Anxiolytic-like effects of the noncompetitive NMDA antagonist MK 801.

The present study examined the effects of the noncompetitive NMDA antagonist, MK 801 (dizocilpine), on behavior in the conditioned suppression of drinking (CSD) punished drinking paradigm, a repeated-measures conflict task. In daily 10- or 15-min sessions, water-restricted rats drank from a tube that was occasionally electrified (0.25- or 0.5-mA shocks signaled by a tone). Trained subjects (4 weeks of CSD testing) exhibited stable baselines for both punished (approximately 40 or 100 shocks received/session at the 0.5- and 0.25-mA shock intensities, respectively) and unpunished (approximately 15 ml/session water intake at either shock intensity) responding. Over a wide range of doses, (+) MK 801 did not increase punished responding when administered using a 10-min, 4-h, or 48-h pretreatment. However, at a 24-h pretreatment (+) MK 801 (0.04-0.4 mg/kg, IP) produced a dramatic and dose-dependent increase in punished responding. The "inactive" (-) isomer of MK 801 did not produce a significant anxiolytic-like effect in the CSD paradigm at doses up to 2 mg/kg when tested using a 24-h pretreatment. These data suggest that the anticonvulsant agent (+) MK 801 also may exert antianxiety effects in humans.     

Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice

N-methyl-D-aspartate (NMDA) receptors are involved in synaptic plasticity and play a critical role in learning and memory. We investigated the effects of the noncompetitive NMDA receptor antagonist (+)MK-801 on classical eyeblink conditioning of mice, using various interstimulus intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). A tone was used for the CS and a periorbital shock was used for the US. In the delay paradigm, in which the US coterminated with the CS or started immediately after CS offset, the effect of (+)MK-801 (0.1mg/kg, i.p.) was a slight impairment in the acquisition of the conditioned response (CR). During subsequent CS-alone trials, the responses of (+)MK-801-injected mice were extinguished as easily as those of saline-injected mice. In the trace paradigm, (+)MK-801 impaired acquisition of the CR with a trace interval of 250 ms more than it did with a trace interval of 100 ms, and more than in the delay paradigm. (+)MK-801 injected after acquisition of 250-ms trace conditioning did not impair expression or extinction of the CR. These results suggest that NMDA receptors are involved in acquisition of the CR during longer trace interval conditioning more than during shorter trace interval conditioning or delay conditioning, and that their contribution to extinction is much smaller than their contribution to acquisition in mouse eyeblink conditioning.     

The dopamine D3 receptor mediates locomotor hyperactivity induced by NMDA receptor blockade

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, like phencyclidine, generate schizophrenic-like symptoms in humans and behavioural abnormalities in animals, such as hyperactivity. We investigated the role of the dopamine D(3) receptor in locomotor hyperactivity produced in mice by dizocilpine (MK-801), another NMDA receptor antagonist, at a low dose (0.12 mg/kg). BP 897, a highly D(3) receptor-selective partial agonist, or nafadotride, a preferential D(3) receptor antagonist, both at low doses (1 mg/kg and lower), had no effects on spontaneous activity and completely inhibited MK-801-induced hyperactivity. Clozapine, an atypical antipsychotic, produced the same effect as BP 897 and nafadotride. Haloperidol, a typical antipsychotic, reduced both spontaneous activity and MK-801-induced hyperactivity. In D(3) receptor knockout mice, MK-801-induced hyperactivity was weaker than that observed in wild-type mice while BP 897 and nafadotride were inactive. On the contrary, the effects of clozapine and haloperidol, which target multiple receptors in addition to the D(3) receptor, were almost completely preserved in D(3) receptor knockout mice. Our results show that hyperactivity produced by a low dose of MK-801 is dependent upon D(3) receptor stimulation and constitutes the first simple response to assess the in vivo activity of D(3) receptor-selective drugs. In addition, since D(3) receptor antagonists and antipsychotics produced very similar effects, our results add to the growing evidence suggesting that D(3) receptor blockade might produce antipsychotic effects.     

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice

This study examined the interaction between various glutamate antagonists and selective D₁ (SKF 38393) and D₂ (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1–1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25–8 mg/kg) and CPP (0.2–20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4–10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2–25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D₁ and D₂ motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants tol-dopa in antiparkinson therapy.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists.

The dopamine (DA) D2-like family of receptors is comprised of three subtypes, the D2, D3, and D4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than at the D2 subtype. However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D3 receptors in these in vivo effects. In order to investigate whether the DA D2 receptor is the subtype that mediates hypothermia and hypolocomotion produced by DA D2/D3 receptor agonists, we tested the effects of ip administration of the DA D2/D3 receptor agonists 7-OH-DPAT and PD 128907, on core temperature and locomotor activity in DA D2 receptor knock-out mice (homozygotes: D2(-/-) and heterozygotes: D2(+/-)), and in wild-type (D2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 (1-10 mg/kg) induced hypothermia and decreased locomotion in D2(+/+) mice, but had no effects in D2(-/-) mice; the magnitude of the hypothermic and locomotor-reducing effects of these two agonists in D2(+/+) mutants was approximately half that of D2(+/+) mice. During the first 10 min in the activity chambers, the level of spontaneous locomotor activity of D2(-/-) individuals was almost 50% below that of D2(+/+) mice; basal locomotor activity of D2(+/-) mice was between that of D2(-/-) and D2(+/+) individuals. Neither type of mutant showed spontaneous catalepsy or deficits in forelimb muscle strength (grip-strength test). These results show that the presence of DA D2 receptors is necessary for the expression of the locomotor- and core temperature-decreasing effects of DA D2/D3 receptor agonists such as 7-OH-DPAT and PD 128907.     

Behavioral effects of dopamine agonists and antagonists in MPTP-lesioned D3 receptor knockout mice

To test the modulatory role of D(3) receptors in normal and dopamine-depleted mice, D(3) receptor KO mice and wild-type (WT) littermates were administered saline, L-dopa/carbidopa (20/2 mg/kg ip), a preferential D(3)>D(2) agonist S32504, a D1+D(2)/D(3) agonist apomorphine, a selective D(3) antagonist S33084, or apomorphine with S33084 prior to and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We monitored lines crossed in a 55-min session, average number of rears, and average number of grooming bouts. MPTP treatment produced equivalent 70% losses of dopamine fibers in the caudate putamen (CPu) and nucleus accumbens (NAC) of WT and D(3) KO mice as compared to their control (vehicle injected) counterparts. D(3) receptors were absent in KO mice, and the number of D(3) receptors was unaffected by MPTP-induced loss of DA terminals in WT mice. The results support a lack of involvement of the D(3) receptor for D1:D2 receptor-mediated behavioral activity (synergy). First, S32504 inhibited all behaviors and to a similar degree in D(3) KO and WT mice. Second, S33084 at the higher concentration increased number of lines crossed in response to high dose apomorphine in both D(3) KO and WT mice. Third, in nonlesioned mice, apomorphine-induced gnawing stereotypies were inhibited by S33084 in both D(3) KO and WT mice. Interestingly, the inhibition of apomorphine-induced gnawing was not apparent in MPTP-lesioned mice, and this stereotypy was elevated in D(3) KO-MPTP-lesioned mice. Thus, the suppressive effects of S32504 could be via D2 autoreceptor inhibition of DA release, and D2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice.     

The effects of dopamine D3/D2 receptor agonists on intracranial self stimulation in the rat

The effects of the dopamine D₃/D₂ receptor agonists quinpirole, quinelorane and (±)7-OH-DPAT [(±) 7-hydroxy-2(N,N-di-n-propylamino) tetralin] on intracranial self-stimulation (ICSS) were investigated. Rats implanted with bipolar electrodes into the lateral hypothalamus were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. Three measures of responding were calculated; the frequency at which responding was 50% of the maximum (M50), the asymptotic response rate and the total area under the curve (AUC) for each frequency sweep. Quinpirole (2.2–66.0 μg/kg SC) significantly increased M50 and reduced both asymptote and AUC. Quinelorane (0.25–79.0 μg/kg SC) had no significant effect on M50 values but significantly reduced both asymptote and AUC. (±)7-OH-DPAT (2.5–74.0 μg/kg) did not significantly affect any of the measures. The data show that low doses of quinpirole and quinelorane, but not (±)7–OH–DPAT, inhibit ICSS maintained by electrodes in the lateral hypothalamus. Either dopamine D₂ or dopamine D₃ receptor stimulation may play a role in mediating ICSS inhibition, but studies with more selective receptor agonists and antagonists are required to define the role of each receptor. Received: 18 August 1997/Final version: 17 April 1998     

Prevention by the NMDA receptor antagonist, MK801 of neuronal loss produced by tetanus toxin in the rat hippocampus.

1. The behavioural and neuropathological effects of tetanus toxin, microinjected directly into the hippocampus, were studied in rats. 2. A single dose (1000 minimum lethal doses, MLDs) of tetanus toxin, injected unilaterally into the hippocampus produced a time-dependent neuronal loss in the CA1 pyramidal cell layer. In comparison with the contralateral, untreated side these effects became statistically significant (P less than 0.05) 7 days (22.0 +/- 1.1% reduction) and 10 days (29.2 +/- 1.7% reduction) after the injection. No significant changes were observed 7 days after treatment with 500 MLDs whereas a reduction of 37.5 +/- 3.1% in the CA1 area cell number was produced 4 days after the injection of 2000 MLDs. 3. Behavioral stimulatory effects were also induced by tetanus toxin (1000 MLDs) within 48 h of the injection and these culminated in generalized convulsions 5-7 days later. Convulsions were observed after a shorter period of latency in rats receiving 2000 MLDs tetanus toxin whereas 500 MLDs were ineffective. 4. No behavioural and neuropathological effects were observed in rats treated with neutralized tetanus toxin (1000 MLDs), bovine serum albumin or phosphate buffer. 5. Pretreatment with MK801 (0.3 mg kg-1, i.p., given 1 h before and after the injection with tetanus toxin and then once daily for 4 or 7 days) prevented the behavioural and neuropathological effects induced by tetanus toxin (1000-2000 MLDs). In addition, such treatment fully protected the animals from the lethal effects induced by 1000 MLDs tetanus toxin.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the locomotor stimulant effects of D1-like receptor agonists in mice

Efficacy in stimulating adenylyl cyclase (AC) has traditionally been used to distinguish dopamine D1-like receptor agonists from dopamine D2-like receptor agonists. However, there is a limited association between the effects of D1-like agonists in behavioral assays and their effectiveness at stimulating AC. Other second messenger actions might contribute to the behavioral effects of D1-like agonists, as there is evidence for a link to the hydrolysis of phosphoinositide (PI). The present study compared the locomotor stimulant effects of five D1-like receptor agonists having different efficacies in assays of AC and PI activity. All D1-like agonists produced long-lasting biphasic effects on locomotor activity. SKF 38393, the prototypical partial agonist (based on AC activity), produced limited changes in locomotor activity, whereas the partial agonists SKF 75670 and SKF 77434 produced locomotor stimulant effects that were similar to or greater than those of the full efficacy agonists SKF 82958 and SKF 81297. However, there did not appear to be a relationship between maximal behavioral effects and AC stimulation or PI hydrolysis. The results suggest a complex relationship between the behavioral effects of D1-like agonists and their intrinsic efficacies as measured by AC and /or PI stimulation. Although a limited number of compounds were examined, neither second messenger system alone appears to account fully for these behavioral effects. The current classification of D1-like agonists according to their intrinsic efficacies as defined by AC stimulation needs further scrutiny.     

Modulation of the discriminative stimulus effects of mu opioid agonists in rats: II. Effects of dopamine D2/3 agonists

Dopamine (DA) D2/3 receptor agonists have been shown to attenuate the behavioral effects of mu opioid agonists. This study was designed to examine the modulatory actions of the D2/3 agonists quinelorane, quinpirole and (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (7-OH-DPAT) on the discriminative stimulus effects of the higher-efficacy mu agonists heroin, methadone and morphine, as well as the lower-efficacy agonist nalbuphine, in rats trained to discriminate heroin from water. All three D2/3 agonists attenuated the heroin-like discriminative stimulus effects of morphine, methadone and nalbuphine, whereas quinpirole and 7-OH-DPAT, but not quinelorane, effectively attenuated the discriminative stimulus effects of heroin. Each D2/3 agonist administered alone occasioned water-appropriate responding and decreased rates of responding. These results extend previous findings, which demonstrated that activation of D2/3 receptors attenuates the antinociceptive effects of mu agonists, to now include their discriminative stimulus effects as well. The exact nature of this modulation of opioid effects by dopamine agonists is unclear, and may include neurochemical interactions as well as psychological mechanisms such as perceptual masking.     

Morphine alters the locomotor responses to a D2/D3 dopamine receptor agonist differentially in adolescent and adult mice

The D2-like dopamine receptors mediate the emotional/aversive state during morphine withdrawal. Given age-dependent differences in the affective responses to withdrawal, this study examined whether the response to dopamine receptor agonists is altered differentially across ages following morphine administration. Adolescent and adult mice were injected with morphine (twice daily, 10-40 mg/kg, s.c.) or saline for 6 days. Subsequently, they were examined for their locomotor response to quinpirole, a D2/D3 receptor agonist, and SKF 38393, a D1 receptor agonist. Quinpirole dose-dependently reduced locomotion in drug-na?ve animals. Initial suppression was also observed in morphine-treated animals, but was followed by enhanced locomotion. Notably, this enhanced locomotion was markedly greater in adolescents than adults. Quinpirole-induced hypo-locomotion is thought to be mediated by the presynaptic D2Short receptors, whereas its activating effect is mediated by postsynaptic D2Long/D3 receptors. This suggests that following morphine administration, the postsynaptic, but not the presynaptic, dopaminergic signaling is differentially modulated across ages. This locomotor supersensitivity was not observed for SKF 38393, a D1 dopamine receptor agonist. The D2/D3 receptors are involved in the pathophysiology of many mental illnesses. Thus, this study offers a potential explanation for the increased psychiatric disorder co-morbidities when drug use begins during adolescence.     

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

Rationale

The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern.

Objectives

This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison.

Methods

Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency–rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2–10.0 mg/kg) and MK-801 (0.032–0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2–20.0 mg/kg/day) and acute cocaine (10.0 mg/kg).

Results

Following acute administration, ketamine (3.2–10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032–0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS.

Conclusions

The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.     

Effects of putative cognition enhancers on the NMDA receptor by [3H]MK801 binding

Piracetam, aniracetam, and d-cycloserine were tested for their ability to reduce inhibition of [³H]MK801 (dizocilpine) binding by 100 μM kynurenate. Piracetam (100 μM-1 mM) failed to reduce inhibition by kynurenate but stimulated [³H]MK801 binding in the absence of kynurenate. In contrast, d-cycloserine (30 μM-1 mM) and aniracetam markedly reduced this inhibition by kynurenate. Thus, cognition enhancers might function via at least some subtypes of NMDA receptors.     

Characteristics of the ambulation-increasing effect of the noncompetitive NMDA antagonist MK-801 in mice: assessment by the coadministration with central-acting drugs.

Characteristics of the ambulation-increasing effect of MK-801, a non-competitive NMDA antagonist, were assessed through the coadministration of MK-801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methamphetamine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) produced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increasing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.3 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by alpha-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-biopterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl)-adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioural and biochemical adaptations to nicotine in rats: influence of MK801, an NMDA receptor antagonist

Chronic exposure of rats to nicotine can result in sensitization to the stimulant effects of nicotine on locomotor activity. At a biochemical level, chronic exposure to nicotine increases the number of CNS nicotinic binding sites, and this has been suggested as the basis for sensitization to nicotine. The present experiment was conducted to examine the effects of MK801, an NMDA receptor antagonist, on sensitization to nicotine. In addition, the hypothesis that MK801 may block behavioural sensitization by preventing the up-regulation of nicotinic receptors was tested by measuring receptor numbers in the same individuals using quantitative autoradiography with [³H]-cytisine and [³H]-MK801. Male Sprague-Dawley rats were chronically treated with nicotine (0.4 mg/kg SC) or saline daily for 7 days. Over the next 2 days, in a counterbalanced order, rats were challenged with nicotine (0.4 mg/kg SC) or saline and locomotor activity was monitored. In saline-pretreated rats, nicotine produced a small increase in activity. Nicotine-pretreated rats exhibited higher levels of activity following a nicotine challenge. This sensitized response was attenuated in rats administered MK801 (0.3 mg/kg IP) 30 min before each daily nicotine injection. Rats pretreated with MK801 alone showed activity scores no different from saline pretreated control groups. Biochemical studies revealed increased [³H]-cytisine binding following chronic nicotine treatment; however, receptor increases were significantly attenuated by MK801 pretreatment. Binding of [³H]-MK801 remained unchanged across the four groups. The results suggest that MK801 prevents behavioural sensitization to nicotine via the prevention of receptor up-regulation. Although the findings support the notion that receptor up-regulation may be the basis for the increased responsiveness to nicotine, other interpretations are possible. Received: 23 January 1997/Final version: 8 May 1997     

Discriminative stimulus effects of putative D3 dopamine receptor agonists in rats

Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001-0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001-0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms.     

Dexamethasone reduces locomotor stimulation induced by dopamine agonists in mice

The interaction between glucocorticosteroids and the dopaminergic system has attracted considerable attention in recent years since this link could be involved in certain psychopathological conditions including depression. Radioligand binding studies have shown the presence of glucocorticoid receptors in neurons of the limbic system, a structure involved in mood control and subtle regulation of hypothalamic-pituitary-adrenal (HPA) axis. Structures of the limbic system are also rich in dopaminergic innervation. It has been hypothesized that glucocorticoids may be important in causing and perpetuating depression. The aim of the present study was to investigate the effect of dexamethasone (DEX) on hyperactivity induced by dopamine agonists (amphetamine, amantadine, quinpirole and bromocriptine) in mice. Male Albino Swiss mice received DEX at a single dose (2, 4 or 8 mg/kg) or for 14 days at the doses of 0.5, 2 or 4 mg/kg/day. After a single or the last injection (in the chronic experiment) of DEX, dopamine agonists were given in the following regimen: D-amphetamine (0.4 mg/kg) and quinpirole (3 mg/kg) - 30 min, amantadine (50 mg/kg) - 60 min and bromocriptine (10 mg/kg) 180 min before the measurement of locomotor activity. The obtained results show that DEX may decrease the locomotor activity and reduce the hyperactivity induced by dopamine agonists in mice. These observations may suggest that DEX weakens the activity of dopamine agonists in the mesolimbic system.     

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.     

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice

RATIONALE: Dopamine (DA) D2-like antagonists block several effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects. Because these compounds generally lack selectivity among the D2-like DA receptors, the specific roles of the subtypes remain unclear. OBJECTIVES: DA D2 receptor knockout (DA D2R KO), heterozygous (HET), and wild-type (WT) mice were used to study the role of D2 DA receptors in the effects of cocaine. Some effects of the relatively selective DA D2-like antagonist raclopride were also studied to further assess the role of D2 receptors. METHODS: DA D2R KO, HET, and WT mice were treated with cocaine (1-10 mg/kg) or vehicle, and their horizontal locomotor activity was assessed. The mice were also trained to discriminate i.p. injections of saline from cocaine (10 mg/kg) using a two-response key, fixed-ratio-20 response, food-reinforcement procedure. A range of doses of cocaine (1.0-17 mg/kg) was administered before 15-min test sessions. RESULTS: Both DA D2R KO and HET mice showed reduced levels of horizontal activity relative to WT mice. Cocaine dose dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. Raclopride, at inactive to fully active doses (0.1-1.0 mg/kg), did not fully substitute for cocaine. Raclopride dose dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice, raclopride was inactive as an antagonist. CONCLUSIONS: The present data indicate an involvement of D2 DA receptors in the locomotor-stimulating effects and the interoceptive discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine.