Effects of aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated protein kinase signal transduction pathway

Based on NMDA hypofunction hypothesis for negative symptoms and cognitive deficits in schizophrenia, MK-801-induced animal models of schizophrenia may help us understand the different effects between typical and atypical antipsychotics. On the other hand, the mitogen-activated protein kinase (MAPK) signaling pathways may participate in antipsychotic actions. The aim of this study was to investigate the effects of aripiprazole on MK-801-induced prepulse inhibition (PPI) disruption and MAPK phosphorylation in mice. To clarify the effects of aripiprazole on MK-801-induced PPI disruption, we measured PPI of 51 ddY male mice after aripiprazole was administered 15 min prior to the injection of MK-801, and measured activation of cytosol and nuclear MAPK phosphorylation by western blotting. Aripiprazole (4.0 mg/kg) significantly reversed the MK-801 (0.15 mg/kg)-induced PPI deficits. Pretreatment of aripiprazole (40 mg/kg) had a tendency to suppress MK-801 (1.0 mg/kg)-induced pMEK/MEK (Ser218/222) activation. In addition, aripiprazole treatment showed a significant decrease of pERK/ERK. Our data suggested that aripiprazole may reverse MK-801-induced PPI deficits through regulation of MAPK phosphorylation in the same way as the atypical antipsychotic drug, clozapine.     

Effects of prior apparatus experience and novelty of testing environment on locomotor activity following MK-801

Robust increases in locomotor activity are observed following administration of dizocilpine maleate (MK-801). The present study investigated the effects of prior apparatus experience and manipulation of the testing environment on locomotor activity following peripheral MK-801. Gerbils were given zero or nine sessions of apparatus exposure prior to testing with MK-801 (0.1 mg/kg ip) or saline. Sessions were 10 min in duration and separated by 24 h. As previously reported, naive animals treated with MK-801 were significantly more active relative to controls. Exposure to the apparatus for nine sessions resulted in a significant reduction in MK-801-induced activity, but did not alter the activity levels of control animals. To evaluate the effect of changes to the testing environment, animals previously evaluated in the familiar condition were retested in the identical apparatus relocated to a novel experimental room. MK-801-treated animals exhibited a significant increase in activity when tested in this novel environment while the locomotor activity of control gerbils was not significantly altered. The results illustrate the importance of repetitive testing and environmental changes as moderating variables in studies that evaluate locomotor activity. These data also indicate that the effects of MK-801 on activity are sensitive to prior experience with the apparatus and the novelty of the testing environment.     

Effect of the N-methyl-d-aspartate receptor antagonist on locomotor activity and cholecystokinin-induced anorexigenic action in a goldfish model

We have previously identified that peripherally administered cholecystokinin (CCK) exerts an anorexigenic action via the vagal afferent, and subsequently the brain melanocortin- and corticotropin-releasing hormone-neuronal pathways in goldfish. N-Methyl-d-aspartate (NMDA) receptors have been shown to be involved in the regulations of locomotor activity and food intake in mammals. Although several neuropeptides and other factors exert similar effects in fish and mammals, the role of NMDA receptor in the control of locomotor activity and feeding behavior in fish is still unclear. In the present study, we examined the effect of the NMDA receptor antagonist, MK-801, on locomotor activity and food intake in the goldfish. Intraperitoneal (IP) injection of MK-801 at 0.15 nmol/g body weight (BW) increased locomotor activity, but did not affect food consumption. IP injection of MK-801 at same dose attenuated peripheral CCK (100 pmol/g BW)-induced anorexigenic, but not peripheral acyl ghrelin (10 pmol/g BW)-induced orexigenic actions. These data show for the first time that the NMDA receptor-signaling pathway is involved in the regulation of locomotor activity and feeding behavior through modulation of the peripheral CCK-induced satiety signal, but not the orexigenic effect of ghrelin.     

Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity

Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field.From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.     

Isolation rearing-induced deficits in prepulse inhibition and locomotor habituation are not potentiated by water deprivation

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating and is reduced in neuropsychiatric disorders such as schizophrenia. Isolation rearing of rats is a developmentally specific, nonpharmacological manipulation that leads to deficits in sensorimotor gating that mimic those observed in schizophrenia patients. This study examined the effects of an added stressor (water deprivation) on the magnitude of the isolation rearing effect on PPI and locomotor activity. At the time of weaning, male (n = 80) and female (n = 80) rats were assigned to either social housing or isolation housing and were subsequently assigned to the water-deprived or non-water-deprived groups. Rats were tested for acoustic startle and PPI at 3, 5 and 7 weeks postweaning. Isolated rats showed a significant decrease in PPI that was apparent at all 3 weeks. Water deprivation did not significantly affect PPI, nor was there a significant interaction between housing and water treatment or between sex and housing. When tested in the Behavior Pattern Monitor to assess locomotor activity, isolated rats displayed decreased habituation across the 1-h test session. Water deprivation did not affect locomotor activity in any significant, independent manner, nor did it potentiate the effects of isolation rearing on locomotor habituation. In these studies, both male and female Long-Evans rats were sensitive to the PPI-disruptive and locomotor-activating effects of social isolation. Isolation rearing significantly disrupts PPI and locomotor habituation independent of any effects of water deprivation.     

Effects of cholinergic system of dorsal hippocampus of rats on MK-801 induced anxiolytic-like behavior

Rationale: Some investigations have shown that the glutamate receptors play a critical role in cognitive processes such as learning and anxiety. Objectives: The possible involvement of the cholinergic system of the dorsal hippocampus in the anxiolytic-like response induced by MK-801, NMDA receptor antagonist, was investigated in the present study. Methods: Male Wistar rats were used in the elevated plus maze apparatus to test the parameters: open arm time (%OAT), open arm entries (%OAE), close arm time (%CAT), close arm entries (%CAE) and other exploratory behaviors (locomotor activity, grooming, rearing and defecation) of anxiety-like response. Results: The data indicated that intra-CA1 administration of MK-801 increased %OAT (2 μg/rat) and %OAE (1 and 2 μg/rat) while decreased %CAT and %CAE and did not alter other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, intra-hippocampal injections of mecamylamine, a cholinergic receptor antagonists (2 μg/rat) and scopolamine (4 μg/rat), by themselves, 5 min before testing, increased %OAT and %OAE but decreased %CAT and %CAE and did not alter locomotor activity and other exploratory behaviors, suggesting an anxiolytic-like effect. On the other hand, intra-CA1 co-administration of an ineffective dose of scopolamine (3 μg/rat), but not mecamylamine (1 μg/rat), with an ineffective dose of MK-801 (0.5 μg/rat) increased %OAT and %OAE and decreased %CAT and %CAE. The data may indicate the possible involvement of the cholinergic system of the CA1 in the anxiolytic-like response induced by MK-801.     

Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior

Lasting increases in anxiety-like behavior (ALB) in the elevated plus-maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus-maze for up to 3 weeks after the exposure. The first study in this series demonstrated that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given systemically 30 min prior to exposure to a cat prevents the increase in ALB assessed 1 week later in the elevated plus-maze. To localize the site of action of systemic MK-801, MK-801 was injected in the amygdala 30 min prior to predator stress. Injections were given either unilaterally in either hemisphere, or bilaterally in both hemispheres. The target of the injection was the basolateral amygdala. The effects of injection depended on both the type of behavior and the hemisphere of injection. Injections of MK-801 in a variety of sites in the basolateral amygdala had no effect on the suppression of open-arm exploration produced by predator stress. Other amygdala nuclei or other limbic sites likely mediate the effects of systemically administered MK-801 on this behavior. In contrast, NMDA receptors in the left lateral amygdala mediate lasting suppression of risk assessment. MK-801, in a variety of sites in the left but not right lateral amygdala, blocked the effects of predator stress on risk assessment. This is clear evidence of separability of neural mechanisms controlling open-arm exploration and risk assessment. Different NMDA-dependent amygdala circuitry mediated effects of predator stress on unconditioned acoustic startle 1 week after cat exposure. The data indicate that integrity of the left lateral amygdala is necessary for potentiation of startle amplitude by predator stress, though NMDA receptors are not involved in this function. Nevertheless, NMDA receptors in the right, but not the left lateral amygdala, mediate initiation of changes in startle. The data also suggest that the right amygdala action is "downstream" from the left amygdala contribution. These findings are consistent with the view that NMDA receptors are involved in initiation, but not maintenance, of neural changes mediating lasting increases in anxiety following severe stress. Finally, the findings of the importance of the right amygdala in stress-induced enhancement of the startle response provides neurobiological face validity to predator stress as a model of aspects of posttraumatic stress disorder.     

Strain differences in the isolation-induced effects on prepulse inhibition of the acoustic startle response and on locomotor activity

The authors investigated the effects of isolation rearing on acoustic startle response, prepulse inhibition (PPI), its modification by apomorphine, and locomotor activity in 3 rat strains: Wistar (WS), Sprague-Dawley (SD), and Lister hooded (LH). SD and LH, but not WS, showed isolation-induced PPI deficits. In 2 consecutive PPI tests, only SD isolates showed significant PPI deficits. An isolation rearing effect in LH was significant only in the 1st PPI test. Apomorphine dose-dependently (0.0-0.5 mg/kg) disrupted PPI, but sensitivity to the drug differed, with WS and SD rats being more sensitive to lower doses (0.01-0.05 mg/kg) than LH rats (0.5 mg/kg). Isolates, irrespective of strain, did not differ from grouped rats in their response to the apomorphine challenge. Only WS and LH isolates demonstrated significantly increased locomotor activity. Strain differences in the different parameters measured did not predict isolation-induced effects on PPI.     

Effects of social isolation rearing on the limbic brain: A combined behavioral and magnetic resonance imaging volumetry study in rats

Rearing rats in social isolation from weaning induces robust behavioral and neurobiological alterations resembling some of the core symptoms of schizophrenia, such as reduction in prepulse inhibition of acoustic startle (PPI) and locomotor hyperactivity in a novel arena. The aim of this study was to investigate whether social isolation rearing induces volumetric remodeling of the limbic system, and to probe for anatomical structure–behavioral interrelations.     

Age-related differences in MK-801- and amphetamine-induced locomotor and stereotypic activities of rats

Changes in locomotor and stereotypic activities induced by an i.p. injection of either (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cycloheptan-5,10-imine maleate (dizocilpine or MK-801; 0.3 mg/kg) or D-amphetamine sulfate (AMPH; 1.5 mg/kg) were studied in male Mill Hill hooded rats of different age. The following age groups of animals were considered: 28-30 postnatal day (PND)-old rats (peripubertal), 48-50 PND-old (pubertal), 3-month-old (adults), 12-month-old (middle-aged) and 24-month-old (aged). The motor response was measured by an automated animal activity measuring system. The obtained results showed that: (1) in contrast to AMPH, MK-801 induced more pronounced increases of both locomotor and stereotypic activities in peripubertal and pubertal than in adult and aged rats; (2) AMPH induced the same locomotor and stereotypic activity increase in pubertal, adult and middle-aged rats; (3) both AMPH and MK-801 led to a senescence-related decrease of motor activity. These data suggest that the balance of the glutamatergic and dopaminergic systems changes during aging. Such a change is important in understanding schizophrenia and the motor system decline observed in the later stages of life.     

Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat

N-methyl-D-aspartate receptor antagonism exerts suppressive influences over dopamine D1 receptor-mediated striatal gene expression and locomotor behavior in the intact rat. The present study examined the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on locomotor activity and striatal preprotachykinin mRNA expression stimulated by the D1 agonist (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in rats with bilateral dopamine lesions. Two months after neonatal dopamine lesions with 6-hydroxydopamine, rats were challenged with (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) 15 min after administration of the N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg). In the intact rat, MK-801 prevented the induction of striatal preprotachykinin mRNA by D1 agonism. Similarly, direct infusion of (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.0 microg) into the intact striatum produced an increase in locomotor activity that was suppressed by MK-801 (1.0 microg) co-infusion. In the dopamine-depleted rat, MK-801 (0.1 mg/kg) administered prior to (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) increased, rather than suppressed, striatal preprotachykinin mRNA levels. Intrastriatal infusion of MK-801 (1.0 microg) failed to inhibit D1-mediated induction of motor activity in dopamine-depleted animals. Together, these data provide further support that N-methyl-D-aspartate receptor antagonists lose their ability to block D1-mediated behavioral activation following dopamine depletion. The activation, rather than suppression, of tachykinin neurons of the direct striatonigral pathway may play a facilitatory role in this mechanism.     

Reduced effects of amphetamine on prepulse inhibition of startle in gastrin-deficient mice

The present study was aimed at investigating the role of gastrin in startle, startle habituation and prepulse inhibition (PPI). There were no significant differences between gastrin knockout mice and their wildtype controls in any of these baseline parameters. The disruption of PPI by treatment with 5 mg/kg of amphetamine was absent in gastrin knockout mice. However, a higher dose of amphetamine disrupted PPI in both genotypes. Similarly, treatment with the dopamine receptor agonist, apomorphine, the N-methyl-D-aspartate receptor antagonist, MK-801, and the serotonin-1A receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT) modulated PPI similarly in gastrin knockout mice and wildtype controls. These data suggest a role of gastrin in the brain in modulating dopamine release in areas involved in PPI.     

Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat

Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.     

The topography of MK-801-induced locomotor patterns in rats

Locomotor patterns in rats given systemic injections of the novel, noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 were characterized using Digiscan Animal Activity Monitoring System. At low systemic doses, MK-801 produced an activity pattern most similar to patterns previously described for less potent noncompetitive NMDA antagonists; this was typified by hyperactive locomotor behavior, with increases in distance travelled, speed, and clockwise/anticlockwise locomotion, and a marked decrease in rearing behavior. Although MK-801 elicited some motor patterns similar to those previously described for sympathomimetic agents, including hyperactivity and increased stereotypy, it did not produce increased rearing behavior, the most prominent sympathomimetic effect. These results demonstrated that the topography of locomotion elicited by low systemic doses of MK-801 is most similar to locomotor patterns previously described for noncompetitive NMDA receptor antagonists.     

The effects of A1 and A2A adenosine receptor agonists on kainic acid excitotoxicity in the guinea pig cochlea

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in schizophrenia patients and in rats with central dopamine (DA) activation. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The aim of this study was to elucidate the role of DA transmission of the IC on the development of acoustic PPI. Bilateral microinjections of apomorphine (9.0 μg/0.5 μL), an agonist of D₂ receptors, into the IC disrupted PPI while microinjections of haloperidol (0.5 μg/0.5 μL), an antagonist of D₂ receptors, into this structure did not alter PPI. These results suggest that dopamine-mediated mechanisms of the IC are involved in the expression of PPI in rodents.     

帕潘立酮对社会交往缺陷的改善作用及对脑皮层GSK3β磷酸化的影响

目的　探讨新型非典型抗精神病药物帕潘立酮（Paliperidone）对精神分裂症（Schizophrenia）社会交往缺陷的改善作用及对脑皮层GSK3β磷酸化的影响。 方法　应用地佐环平（dizocilpine,MK-801）连续腹腔注射,建立了精神分裂症模型小鼠。实验分为3组：对照组（腹腔注射同体积0.9%生理盐水）、MK-801组（模型组,给予0.5 mg·kg-1·d-1 MK-801腹腔注射,连续注射7 d）、MK-801+Paliperidone组（帕潘立酮治疗组,给予0.25 mg·kg-1·d-1 帕潘立酮+0.5 mg·kg-1·d-1 MK-801腹腔注射,连续注射7 d）。应用刻板性旋转实验评价精神分裂症模型的建立,并应用Miceprofile软件分析各组小鼠在自由活动状态下的社会交往行为变化。Western blotting(WB)检测鼠额叶皮层脑组织糖原合成激酶3β（glycogen synthase kinase 3β, GSK3β）的表达变化。 结果　MK-801处理后明显增加实验小鼠的刻板性旋转动作,成功建立了精神分裂症小鼠模型。Miceprofile视频分析结果显示,模型鼠的交往接触次数和时长明显低于对照组（P<0.01）,帕潘立酮处理后,明显改善交往接触次数和时长（P<0.01）。WB分析结果显示MK-801明显降低脑皮层GSK3β的磷酸化水平,而帕潘立酮处理后可升高GSK3β磷酸化水平。 结论　本项研究表明新型抗精神病药物帕潘立酮可改善动物社会交往缺陷行为,可能与增加脑皮层的磷酸化GSK3β有关。     

Contribution of peripheral N-methyl-D-aspartate receptors to c-fos expression in the trigeminal spinal nucleus following acute masseteric inflammation

In this study, we examined the contribution of N-methyl-D-aspartate (NMDA) receptors on c-fos expression in the trigeminal brainstem nuclei following acute muscle inflammation. Mustard oil (MO; 20%, 30 microL) injected into the masseter muscle induced extensive peripheral edema and Fos-like immunoreactivity (Fos-LI) in several trigeminal brainstem areas including the subnucleus caudalis of the trigeminal spinal nucleus (Vc), the ventral and dorsal regions of the Vc/subnucleus interpolaris transition zone, and the paratrigeminal nucleus. In order to assess the effect of antagonizing NMDA receptors on MO-induced Fos-LI, rats were pre-treated with two different doses of i.v. MK-801 (0.3 mg/kg, 3 mg/kg), a non-competitive NMDA receptor antagonist, 30 min prior to MO injection. Additional groups of rats received MK-801 (0.3 mg/kg) directly in the masseter muscle or in the biceps muscle 5 min prior to MO injection. A higher dose of i.v. MK-801 (3 mg/kg) and MK-801 given locally into the masseter muscle (0.3 mg/kg) produced a significant reduction in total number of MO-induced Fos-LI. Further analyses revealed that pre-treatment with MK-801 (3 mg/kg i.v.) significantly reduced the Fos-LI all throughout the Vc. Only at the caudal Vc, there was a dose-dependent reduction of MO induced Fos-LI. Pre-treatment with masseteric MK-801 also significantly reduced the Fos-LI in the caudal Vc, with the effect greater than that produced by the same dose of MK-801 given intravenously. These results suggest that peripheral NMDA receptors contribute to nociceptive processing from craniofacial muscles.     

Effect of nitric oxide synthase inhibitor and NMDA receptor antagonist on the development of nicotine sensitization of nucleus accumbens dopamine release: An in vivo microdialysis study

We have previously found that the neuronal nitric oxide synthase inhibitor N-nitro-l-arginine (l-NNA) and the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 prevent behavioral sensitization to nicotine. This study aimed to investigate the effect of l-NNA and MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drugs on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague–Dawley rats were pretreated with l-NNA (15 mg/kg, i.p.), MK-801 (0.3 mg/kg, i.p.), or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for seven consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens for 60 min and DA release was monitored using in vivo microdialysis. In rats treated with repeated nicotine, acute nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response = 969 ± 235% (mean ± S.E.M.) of basal level versus 520 ± 93%, p = 0.042). Co-administration of l-NNA or MK-801 with nicotine attenuated an increase of DA release elicited by acute nicotine challenge, compared with nicotine alone (maximal DA response = 293 ± 58% and 445 ± 90% of basal level, respectively versus 969 ± 235%, p = 0.004 and p = 0.013, respectively). These data demonstrate that l-NNA and MK-801 block the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of nitric oxide and NMDA receptors in the development of behavioral sensitization to nicotine.     

The effect of MK-801 on mTOR/p70S6K and translation-related proteins in rat frontal cortex

In experimental animals, including rats, MK-801 produces characteristic behavioural changes that model schizophrenia. It has been hypothesized that these changes accompany long-term synaptic changes, which require protein neosynthesis. We observed the effect of MK-801 on the “mammalian target of rapamycin” (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway that regulates protein synthesis in the rat frontal cortex. A single injection of MK-801 (0.5, 1, or 2 mg/kg) induced an acute increase in the phosphorylation of Akt (Ser-473) eIF4E-binding protein (4E-BP1) (Thr-37/46) and p70S6K (Thr-389). In contrast, after repeated treatment with MK-801 (1 mg/kg for 5 or 10 days), the phosphorylation of Akt (Ser-473), mTOR (Ser-2481), 4E-BP1 (Thr-37/46), p70S6K (Thr-389), and S6 (Ser-240/244) increased. Thus, proteins in the mTOR/p70S6K pathway are modulated in chronic MK-801 animal models. These findings may suggest that repeated MK-801 treatment activates the signal transduction pathways involved in the initiation of protein synthesis in the rat frontal cortex.     

Neonatal exposure to MK801 promotes prepulse-induced delay in startle response time in adult rats

The acoustic startle reflex in rats can be inhibited if a prepulse stimulus is presented just before the startle stimulus (prepulse inhibition; PPI). When postnatal day 7 (P7) rats are exposed to agents that block the NMDA receptor (NMDAR), robust apoptosis is observed within hours and is thought to be followed at later ages by a significant loss of PPI. To understand these observations further, we exposed rat pups to vehicle or the NMDAR antagonist MK801 (1 mg/kg) at P6, P8, and P10. We then examined animals for PPI at P28 and P56. Compared to vehicle controls, we found no evidence for PPI deficits in the MK801-treated group, although we did observe prepulse-induced delay in response time at P56 (but not at P28). In a parallel study, we also performed histological analysis of brain sections for evidence of the pro-apoptotic marker activated caspase-3, 8 h after vehicle or MK801 injection into P6 animals. We found that there was a robust increase in this marker of cell death in the inferior colliculus of MK801 compared to vehicle-treated animals. Thus, transient blockade of the NMDAR during the postnatal period not only promotes early apoptosis in a brain region critical for acoustic processing but also leads to auditory deficits at a later age, suggesting that injury-induced loss of collicular neurons leads to network reorganization in the auditory system that is progressive in nature. A. Lyall and J. Swanson are co-first authors.