Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

Rationale Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. Objective To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. Materials and methods LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. Results Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. Conclusions These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

Rationale A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.Objectives The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.Results PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.Conclusions The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.     

Evidence for dissociable mechanisms of amphetamine-and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg IP) or haloperidol (0.10 or 0.25 mg/kg IP). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeatedd-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg IP) 15 min before each of ten amphetamine injections (1.0 mg/kg IP, administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline andd-amphetamine (1.5 mg/kg IP). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine-and stress-induced behavioral sensitization may arise through different mechanisms.     

Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine in the rat

Rationale Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit.Objectives The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter.Methods Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm.Results PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg).Conclusions Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.     

Facilitating effects of some chlorpromazine-d-amphetamine mixtures on avoidance learning

The effects of several chlorpromazine-d-amphetamine mixtures on discriminated avoidance learning in rats have been studied and compared with the effects of d-amphetamine alone, and it has been found that some of these mixtures increase shock avoidance very significantly. The different mixtures cannot be compared on the basis of the same dose ratio, but some of the observed effects can probably be explained in terms of more or less sustained brain levels of d-amphetamineThe combined treatment of 1 mg/kg chlorpromazine and 1 mg/kg d-amphetamine is one of the most effective and an increase of conditioned responses and a decrease of interresponses is observed in this group as compared with the corresponding d-amphetamine 1 mg/kg group. The significance of these findings and the possible sources of this especial behavioural interaction of the two drugs are discussed.A preliminary report of this study was presented at the 7th International C.I.N.P. Congress, Praha, August 1970.With the technical assistance of Miss M^a Luz de Toro.     

Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area

Rationale: The activation of NMDA receptors in the rat ventral tegmental area has been proposed to be necessary for the induction of locomotor sensitization by amphetamine, yet there has been no direct assessment of this view. Objective: The present study examined the ability of the competitive NMDA receptor antagonist d(–)-2-amino-5-phosphonopentanoic acid (AP-5) to block this effect when infused either into the ventral tegmental area or, for comparison, into the nucleus accumbens. These sites are known to be important for the induction and expression, respectively, of locomotor sensitization by amphetamine. Methods: Rats in different groups received four pairs of injections (one IC and one IP), one pair given every third day. The IC injection (0, 1 or 5 nmol/side AP-5) was administered immediately before the IP injection (saline or amphetamine, 1 mg/kg). Locomotor activity was measured following each pair of injections and again 2 weeks later when all rats were tested for sensitization following a challenge injection of amphetamine (1 mg/kg, IP). AP-5 was not administered on this test. Results: As expected, rats previously exposed to amphetamine alone showed higher levels of horizontal locomotion and rearing on the test for sensitization when compared to saline pre-exposed rats. Preceding the amphetamine pre-exposure injections with infusions of AP-5 into the ventral tegmental area, but not the nucleus accumbens, dose-dependently blocked the induction of this effect. Rats previously exposed to AP-5 alone in either site did not differ significantly from saline pre- exposed rats on the test for sensitization. Conclusion: The results indicate that NMDA receptor activation in the ventral tegmental area, but not the nucleus accumbens, is necessary for the induction of locomotor sensitization by amphetamine. Received: 7 December 1999 / Accepted: 30 March 2000     

Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist,MK-801

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, has been shown to block the development of sensitization of the behavioral activating effects of amphetamine. Three experiments were designed to determine in rats whether MK-801 had its effects through interference with long-term changes underlying sensitization, per se, or through interference with the development of conditioning of the drug effect to the environment where the drug was given. In experiment 1, conditioning was promoted by explicitly pairing amphetamine (1.5 mg/kg, IP) with the testing environment. In experiment 2, a random-pairing procedure was used to eliminate the possibility of association between the drug and a specific context. Experiment 3 was carried out to assess the duration of the blockade of sensitization by MK-801. The effect of MK-801 (0.25 mg/kg, IP) during amphetamine pre-exposure was studied in tests for conditioning (following saline injections, experiment 1) and in tests for sensitization (following 0.75 mg/kg amphetamine, experiments 1, 2 and 3). It was found in experiment 1 that MK-801 given with amphetamine during the amphetamine pre-exposure phase blocked the development of both conditioning activity and environment-specific sensitization to amphetamine. The results of experiment 2, showing that sensitization to amphetamine was blocked by MK-801 even when conditioning was prevented, suggest that the two effects of MK-801 are independent, and may implicate different sites of action. Experiment 3 showed that the blockade of sensitization by MK-801 was evident in tests made 10 days after pre-exposure to amphetamine, supporting the view that MK-801 interferes with long-term changes underlying sensitization to amphetamine.     

Modulators of the glycine site on NMDA receptors, <Emphasis Type="SmallCaps">d</Emphasis>-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia

Rationale Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.Objectives This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, d-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801.Methods C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise–foot shock pairings.Results Clozapine (3 mg/kg) and d-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by d-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, d-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801.Conclusions d-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.     

NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats

Rationale and objectives To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinsons disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD.Methods Following unilateral injections of 12 µg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both front paws was measured separately as the paws were dragged backwards and laterally. The effects of IP injections of varying doses of l-dopa, the non-competitive NMDA receptor antagonist dizocilpine [(+)-MK-801], the competitive NMDA receptor antagonist CPP, and combinations of l-dopa and NMDA receptor antagonists were then examined on stepping in three separate groups of rats.Results The lesioned rats stepped less often with their contralateral paw than with their ipsilateral paw, and the magnitude of this stepping deficit was positively correlated with the amount of DA depletion in the ipsilateral dorsal striatum. l-Dopa (1–25 mg/kg) dose dependently enhanced stepping with the contralateral paw, and 0.15-0.3 mg/kg dizocilpine and 1.5–6.25 mg/kg CPP enhanced stepping with the contralateral paw as much as did 8 mg/kg l-dopa. The combinations of l-dopa and each of the NMDA receptor antagonists did not significantly improve stepping more than either drug alone. Moreover, none of the drugs completely eliminated the stepping deficits, and high doses began to impair stepping with the ipsilateral paw by inducing turning.Conclusions These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.     

Can the ”state-dependency” hypothesis explain prevention of amphetamine sensitization in rats by NMDA receptor antagonists?

 Many laboratories have reported that coadministration of N-methyl-d-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative ”state-dependency” interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the ”state-dependency” hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction. Received: 29 January 1998 / Final version: 23 July 1998     

Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine,and the dopamine reuptake inhibitor GBR12909 in mice

Rationale Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, d-amphetamine, and the dopamine reuptake inhibitor GBR12909.Methods Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), d-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined.Results MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, d-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg.Conclusions Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, d-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.     

Effects ofd-fenfluramine and metergoline on responding for conditioned reward and the response potentiating effect of nucleus accumbensd-amphetamine

These studies investigated the effects of the 5-hydroxytryptamine (5-HT) releaser, and re-uptake inhibitor,d-fenfluramine, and the non-selective 5-HT receptor antagonist metergoline, on responding for conditioned reward (CR), and on the potentiation of responding for CR following amphetamine injected into the nucleus accumbens. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase, water was not delivered but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers; responding on the other lever was not reinforced. Overall, rats responded at a higher rate on the lever delivering the CR.d-Amphetamine (1, 3 and 10 µg) injected into the nucleus accumbens dose-dependently enhanced responding on the CR lever. Treatment withd-fenfluramine (0.5 and 1 mg/kg) reduced responding for the CR, and abolished the potentiating effect ofd-amphetamine. Responding on the inactive lever was also reduced by 1 mg/kg but not 0.5 mg/kgd-fenfluramine. The reduction ofd-amphetamine's effect on responding for CR was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Control experiments showed that changes in thirst and motor performance, as well as deficits in learning ability, cannot account for the effects ofd-fenfluramine in this paradigm. In a separate experiment, 1 mg/kg metergoline failed to enhance responding for CR, and to augment the response potentiating effect of a low dose (2 µg) ofd-amphetamine injected into the nucleus accumbens. Thus, elevating brain 5-HT activity appears to reduce the ability of secondary reinforcing stimuli to elicit and maintain behaviour, and antagonizes the effects of enhanced dopamine activity within the nucleus accumbens. However, reduced 5-HT function induced by blockade of 5-HT_1/2 receptors does not appear to influence responding for CR, or the response potentiating effect ofd-amphetamine. These results suggest that 5-HT may play an important role in mediating incentive motivation.     

Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine)

Rationale: It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol. Objectives: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine. Methods: Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1–10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days). Results: The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity. Conclusions: Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation. Received: 14 October 1999 / Accepted: 7 March 2000     

Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors

Rationale Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear.Objective We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801).Methods In adult, male CFW mice, sensitization was induced by either ten daily injections of d-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined.Results The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization.Conclusions These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.     

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats

 This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, IP) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, SC) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed. Received: 15 May 1997/Final version: 7 July 1997     

The NMDA positive modulatord-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat

According to the view that N-methyl-d-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulatord-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D₁ dopamine receptor blocker SCH 23390 or the D₂ antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore, the positive NMDA modulator allowed (–)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.     

Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine

Rationale Our group has recently shown that methamphetamine (METH) (2.5 mg/kg) induced delayed increases in glutamate (Glu) levels in the rat nucleus accumbens (NAC), and that its repeated administration leads to behavioral cross-sensitization to a selective uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801).Objectives The present study aims to examine whether valproate (VPA) would inhibit the delayed increases in Glu levels and prevent METH (2.5 mg/kg)-induced behavioral cross-sensitization to MK-801 (0.2 mg/kg).Materials and methods We examined the effects of post-treated VPA (50 mg/kg) on METH (2.5 mg/kg)-induced delayed increases in Glu levels. We injected VPA (50 mg/kg) at 120 min after each METH (2.5 mg/kg, once every other day, total of five times) administration and measured locomotor activity induced by challenge with MK-801 (0.2 mg/kg) or METH (0.15 mg/kg) after sufficient withdrawal period. Finally, we measured locomotion induced by MK-801 (0.2 mg/kg) after pretreatment of a competitive NMDA receptor antagonist, CPP (30 mg/kg). Effects of VPA on extracellular Glu levels were examined by using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor.Results VPA administered 120 min after METH injection had no effect on METH-induced hyperlocomotion, and inhibited METH-induced delayed increases in Glu levels. Repeated VPA administration prevented METH-induced behavioral cross-sensitization to MK-801, but not sensitization to METH. MK-801-induced hyperlocomotion was enhanced when pretreated with the competitive NMDA receptor antagonist, CPP.Conclusions These results suggest that VPA inhibits high-dose METH-induced delayed increases in Glu levels to prevent development of behavioral cross-sensitization to an NMDA antagonist, but not sensitization to METH.     

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice

Rationale Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.Objectives The effects of N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, and a combination of a NO precursor l-arginine and l-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.Methods Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, l-NAME (15–60 mg/kg) and l-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.Results Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of l-NAME blocked the development of sensitization to nicotine; and, l-arginine (1 g/kg) pretreatment reversed this effect of l-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of l-NAME inhibited the expression of sensitization to nicotine on day 18; and, l-arginine (1 g/kg) pretreatment reversed this inhibitory effect of l-NAME.Conclusions Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.