of amphetamine in the rat are much greater when this drug is administered in association with environmental novelty than when it is given in a home environment. The main purpose of the present study was to explore the neural basis of this phenomenon. We found, using in situ hybridization of c-fos mRNA, that the pattern of neuronal activation in the cortex, in the caudate, in the shell and core of the nucleus accumbens, and in other subcortical structures was markedly different when amphetamine (2.0 mg/kg, i.p.) was given in association with exposure to environmental novelty relative to when it was given at home. In most brain regions the magnitude of c-fos expression was over two times greater in rats given amphetamine plus novelty than in rats given amphetamine alone. In contrast, an in vivo microdialysis study indicated that environmental novelty did not affect amphetamine-induced dopamine release in either caudate or nucleus accumbens. Furthermore, a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system reduced amphetamine- but not novelty-induced c-fos expression. Finally, we found no differences in the amount of corticosterone secreted after exposure to novelty, amphetamine, or both, suggesting that corticosterone does not play a critical role in the ability of novelty to modulate amphetamine-induced psychomotor activation. In conclusion, it seems that environmental novelty alters the neurobiological effects of amphetamine independently of the primary neuropharmacological actions of this drug in the striatum.     

Evidence for a role of N-methyl-D-aspartate receptors in L-arginine-induced attenuation of morphine antinociception

Twice daily injections of L-arginine (50, 100 or 200 mg/kg, i.p.) for 4 days dose-dependently, decreased morphine antinociception in male Swiss-Webster mice as measured by the tail-flick test. To determine the possible role of N-methyl-D-aspartate (NMDA) receptor in the action of L-arginine, the effects of MK-801, a noncompetitive antagonist of the NMDA receptor and of LY 235959, a competitive antagonist of the NMDA receptor on L-arginine-induced attenuation of morphine antinociception were determined. MK-801 (0.01-0.10 mg/kg, i.p.) or LY 235959 (1.0-4.0 mg/kg, i.p.) given 10 min before each injection of L-arginine (200 mg/kg, i.p.) reversed the action of the letter in a dose-dependent manner on morphine antinociception. It is concluded that NMDA receptors are involved in the action of L-arginine in attenuating morphine antinociception.