MK-801 blocks the development of sensitization to the locomotor effects of methylphenidate

Male Sprague-Dawley rats were divided to three groups (each n = 8) and were housed in test cages where motor activity was recorded continuously for 16 days using a computerized motor activity monitoring system to determine whether repeated administration of MK-801 could block the development and/or the expression of sensitization to the locomotor effects of methylphenidate (MPD). One group of rats received six daily injections (days 4-9) of 0.30 mg/kg MK-801, followed by 5 days without injection (days 10-14) and re-challenged (day 15) with 0.30 mg/kg MK-801. The second group received a challenge dose of 2.5 mg/kg MPD (day 4) followed by 5 days of co-treatment with MK-801 (0.30 mg/kg) given 1 h prior to MPD (days 5-9). This group was then re-challenged with MPD (2.5 mg/kg) on day 15. The last group received six daily injections of 2.5 mg/kg MPD (days 4-9). They were then split into two subgroups of rats which received either no treatment (control) or five daily injections of 0.30 mg/kg MK-801 (days 10-14) before being re-challenged on day 15 with 2.5 mg/kg MPD. MK-801 sensitized to its own locomotor effects. MK-801 given after sensitization had developed (i.e., days 10-14) was able to mask the expression of a sensitized response on day 15, but the effect was only transient since the sensitized response was present 3 weeks later. Moreover, MK-801, when coadministered during the repeated treatment phase was able to block the development of a sensitized response, which suggest that NMDA receptors involved in the process of MPD sensitization.     

Prior and delayed applications of dizocilpine or ethanol alter locomotor sensitization to morphine

Three experiments compared the effects of prior versus delayed applications of dizocilpine (MK-801), a noncompetitive NMDA antagonist, to ethanol, a putative NMDA antagonist, on morphine locomotor activity. In Experiment 1, rats received MK-801 (0.1 mg/kg), ethanol (1 g/kg), or vehicle injections 30 min prior to morphine (0 or 10 mg/kg) injections for 14 days. The expression of morphine (0 or 3 mg/kg) locomotor sensitization was assessed 1 week later. Both MK-801 and ethanol attenuated morphine-induced locomotor activity. Chronic MK-801 with or without morphine eliminated morphine's temporal pattern of activity calling into question the specificity of its effect on sensitization. In contrast, chronic ethanol administration attenuated morphine locomotor sensitization. In Experiment 2, the effects of the agents on the acute biphasic locomotor effects of morphine (hypoactivity followed by hyperactivity) were examined. Agents were administered 30 min prior to or 120 min after morphine (or vehicle). Neither agent at either administration time altered morphine's acute locomotor effects. In Experiment 3, the effects of chronic delayed application of MK-801 or ethanol (120-min post-morphine administration for 14 days) on the expression of morphine locomotor sensitization were assessed. Results were similar to the prior application effects of Experiment 1. These data suggest that the delayed effects of morphine are important in changes seen with chronic administration and these may involve NMDA receptor activation. Further, in conjunction with our previous work, ethanol appears to alter plasticity effects of chronic morphine administration perhaps via its NMDA antagonist effects.     

MK-801 (Dizocilpine): Synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization

Intraperitoneal injections of the D₂/D₃ dopamine agonist bromocriptine (5.0 mg/kg, IP) induced locomotion that became progressively stronger on successive days of testing. The sensitized response developed twice as rapidly when the non-competitive NMDA antagonist MK-801 (0.25 mg/kg, IP) was given 30 min after bromocriptine (so that the peak effects of the two drugs overlapped). In a second group of animals, MK-801 was given 30 min prior to bromocriptine (the pretreatment regimen typical of studies where MK-801 is reported to block cocaine, amphetamine or morphine sensitization) and locomotion was monitored during the pretreatment period; in this case sensitization to the locomotor-stimulating effects of MK-801 alone (in the pretreatment period) as well as sensitization to the locomotor-stimulating effects of the drug combination (following the second injection) were observed. No sensitization to the effects of MK-801 alone (pretreatment) were seen in animals that received saline rather than bromocriptine as their second injection in this experiment. Thus MK-801 does not block but rather enhances bromocriptine sensitization; it appears to do so by a synergism with the locomotor effects of bromocriptine and by becoming a conditioned stimulus for the sensitized response. These findings confirm the earlier report that NMDA receptor activation is not critical to bromocriptine-induced sensitization, and they illustrate the importance of controls for conditioning and state-dependency phenomena in studies of drug interactions in psychomotor sensitization. © 1996 Wiley-Liss, Inc.     

Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine

Repeated amphetamine administration produced behavioral sensitization to subsequent amphetamine challenge. The development of sensitization was blocked by coadministration of the N-methyl-d-aspartate (NMDA) antagonist MK-801. Conditioned locomotion, as revealed by saline challenge, was also blocked by MK-801, suggesting that behavioral sensitization and conditioned locomotion may share a requirement for NMDA receptor stimulation. Repeated MK-801 administration produced behavioral sensitization to MK-801 but not amphetamine challenge, suggesting that MK-801 itself produces sensitization through a different mechanism than amphetamine.     

Behavioral sensitization to ethanol results in cross-sensitization to MK-801 but not to NMDA administered intra-accumbens

In mice, repeated ethanol administration may induce behavioral sensitization - a process of progressive potentiation of its stimulant effects, associated with neuroadaptations in the brain reward system. Few studies have directly investigated the subsequent neuroadaptations in the nucleus accumbens (NAc), the central area of the brain reward system, after chronic ethanol administration. The goal of the present study was to analyze the involvement of accumbal glutamate NMDA receptors in the locomotion behavioral response to an NMDA agonist or to an NMDA antagonist in mice previously treated with ethanol. Swiss Albino mice received repeated daily administrations of 2.2g/kg ethanol or saline for 21 days. According to their locomotor response on the last day of treatment, ethanol-treated mice were classified into sensitized or non-sensitized groups. They were then submitted to a surgical procedure to implement intra-NAc cannulae. After recovery, mice were challenged with intra-NAc administration of saline and, two days later, with NMDA (NMDA agonist) or MK-801 (NMDA antagonist), having their locomotor activity recorded for 1h. The administration of NMDA induced similar locomotor behavior in all groups. On the other hand, the administration of 3μg/side MK-801 induced a significant stimulant effect which was more prominent during the first 15min in the sensitized group than in the non-sensitized or saline groups. Despite no effect of the agonist administration, only in sensitized mice did we observe cross-sensitization between repeated ethanol treatment and the intra-NAc administration of MK-801.     

Cortical alpha 1-adrenergic regulation of acute and sensitized morphine locomotor effects.

The role of alpha1-adrenergic transmission was tested on locomotor effects of acute or repeated morphine (5 mg/kg, i.p.) administration. Prazosin, an alpha1-adrenergic antagonist, administered 30 min before morphine, either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (200 pmol/side) reduced the stimulatory influence of morphine on locomotion. The progressive increase of the locomotor response induced by repeated morphine injections was blocked by a prazosin pretreatment but not the behavioral sensitization on the test day. These data suggest that blockade of cortical alpha1-adrenergic receptors reduces the expression of acute and sensitized locomotor responses to morphine, but does not prevent the induction of behavioral sensitization.     

Morphine-induced place preference: involvement of the central amygdala NMDA receptors

In the present study, the effects of bilateral injections of N-methyl-d-aspartate (NMDA) receptor agonist and/or antagonist into the central amygdala (CeA) on the acquisition and expression of morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Animals that received 3 daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg) indicated a significant preference for compartment paired with morphine in a dose dependent manner. Intra-CeA administration of the NMDA (0.01, 0.1 or 1 microg/rat) with an ineffective dose of morphine (1 mg/kg, s.c.) elicited a significant CPP. Administration of the non-competitive NMDA receptor antagonist, MK-801 (0.1, 0.3 or 0.5 microg/rat), into the central amygdala dose-dependently inhibited the morphine (6 mg/kg, s.c.)-induced place preference. Furthermore, intra-CeA administration of MK-801 (0.25, 0.5 or 1 microg/rat) reduced the response induced by NMDA (1 microg/rat, intra-CeA) plus morphine (1 mg/kg, s.c.). Neither NMDA nor MK-801 alone produce a significant place preference or place aversion. Moreover, intra-CeA injection of NMDA but not MK-801 before testing significantly increased the expression of morphine (6 mg/kg, s.c.)-induced place preference. NMDA or MK-801 injections into the CeA had no effects on locomotor activity on the testing sessions. These results suggest that the NMDA receptor mechanisms in the central amygdala may be involved in the acquisition and expression of morphine-induced place preference.     

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations.

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.     

Behavioural sensitization to cocaine is dissociated from changes in striatal NMDA receptor levels

Changes in glutamate transmission and alterations in glutamate receptor expression produced by the repeated administration of psychomotor stimulant drugs are considered an important neuroadaptation underlying the development and expression of behavioural and neurochemical sensitization to stimulant drugs. Two parallel experiments investigated the effects of repeated cocaine administration (five, once daily injections of 15 mg/kg, i.p.; 2 weeks withdrawal) on the expression of behavioural sensitization in response to a cocaine challenge (20 mg/kg, i.p.) and the changes in NMDA receptor binding in pooled tissue from the nucleus accumbens and the striatum. Compared with acute cocaine controls (n = 11), animals administered cocaine repeatedly displayed a sensitized stereotypic response to the cocaine challenge injection (n = 8). Despite this, no differences in either NMDA receptor density or affinity were observed between rats administered repeatedly with cocaine or saline, as indexed by [3H]MK-801 binding. The present findings call to question the rationale for NMDA receptor-based pharmacotherapies for the treatment of the enduring symptomatology of stimulant addiction.     

Effects of blockade of glutamate NMDA receptors or of NO synthase on the development or the expression of associative or non-associative sensitization to locomotor activation by morphine

Summary. The sensitization to the pharmacological actions of morphine is probably a critical factor in the addictive properties of this drug. A discrimination between associative and non-associative type of sensitization might be relevant for possible differences in drug effects on sensitization phenomena. Furthermore, blockade of NMDA receptors might lead to an inhibition of NO-synthesis, and, accordingly, both of these effects might influence sensitization phenomena in a similar way. Male Wistar rats were sensitized to morphine by administrations of 3 mg/kg of morphine i.p. on day 1, 3, 5, and 7 and saline on days 2, 4, and 6. In part of the animals, the administration of morphine was performed in association with conditional stimuli, CS (test cage plus an auditory and an olfactory stimulus), in the other part not (pseudoconditioned, PCS). On day 17, the sensitization was more pronounced in the CS than the PCS group. The effects of dizocilpine (MK-801; 0.1 mg/kg i.p.), a blocker of NMDA glutamate receptors, or of L-NAME (N(G)-nitro-L-arginine methylester; 10 mg/kg i.p.), a non-specific inhibitor of NO synthase and the effect of N(ω)-propyl-L-arginine (20 mg/kg i.p.), a specific inhibitor of neuronal NO synthase, on expression or development of sensitization to morphine was studied. Neither MK-801 nor L-NAME influenced the development of associative and non-associative behavioural sensitization to morphine. The expression of sensitization to morphine was not influenced by MK-801. L-NAME inhibited the expression of associative, but not of non-associative sensitization. Surprisingly, inhibition of neuronal NO synthase, did not influence the expression of associative sensitization. We suggest that NMDA receptors were not involved in development or expression of both types of sensitization. Furthermore, the manifestation of the associative, but not the non-associative sensitization to morphine appeared to be dependent on a type of NO synthase, which is not the neuronal NO synthase, but probably the inducible NOS.     

The effect of MK-801 and SCH23390 on the expression and sensitization of morphine-induced oral stereotypy

Repeated high doses of morphine sulfate, administered in a 24–36 h period, stimulates the expression of oral stereotypy in rats. Sensitization to this effect of morphine is demonstrated by the reexpression of the stereotypy by the administration of 4.0 mg/kg of morphine one week following the original exposure. To investigate the role ofN-methyl-d-aspartic acid (NMDA) and D₁ dopamine (DA) receptors in the acute expression and sensitization of morphine-induced oral stereotypy, rats were administered four injections of morphine (10.0 mg/kg) one injection every 12 h and observed for the expression of stereotyic behaviors following pretreatment with selective antagonists. Pretreatment with the NMDA antagonist, MK-801 (0.7 mg/kg), before each of the four morphine injections antagonized both the initial expression of oral stereotypy and the development of sensitization. In contrast, the DA D₁ receptor antagonist SCH23390 (40.0 μg/kg) administered during the four high-dose treatments with morphine antagonized the initial expression of oral stereotypy and not the development of sensitization. These findings implicate glutamate's action at the NMDA receptor in both the acute expression of morphine-induced oral stereotypy, and the development of sensitization of this morphine effect, whereas DA D₁ receptors may only be involved in the acute expression of the stereotypy.     

Delayed application of MK-801 attenuates development of morphine tolerance in rats

To investigate the possible involvement of enduring or delayed changes at the N-methyl-D-aspartic acid (NMDA) receptor in the mechanisms of morphine tolerance, rats were treated with the specific NMDA receptor antagonist, MK-801 (0.15 mg/kg) 2 h after morphine injection (20 mg/kg) during a 4-day induction period of tolerance. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by MK-801. These findings suggest that long-lasting or delayed changes at the NMDA receptor underlie the development of morphine tolerance. Moreover, because MK-801 was delivered 2 h after morphine and therefore could not serve as a cue for morphine administration, these findings indicate that the attenuating effect of MK-801 on the development of morphine tolerance is not attributable to state-dependent learning.     

Sex difference in sensitization to the locomotor effects of mazindol in rats

Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization to its locomotor stimulatory effect in both sexes on day 7 with a nondose-dependent pattern of response. However, the locomotor activity appeared to be sex dependent, female rats being more sensitive. Following a challenge dose of mazindol (10 and 20 mg/kg) on day 10, a marked enhancement of locomotion was seen in female rats. These findings indicate that repeated administration of mazindol produces sex-dependent sensitization to its effect on locomotor behavior.     

Effects of zotepine,haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats

Summary In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing sterotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.     

Involvement of NMDA receptors in morphine state-dependent learning in mice

In the present study, the effects of intracerebroventricular (i.c.v.) injection of NMDA receptor agonist and antagonist on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pretraining administration of morphine (5 mg/kg; s.c.) decreased the learning of one-trial passive avoidance task. Pretest administration of morphine (5 mg/kg) induced state-dependent learning acquired under pretraining morphine influence. Pretest administration of NMDA receptor agonist, L-glutamate (0.00001 and 0.0001 and 0.001 microg/mouse, i.c.v.) following pretraining saline treatment did not affect retention. Amnesia induced by pretraining morphine was significantly reversed by pretest administration of L-glutamate (0.0001 and 0.001 microg/mouse, i.c.v.). Pretest administration of noncompetitive NMDA receptor antagonist, MK-801 (0.5, 1, and 2 microg/mouse, i.c.v.) significantly impaired memory formation. Amnesia induced by pretraining morphine was increased by pretest administration of MK-801 (2 microg/mouse, i.c.v.). Pretest coadministration of L-glutamate (0.0001 and 0.001 microg/mouse, i.c.v.) or MK-801 (0.5, 1, and 2 microg/mouse, i.c.v.) with morphine (5 mg/kg, s.c.) increased and decreased morphine state-dependent learning, respectively. The results suggest that NMDA receptors are involved in morphine state-dependent learning in mice.     

INVOLVEMENT OF NMDA RECEPTORS IN MORPHINE STATE–DEPENDENT LEARNING IN MICE

In the present study, the effects of intracerebroventricular (i.c.v.) injection of NMDA receptor agonist and antagonist on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pretraining administration of morphine (5 mg/kg; s.c.) decreased the learning of one-trial passive avoidance task. Pretest administration of morphine (5 mg/kg) induced state-dependent learning acquired under pretraining morphine influence. Pretest administration of NMDA receptor agonist, L-glutamate (0.00001 and 0.0001 and 0.001 μg/mouse, i.c.v.) following pretraining saline treatment did not affect retention. Amnesia induced by pretraining morphine was significantly reversed by pretest administration of L-glutamate (0.0001 and 0.001 μg/mouse, i.c.v.). Pretest administration of noncompetitive NMDA receptor antagonist, MK-801 (0.5, 1, and 2 μg/mouse, i.c.v.) significantly impaired memory formation. Amnesia induced by pretraining morphine was increased by pretest administration of MK-801 (2 μg/mouse, i.c.v.). Pretest coadministration of L-glutamate (0.0001 and 0.001 μg/mouse, i.c.v.) or MK-801 (0.5, 1, and 2 μg/mouse, i.c.v.) with morphine (5 mg/kg, s.c.) increased and decreased morphine state-dependent learning, respectively. The results suggest that NMDA receptors are involved in morphine state–dependent learning in mice.     

Influence of acute or repeated restraint stress on morphine-induced locomotion: involvement of dopamine,opioid and glutamate receptors

The development of restraint stress-induced sensitization to the locomotor stimulating effect of morphine (2 mg/kg i.p.) was investigated. In experiment 1, both a single restraint session (2 h) and a repeated restraint stress (2 h per day for 7 days), similarly enhanced the effects of morphine on motor activity. In experiment 2, we observed that this sensitization was prevented by administration of both D(1) and D(2) dopaminergic antagonist [SCH-23390 (0.5 mg/kg i.p.) and (+/-)-sulpiride (60 mg/kg i.p.)] 10 min prior to the stress session. In experiment 3, we showed that an opioid antagonist pretreatment [naltrexone (1 mg/kg i.p.) 10 min prior to stress session, suppressed the stress-induced sensitization after morphine administration. In experiment 4, pretreatment with a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors [(+)-MK-801 (0.1 mg/kg i.p.)], 30 min prior to the acute restraint session, prevented the development of sensitization to morphine. All these results suggest that: (1) sensitization to morphine on stimulating locomotor effect does not depend on the length of exposure to stress (acute vs. repeated); (2) stimulation of both D(1) and D(2) dopaminergic receptors is necessary for the development of restraint stress-induced sensitization to morphine; (3) an opioid system is also involved in this sensitization process; and (4) the stimulation of glutamatergic NMDA receptors is involved in this acute restraint-induced effect.     

The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopamine responses produced by repeated morphine treatment

18-Methoxycoronaridine (18-MC), a novel synthetic iboga congener, attenuates the reinforcing efficacy of morphine, disrupts some signs of morphine withdrawal in physically dependent rats and attenuates the dopamine response in the nucleus accumbens to acute morphine. The present study further investigated the interactions between 18-MC and morphine by examining the effects of 18-MC (40 mg/kg, i.p., 19 h earlier) on the expression of dopamine sensitization in the nucleus accumbens in response to morphine (20 mg/kg, i.p.) and on the dose-effect curves for morphine-induced locomotion (0-30 mg/kg, i.p.) in rats treated either acutely or repeatedly (five, once daily, injections of 20 mg/kg, i.p.) with morphine. Compared to vehicle pretreated controls, 18-MC increased the potency of morphine, shifting the dose-response curve to the left, in acute morphine treated rats; however, 18-MC did not alter the potency of morphine in rats treated repeatedly with morphine. Repeated morphine administration induced locomotor sensitization in approximately 50% of the rats tested; in vehicle pretreated rats, the morphine dose-response curve was shifted to the left in sensitized as compared to non-sensitized rats. In 18-MC pretreated rats, sensitized and non-sensitized rats responded similarly to morphine, revealing a blockade of sensitization by 18-MC. Consistent with this behavioural finding, 18-MC pretreatment completely abolished the sensitized dopamine response in the nucleus accumbens expressed by rats repeatedly treated with morphine. It is suggested that the potential anti-addictive efficacy of 18-MC might be related to an ability to restore normal functioning to a hypersensitive mesolimbic dopamine system produced by previous repeated morphine administration.     

Individual differences to repeated ethanol administration may predict locomotor response to other drugs, and vice versa

Repeated administration of drugs may induce adaptations which affect the behavioral responses to the drug itself or to other drugs. Whether individual characteristics to repeated drug administration predict sensitivity to the effects of another drug is not clear. We evaluated whether or not mice that present higher vs. lower locomotor response after repeated treatment with ethanol display increased or decreased locomotor responses when challenged with methamphetamine or morphine, and vice versa. Mice received daily i.p. 2.2 g/kg ethanol (21 days), 1.0 mg/kg methamphetamine or 10 mg/kg morphine (10 days). According to the response presented during repeated drug treatment, mice were classified as HIGH or LOW activity groups. Locomotor activity was monitored after mice were challenged with saline, and 48 h later with a drug. Ethanol-treated mice were challenged with methamphetamine or morphine, methamphetamine- and morphine-treated animals were challenged with ethanol. After repeated treatment with ethanol or methamphetamine, locomotor sensitization was observed only in HIGH mice, not LOW mice. Ethanol-treated mice with HIGH activity showed sensitized, increased locomotor responses to methamphetamine (p<0.05), but not to morphine. Locomotor responses to ethanol were not affected by a previous history of methamphetamine treatment. Although repeated administration of morphine failed to induce sensitization, morphine-treated mice with HIGH activity presented sensitized locomotor responses after an ethanol challenge. The current experiments confirm important individual differences in response to repeated administration of ethanol, methamphetamine and morphine, which in some cases affected the locomotor response to a second drug challenge, in an asymmetrical pattern.     

A single pretreatment with MK-801 or cocaine enhances their locomotor stimulant effects in rats

A single dose of MK-801 (1.0 mg/kg, s.c.) induces an enhanced locomotor response to a subsequent lower dose of MK-801 (0.3 mg/kg) administered 4, 7 or 14 days later in young adult rats (>90 days). MK-801 (1.0 mg/kg) administration did not significantly enhance the effects of cocaine (10, 20 mg/kg) administered 7 days later. Cocaine (20 mg/kg) enhanced the effect of a subsequent dose of 10 mg/kg cocaine, but did not significantly alter the response to a higher dose cocaine (20 mg/kg) or of MK-801 (0.1 or 0.3 mg/kg) again given 7 days later. MK-801 (1.0 mg/kg) did not significantly enhance the locomotor response to a second dose of MK-801 (0.3 mg/kg) in 28-day-old rats tested 7 days after the initial dose, but did enhance the effects of a lower (0.1 mg/kg) dose. These findings indicate that even a single dose of a stimulant such as MK-801 and cocaine can induce enduring changes in sensitivity to subsequent doses of the same stimulants in young adult rats. The lack of significant effects seen in cross-sensitization studies suggests that separate mechanisms maybe involved in the sensitization to cocaine and MK-801. The more pronounced enhancement of activity in the older animals is in accord with previous findings that sensitization processes are developmentally regulated.