Conditioned behavioural responses to apomorphine: extinction and haloperidol-induced inhibition

Summary In previous studies it was established that stereo-typies (sniffing, licking, gnawing) produced by apomorphine can be conditioned and after repeated pairings with defined conditioned stimuli (auditory, tactile + olfactory) these stereotypies can be observed in the presence of the conditioned stimuli alone. In the present experiments, the extinction of these conditioned stereotypies was studied in one series; in another series, the possible inhibition of conditioned stereotypies by the blocker of dopamine receptors, haloperidol, was measured. The rats were conditioned (or the controls pseudoconditioned, respectively) for either 3 or 10 days with 2.0 mg/kg s. c. apomorphine or 6 days with 0.5 mg/kg s. c. of the drug and by placing them into particular cages in the presence of an auditory and an olfactory stimulus. Under all these conditions, episodes of conditioned stereotypies were observed, when solvent + conditioned stimuli instead of apomorphine was applied 1 day after the last conditioning session (first session of extinction). The conditioned responses seemed to be on the highest level after conditioning with 2.0 mg/kg apomorphine 3 days, lower after conditioning with the same dose on 10 days, and even lower after conditioning for 6 days with 0.5 mg/kg. Under all these conditions, the stereotypies summed up and averaged for the total observation period of 60 min rapidly decreased during the extinction period, so that on day 4 of the extinction period, no further significant differences between conditioned and pseudoconditioned animals were observed, although a short initial period was still observed on the fourth day. On day 3 of extinction, not only an early, but also a late episode of conditioned stereotypies was manifest, interrupted by an almost silent period. The acute (unconditioned) stereotypies produced by 0.5 mg/kg s. c. apomorphine were almost completely suppressed by pre-treatment with 0.1 mg/kg i. p. haloperidol. In contrast, the same dose of haloperidol produced a much less pronounced inhibition of conditioned stereotypies after conditioning with the same dose of apomorphine for 6 times. These results, together with previous findings, suggest that the conditioned behavioural effects are not due to an activation of dopaminergic mechanisms during conditioning with apomorphine. Send offprint requests to K. Kuschinsky at the above address     

Deficient prepulse inhibition of acoustic startle in Hooded-Wistar rats compared with Sprague-Dawley rats

1. Prepulse inhibition of acoustic startle has been suggested as a model of sensorimotor gating and central sensory information processing. Prepulse inhibition is impaired in patients with schizophrenia and responses can be restored by antipsychotic drug treatment. In the present study, startle and prepulse inhibition of startle were compared in different rat strains. 2. Sprague-Dawley rats showed robust inhibition of startle responses by increasing intensities of prepulse delivered just before the startle stimulus. In contrast, at both 4 and 10 weeks of age, rats of the Hooded-Wistar line had markedly reduced prepulse inhibition, although startle responses were not different. 3. Treatment with the dopamine receptor agonist apomorphine (0.1 mg/kg) or the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (0.1 mg/kg) caused disruption of prepulse inhibition in Sprague-Dawley rats. In Hooded-Wistar rats, apomorphine further reduced the already low level of prepulse inhibition, but MK-801 treatment had no significant effect. This suggests that the impaired prepulse inhibition in Hooded-Wistar rats could be caused by changes in glutamatergic activity and/or NMDA receptors in these rats. 4. In photocell cages, spontaneous exploratory activity and inner zone activity were significantly lower in Hooded-Wistar rats than in Sprague-Dawley rats. Similarly, on the elevated plus-maze, Hooded-Wistar rats showed a lower propensity to visit the open arms. In contrast, amphetamine (0.5 mg/kg)-induced locomotor hyperactivity, an animal model of psychosis, was enhanced in Hooded-Wistar rats. 5. These data suggest that the Hooded-Wistar line could be a useful genetic animal model to study the interaction of glutamatergic and dopaminergic mechanisms in anxiety and schizophrenia.     

MK-801 prevents the enhanced behavioural response to apomorphine elicited by repeated electroconvulsive treatment in mice

Repeated administration of electroconvulsive stimuli (ECS) to mice once daily for a period of 7 days results in an enhanced locomotor response induced by apomorphine (1.0 mg/kg, IP). Pretreatment (30 min) with the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.01–1.0 mg/kg IP), suppressed ECS-induced seizure activity in a dose-dependent manner. MK-801 (0.01 and 0.033 mg/kg, IP) given 30 min before each ECS dose-dependently decreased apomorphine-mediated responses. Administration of MK-801 (0.033 mg/kg IP) 30 min after each convulsion had the same effect. These results indicate that MK-801 can abolish the ECS-induced enhancement of dopamine-mediated behaviour possibly by interfering with postictal processes. Thus, NMDA receptors seem to be involved in the behavioural changes and presumably also in the neural adaptations produced by repeated ECS.     

Effect of NMDA receptor antagonists on D1, D2 and D1/D2 mediated behaviors in intact rats

The effect of treatment with the competitive (CGP 43487) and non-competitive (MK-801) NMDA antagonists on behaviors induced by the stimulation of D₁ (SKF 38393 induced grooming), D₂ (LY 171555 elicited hypermotility) or D₁/D₂ (apomorphine induced locomotion and stereotypies) was observed in intact rats. The administration of low doses of MK-801 (0.03 and 0.06 mg/kg) or CGP 43487 (0.375 and 0.75 mg/kg), which were without effect by themselves on animal locomotion, reduced the hyperactivity induced by LY 171555 (0.15 mg/kg) and did not change the stimulating motor effect of a low dose of apomorphine (0.15 mg/kg). Spontaneous grooming behavior was inhibited by both NMDA antagonists, whereas the administration of CGP 43487 but not of MK-801 potentiated grooming response to SKF 38393 (10 mg/kg). Both antagonists increased stereotyped behavior induced by 0.25 mg/kg apomorphine. The results, according to those obtained by other authors in DA depleted/lesioned animals, support the view of interaction between NMDA/D₁,D₂ receptors in intact rats.     

Cerebral oligemic hypoxia and MK-801 treatment: effect on alternation behavior in mice

It is known that glutamatergic system is one of neurotransmitter systems affected by a transiently reduced oxygen supply. The aim of the present study was to examine the effects of MK-801, a noncompetitive NMDA receptor antagonist, on spontaneous alternation in mice exposed to cerebral oligemic hypoxia. Spontaneous alternation behavior and locomotor activity were evaluated using the Y-maze task. Transient cerebral oligemia was induced by bilateral clamping of carotid arteries (BCCA) for 30 min under pentobarbital anesthesia. MK-801 was injected 48 h after BCCA or sham surgery, 30 min before the test session. Treatment with MK-801 (0.1 mg/kg ip) impaired spontaneous alternation both in sham-operated and BCCA mice. MK-801 (0.1 mg/kg ip) significantly enhanced the locomotion of mice. The effects of MK-801 were not exacerbated by BCCA. These results show that cerebral oligemic hypoxia induced by BCCA does not change alternation behavior of mice treated with MK-801.     

Studies on interactions between conditioned and unconditioned behavioural responses to apomorphine in rats

Summary Interactions between the direct (unconditioned) behavioural effects apomorphine and its conditioned effects after pairing with previously neutral stimuli were studied. Rats were injected once daily for 3–12 times, with apomorphine (2.0 mg/kg or 0.5 mg/kg or 0.07 mg/kg s.c. the dose kept constant in each series), in the presence of defined environmental stimuli (a wire cage in association with an acoustic and an olfactory stimulus) as conditional stimuli. The two larger doses produced stereotyped sniffing, licking, and gnawing, the smallest dose akinesia, ptosis, yawning and penile erections. During the conditioning phase, the drug produced most of the effects with increasing intensity and in the case of the stereotypies, there also was a shift to higher scores of stereotypy, with a reduced latency in onset of the signs. On the test day, 1 day after the last administration of apomorphine, the conditioned rats as well as pseudoconditioned controls were treated with a test dose of apomorphine in the presence of the conditional stimuli. Pseudoconditioned rats had been treated with the same pharmacological schedule of apomorphine and had the same familiarity with the stimuli, but both were kept separate. A test dose of 0.5 mg/kg of apomorphine produced stereotypies with a significantly higher score and shorter latency in onset in conditioned than in pseudoconditioned rats. Rats conditioned with the lowest dose showed a significantly longer total duration and a shorter latency in onset of akinesia and ptosis. In rats conditioned with the largest dose (2.0 mg/kg), administration of the lowest dose on the test day produced no stereotypies; neither the akinesia nor the ptosis were different between conditioned and pseudoconditioned rats, but yawning occurred with a higher frequency and a shorter latency in pseudoconditioned rats. When rats were conditioned with the lowest dose and tested with 0.5 mg/kg, the level of stereotypies was identical in both groups of rats, whereas akinesia and ptosis were not observed. Yawning and penile erections occurred more frequently, but for short periods only, in conditioned rats.The results showed that apomorphine-induced stereotypies, akinesia and ptosis could be conditioned, and the conditioned effects mimicked the unconditioned responses, which depended on the dose. Conditioned and unconditioned signs of an increased dopaminergic neurotransmission, observed after large doses of apomorphine, thus acted in a synergistic way; the same applied to conditioned and unconditioned signs observed after a small dose and were perhaps due to a decreased dopaminergic transmission. In contrast, when conditioned and unconditioned signs acted in a mutually antagonistic way (increased vs. decreased dopaminergic transmission), the unconditioned signs predominated. Send offprint requests to K. Kuschinsky at the above address     

The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems.

The non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), induces in rats a characteristic behavioural syndrome with ataxia, stereotypies and hyperlocomotion. At least part of this behavioural syndrome is thought to be related to interactions between glutamatergic and dopaminergic neurotransmission. Based on recent biochemical evidence that serotonin (5-HT) might also be involved in the effects of MK-801 several 5-HT receptor ligands were tested for effects on MK-801-induced behaviours. The 5-HT1A receptor ligands, ipsapirone and NAN-190, which are known to display antagonist-like properties in functional models of postsynaptic 5-HT1A receptor activity attenuated or blocked the hyperlocomotion and head weaving observed after administration of MK-801, whereas the 5-HT2 receptor antagonist, ritanserin, was ineffective in this respect. The dopamine receptor antagonist, haloperidol, and the alpha 1-adrenoceptor antagonist, prazosin, also attenuated behaviours induced by MK-801. In contrast to its effects on stereotypies induced by MK-801, ipsapirone potentiated rather than attenuated the stereotyped behaviour induced by the dopamine receptor agonist, apomorphine, indicating that antagonism of MK-801-induced stereotypies by ipsapirone may not be related to the dopaminergic system. The data indicate that, in addition to catecholaminergic systems, serotonergic neurotransmission is significantly involved in the mechanisms by which MK-801 alters behaviour in rats.     

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.     

The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function

The administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03–1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188–6 mg/kg IP) and APV (2.5–20 g/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease.     

Effects of the NMDA-antagonist,MK-801, on stress-induced alterations of dopamine dependent behavior

The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day × 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.     

WAY 100135, an antagonist of 5-HT1A serotonin receptors, attenuates psychotomimetic effects of MK-801.

In the present study, we investigated whether the antagonist of 5-HT1A receptors, WAY 100135, was capable of modifying the psychostimulant and psychotomimetic effects of MK-801, a non-competitive antagonist of NMDA receptors. It was found that: 1) WAY 100135 (10 and 20 mg/kg, but not 1.25, 2.5, and 5 mg/kg) transiently, in a dose dependent manner, attenuated the locomotor stimulant effects of MK-801 (0.4 mg/kg). Given alone, WAY 100135 had no effect on the locomotor activity of rats; 2) WAY 100135 (1.25 and 2.5 mg/kg, but not 10 or 20 mg/kg), attenuated or abolished the disruptive effects of MK-801 on the sensorimotor gating measured in a prepulse-induced inhibition of the acoustic startle response paradigm. WAY 100135 in all tested doses had no effect on the sensorimotor gating or amplitude of the acoustic startle response; 3) WAY 100135 (1.25, 2.5 mg/kg, but not 5 mg/kg) attenuated the detrimental effects of MK-801 on working memory and selective attention, measured in a delayed alternation task. Again, given alone, WAY 100135 did not influence the behavior of rats in that experimental paradigm; and 4) MK-801 (0.4 mg/kg) had no effect on the 5-HT1A receptor mRNA level in rat hippocampus, measured 2 and 24 hours after MK-801 administration. These data indicate that 5-HT1A receptors might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists. In addition, 5-HT1A serotonin receptor antagonists and partial agonists may have potential antipsychotic properties.     

NMDA-type glutamatergic modulation in dopaminergic activation measured by apomorphine-lnduced cage climbing behaviors

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced dopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). I.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic stimulation, but not AMPA/Kainate and mGlu type glutamate receptors.     

Effects of buspirone on dopamine dependent behaviours in rats

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.     

Conditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats

We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus (conditioned rats). Control animals (pseudoconditioned rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described.The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover.These results suggest that only behavioural signs due to an activation of postsynaptic dopamine receptors, but also some symptoms produced by an activation of dopamine autoreceptors can be conditioned.     

Opposite effects of MK-801 on the expression of food and morphine-induced conditioned place preference in rats

Behavioural studies have provided strong evidence for common substrates in the rewards of natural and addictive substances, but it is still unclear whether there is a common glutamatergic NMDA receptor mechanism involved in the processing of reward for both. The present study was designed to investigate the effects of MK-801 (0.1mg/kg) on the expression of place preference conditioned with food and morphine (5.0mg/kg) in rats. The data indicates that MK-801 potentiates the expression of food-induced conditioned place preference (CPP) but retards that of morphine CPP. It also demonstrates that the opposite effects of MK-801 on food and morphine CPP expression were caused neither by hyperactivity nor by the impairment of memory retrieval. These results suggest that MK-801 enhances food craving and inhibits morphine craving in rats, and that the roles of glutamatergic NMDA receptor mechanisms in the reward processing of natural reinforcers and addictive drugs may be dissociable.     

Inhibitory effects of MK-801 on contextual sensitization to climbing behavior and on development of tolerance to hypothermia induced by a single high dose of apomorphine

A single high dose of apomorphine (10 mg x kg(-1)) produced not only contextual sensitization to and conditioning of climbing behavior, but also context-independent tolerance to hypothermia. MK-801 (0.15 and 0.3 mg x kg(-1)) inhibited contextual sensitization to and conditioning of climbing behavior. Development of tolerance to hypothermia was also inhibited by MK-801. Dopamine D1 antagonist, SCH23390 (0.5 mg x kg(-1)), but not D2 antagonist, sulpiride, inhibited sensitization to and conditioning of climbing behavior. D2 antagonist, sulpiride (50 mg x kg(-1)), but not D1 antagonist, SCH23390, inhibited development of tolerance to hypothermia. These results suggest that MK-801 inhibited contextual sensitization to climbing behavior and development of tolerance to hypothermia through glutamatergic modulation of dopaminergic functions at dopamine receptors.     

NR2B subunit-specific NMDA antagonist Ro25-6981 inhibits the expression of conditioned fear: a comparison with the NMDA antagonist MK-801 and fluoxetine

N-methyl-D-asparate (NMDA)-mediated glutamatergic neurotransmission is strongly involved in the development of trauma-induced behavioral dysfunctions, and indirect evidence suggests that NR2B subunit-expressing NMDA receptors are primarily involved in this process. Earlier studies showed that NR2B blockers inhibit the acquisition of conditioned fear, a frequently used model of post-traumatic stress disorder, but their effects on the expression of conditioned fear was poorly studied. We investigated here the effects of the selective serotonin reuptake blocker, fluoxetine, the NMDA blocker, MK-801, and the NR2B subunit blocker, Ro25-6981 on the expression of conditioned fear. Rats received 10 foot shocks administered over 5 min and were tested 24 h later in the shocking context. Treatments were administered 1 h before testing. Shocks dramatically increased freezing and reduced exploration. MK-801 and Ro25-6981 significantly ameliorated both changes. The effects of fluoxetine were less pronounced. In the open field, MK-801 increased locomotion, ataxia, and stereotypy (effects typical of NMDA blockade). Neither fluoxetine nor Ro25-6981 affected locomotion in the open field. Thus, the NR2B-specific NMDA blockade preserved the beneficial effects of general NMDA antagonists on the expression of conditioned fear but did not produce the locomotor side-effects typical of the latter. These findings warrant further studies on the effects of NR2B antagonists in models of post-traumatic stress disorder.     

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.     

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.     

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225–250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine.(+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.