Effects of stimulation of alpha1-adrenergic and NMDA/glycine-B receptors on learning defects in aged rats

The present study was designed to investigate the efficacy of stimulation of alpha₁-adrenoceptors and the strychnine insensitive glycine-B binding sites of the N-methyl-D-aspartate (NMDA) receptor complex to alleviate the age-related defect in water maze (WM) spatial (hidden platform) navigation. We found that daily pretraining IP treatment with 2-(2-chloro-5-trifluoromethylphenylamino) imidazole nitrate (ST 587), an alpha₁-adrenoceptor agonist, at 3000 μg/kg, but not at 1000 μg/kg, facilitated acquisition of water maze spatial navigation in aged rats. However, ST 587 3000 μg/kg (IP) did not stimulate WM spatial reversal learning or cue navigation to a visible platform in aged rats. A partial strychnine insensitive glycine-B binding site agonist, D-cycloserine (DCS) at 10000 μg/kg stimulated acquisition of WM navigation, but had no effect on reversal learning or cue navigation. DCS at 1000 or 3000 μg/kg (IP) had no marked effect on WM spatial navigation, and did not enhance the WM performance improving effect of ST 587 in aged rats. A subthreshold dose of ST 587 1000 μg/kg did not enhance the therapeutic effect of DCS 10000 μg/kg. The present results indicate that activation of alpha₁-adrenoceptors and glycine binding sites of NMDA receptor may to some extent alleviate the age-related defect in spatial navigation. DCS treatment does not enhance the therapeutic effects of ST 587 and vice versa. Received: 20 August 1996/Final version: 21 November 1996     

Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex

Prepulse inhibition (PPI) of the startle reflex in rats is disrupted by N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (phencyclidine-like compounds). In order to explore more thoroughly the control exerted by NMDA receptors on PPI, we assessed the effects of i.p. administration, in Sprague-Dawley rats, of compounds acting as antagonists or agonists at the five binding sites of the NMDA receptor complex. The non-competitive NMDA receptor antagonists phencyclidine (1-6 mg/kg) and MK-801 (dizocilpine: 0.05-0.2 mg/kg) robustly and dose-dependently disrupted PPI. A similar effect was obtained with the competitive NMDA receptor antagonists CGS 19755 (1-20 mg/kg) and CPP (3-20 mg/kg), but not with the cation Mg2+ (100 and 200 mg/kg), the glycine/NMDA binding site antagonist L-701,324 (1-10 mg/kg), or the polyamine/NMDA binding site antagonist eliprodil (3-20 mg/kg). Potentiation of glutamatergic neurotransmission by NMDA (10-50 mg/kg), and the glycine/NMDA site partial agonist d-cycloserine (1-30 mg/kg) also failed to modify PPI, though d-cycloserine diminished PPI at higher doses (50-200 mg/kg). Co-administration of sub-threshold doses of CPP (3 mg/kg) and phencyclidine (2 mg/kg) resulted in an additive effect, disrupting PPI. In contrast, co-administration of L-701,324 (6 mg/kg) with phencyclidine (2 mg/kg), eliprodil (20 mg/kg), or CPP (3 mg/kg), did not disrupt PPI. These results demonstrate that PPI-disrupting effects can only be obtained with phencyclidine-like compounds and NMDA receptor competitive antagonists. Treatment with compounds that potentially augment glutamatergic tone were without effect. Finally, despite the permissive control of the glycine/NMDA binding site on glutamatergic neurotransmission, the glycine/NMDA binding site antagonist L-701,324 did not produce synergistic activity when combined with antagonists at the glutamate, polyamine/NMDA or phencyclidine-like compound binding sites.     

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

 The effects of the NMDA/glycine site antagonist, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324), and the benzodiazepine receptor agonist, diazepam, were examined in the elevated plus-maze and in the Vogel’s conflict test. Oral administration of L-701,324 caused a dose-dependent increase (2.5 and 5.0 mg/kg, −30 min) in the percent time spent in the open arms with no change in the total number of arm entries or in the percent entries into the open arms of the plus-maze. The same doses of L-701,324 increased punished responding in the Vogel’s conflict test in a dose-dependent fashion, with no influence on unpunished drinking behavior. The anxiolytic-like effects of L-701,324 were obtained at doses which by themselves had no influence on the locomotor activity of the animals. Diazepam (2 mg/kg, IP, −30 min) was slightly more effective than L-701,324 in the plus-maze situation, whereas the increase in punished drinking in the Vogel’s test was of the same magnitude for both compounds. Our present results suggest that inhibition of NMDA receptor activity via a blockade of the NMDA/glycine-sensitive site at the NMDA receptor is accompanied by a reduction of anxiety-like behavior in both non-conditioned and conditioned conflict behavior situations. Received: 13 April 1997/Final version: 22 July 1997     

Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice

 Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine>TCP>(–)-MK-801>SKF 10,047>dextrorphan>PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [³H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABA_A receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (±)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers. Received: 29 October 1996 / Final version: 9 April 1997     

Differential effects of diazepam on anxiety in streptozotocin induced diabetic and non-diabetic rats

 The anxiolytic activity of diazepam (DZP) (0.25–1 mg/kg) was investigated in streptozotocin (STZ)-induced diabetic adult Charles Foster albino rats of either sex. Diabetes was induced by injecting STZ IP (50 mg/kg; in citrate buffer, pH 4.5). Experiments were performed 72 h later. The rats were subjected to various anxiety paradigms, including the open-field exploratory behaviour, elevated plus maze and elevated zero maze behaviours and the social interaction tests. In addition, rat brain tribulin activity was also assessed as a biochemical marker of anxiety. The results indicate that diabetic rats showed significantly more anxiogenic activity in comparison to non-diabetic rats on open-field, elevated plus maze, zero maze and social interaction tests. In diabetic rats, brain tribulin activity (MAO-A inhibitory component) was significantly increased. DZP dose dependently produced anxiolytic activity on the various behavioural parameters in non-diabetic rats. DZP (0.5 and 1 mg/kg) partially reversed the anxiogenic behaviour of STZ diabetic rats in elevated plus maze and zero maze tests. However, in open field behaviour and social interaction tests significant anxiolytic activity was observed only at a higher dose of DZP (1 mg/kg). The findings indicate that STZ-induced diabetic rats exhibited augmented anxiety on various experimental paradigms and that the anxiolytic effect of diazepam was less marked in diabetic rats as compared to their euglycaemic counterparts. Received: 5 May 1997 / Final version: 14 August 1997     

Enhancement of dopamine-mediated behaviour by the NMDA antagonists MK-801 and CPP: similarities with repeated electroconvulsive shock

The behavioural effect of dopamine D₁-like receptor agonists (SKF 38393, SKF 81297) and a D₂-like receptor agonist (quinpirole), administered alone and in combination, was tested in rats pretreated with a single injection of an NMDA antagonist (MK-801, CPP) or vehicle. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Pretreatment with MK-801 (0.05 mg/kg, SC, 30 min) had no significant effect (compared to controls) on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC) or quinpirole (0.1 and 0.25 mg/ kg SC) administered alone. In contrast, MK-801 markedly increased locomotion (activity counts and scores) induced by co-administration of a D₁-like plus a D₂-like agonist [SKF 38393 (7.5 mg/kg) plus quinpirole (0.25 mg/kg), SKF 81297 (0.2 mg/kg) plus quinpirole (0.1 mg/kg)]. The behavioural response to the non-selective dopamine agonist apomorphine (0.5 mg/ kg SC) was also enhanced by MK-801. Pretreatment with CPP (0.1 mg/kg SC, 30 min) also significantly increased the locomotor response to co-administration of SKF 38393 plus quinpirole administered alone, but had no effect on the behavioural response to separate injection of these agonists. MK-801 (0.05 mg/kg SC, 30 min) also enhanced the behavioural response to bilateral injection into the nucleus accumbens of SKF 38393 plus quinpirole (1.0 plus 0.4 μg/side, respectively). These data suggest that in the intact rat, the enhancement of dopamine-mediated behaviour by either MK-801 or CPP requires concomitant stimulation of D₁-like and D₂-like receptors, possibly located within the nucleus accumbens. The effect of these NMDA antagonists on dopamine function is similar to that of repeated electroconvulsive shock (ECS), indicating that one of the actions of ECS may be to reduce NMDA receptor function. Received: 24 January 1997/Final version: 21 March 1997     

NMDA receptor channel antagonism by dizocilpine (MK-801) impairs performance of rats in aversively motivated complex maze tasks

To determine the involvement of the N-methyl-D-aspartate (NMDA) receptor in shock-motivated complex maze performance, the drug dizocilpine (DIZO; a.k.a. MK-801) was administered a) to naive, 3-month-old male F-344 rats prior to acquisition (AQ) in the 14-unit T-maze (Experiment 1), and b) to well-trained 11-month-old male F-344 rats prior to testing in a delayed-matching-to-sample (DMTS) task in the detour maze (Experiment 2). For Experiment 1, rats first were pretrained in a straight runway on one-way active avoidance (13/15 correct avoidances) for a maximum of 30 trials. On the following day, either DIZO 0.025 (n=8), 0.05 (n=8), 0.1 (n=8), mg/kg, or saline (SAL; n=15) was administered subcutaneously (SC) 20 min prior to 15 AQ trials in the shock-motivated 14-unit T-maze. The highest dose disrupted all measures of maze performance including errors, alternation errors, runtime, shock duration and frequency, but also produced marked motor ataxia. The 0.05-mg/kg group displayed significant impairment in AQ of this task but only on the cognitive measures, errors and alternation errors, and the 0.025-mg/kg group was impaired on the alternation measure only. One week later, the 15 SAL rats were divided into 2 groups and tested on retention with either SAL or 0.05 mg/kg DIZO. No effects on maze performance were observed. For Experiment 2, after receiving extensive pretraining in the shock-motivated detour maze, 7 rats were exposed to a novel sequence of 4 problems (P) during each of 7 daily sessions. Performance was evaluated 20 min after SC injection of either DIZO—0.025, 0.05, 0.125 mg/kg, or SAL. The 0.125-mg/kg dose caused extreme motor ataxia which precluded testing during that session. The 0.05-mg/kg but not the 0.025-mg/kg dose significantly disrupted performance on both error and trials to criterion measures. Both problem and interaction effects were significant. Disruption was most evident on two specific problems, those involving a side change from the first to second detour. Also, rats had more difficulty switching sides from problem to problem (few errors on P-1 and most on P-4), suggesting proactive interference effects. In sum, DIZO was observed to significantly disrupt performance in both mazes in a dose-related manner similar to effects observed in previous studies following administration of the anticholinergic drug scopolamine. For the 14-unit T-maze, the present results simulate age-related deficits previously found in acquisition of that task.     

Effects of the NMDA antagonists CPP and MK-801 on radial arm maze performance in rats

The dose- and time-dependent effects of N-methyl-D-aspartate receptor/channel antagonists on radial 8-arm maze performance were examined in rats. Both CPP (1.0-30 mg/kg), a competitive NMDA antagonist, and MK-801 (0.1-1.0 mg/kg), a noncompetitive NMDA antagonist, produced dose-dependent increases in the number of errors made to sample all 8 baited arms. The effective doses of both drugs produced maximal performance impairments 2 hr after IP injection, and no effects after 24 hr. In a second radial arm maze task where only 4 arms were baited, CPP (10 mg/kg) had a somewhat greater effect on the number of working memory errors than on reference memory errors. MK-801 (0.1, 0.33 mg/kg) had no effects on either this task or on a task involving a 1-hr delay between correct choices 4 and 5 on the 8 choice task. CPP (10 mg/kg), however, impaired performance on this latter task. These results indicate that doses of NMDA antagonists, sufficient to block hippocampal long-term potentiation, also disrupt radial arm maze performance.     

Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats

The discovery that glutamate's activity at the N-methyl-D-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine(B) receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine, receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine, receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10-40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25-5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.     

Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis

RATIONALE: Several studies have provided evidence that antagonists and partial agonists of glycine(B) receptors exhibit an anxiolytic-like activity in different animal models. OBJECTIVE: Using the conflict-drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of D-cycloserine (DCS), a partial agonist of the glycine(B) site of the N-methyl-D-aspartate (NMDA) receptor complex. Diazepam was used as a reference drug. RESULTS: DCS (200 and 300 mg/kg) and diazepam (5 mg/kg) produced an anxiolytic-like effect in rats by increasing the number of shocks accepted. We also demonstrated that NMDA (15 mg/kg) reduced the anxiolytic-like activity of DCS (200 mg/kg), whereas glycine (800 mg/kg) and flumazenil (10 mg/kg) did not affect the anticonflict effect of DCS (200 mg/kg). The anticonflict effect of diazepam (5 mg/kg) was totally blocked by flumazenil (10 mg/kg). CONCLUSION: The obtained results have shown that DCS exhibits an anxiolytic-like activity which depends on NMDA receptors rather than on glycine(B) or benzodiazepine sites.     

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB₁ cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03–3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3–1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3–1 mg/kg), suggesting that it was accounted for by the stimulation of CB₁ receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA. Received: 14 March 1997 / Final version: 28 July 1997     

Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat

The discriminative stimulus properties of compounds that interact with the NMDA receptor complex were investigated in rats trained to discriminate ethanol from saline. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses [fixed ratio 10 (FR10)] for food after ethanol (1 g/kg IP; 12% v/v ethanol solution) and saline vehicle injections. Drug effects were assessed by means of generalization and antagonism tests. In the generalization tests, the noncompetitive NMDA antagonists acting at the ion channel dizocilpine, memantine, phencyclidine (PCP) and the sigma₁ receptor agonists (+)-pentazocine and (+)-N-allyl-normetazocine (NANM) dose-dependently generalized for ethanol, whereas the α-amino-3-hydroxy- 5-methyl-4-isoxazole-propionate (AMPA) antagonist GYKI 52466, the glycine antagonists L-701,324 and MRZ 2/502, the polyamine site antagonist arcaine and the polyamine site ligand spermidine, did not. Our results show that the noncompetitive NMDA antagonists fully substitute dose-dependently for ethanol in a drug-discrimination task. The ethanol-like discriminative stimulus effects of PCP, pentazocine and NANM, which are also sigma receptor ligands, are likely to be attributed to their activity at NMDA receptors. We therefore assume that some of the acute effects of ethanol are mediated via NMDA receptor antagonism at the PCP binding site. Received: 28 January 1997/Final version: 10 June 1997     

Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor.

Glycine has been shown to modulate N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which have been implicated in learning and memory. We report that d-cycloserine (DCS) which has a high affinity for the glycine modulatory site in the NMDA receptor complex modulated memory processing in a dose-dependent manner. Mice were trained on a footshock avoidance task. Immediately after training DCS was administered (2.5 to 50 mg/kg s.c.). When retention was tested a week later, 20 mg/kg facilitated retention the best with lower and higher doses be less effective in weakly trained young mice. DCS also facilitated retention in 'senescence-accelerated mice' in which impairment of learning and memory increases with age. DCS had to be administered at higher doses to improve retention as impairment of learning and memory increased.     

Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference.

Effects of the novel NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with morphine (5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) for 3 conditioning trials, alone or in combination of these drugs with L-701,324 (2.5 mg/kg and 5 mg/kg, p.o.). L-701,324 prevented acquisition of the place preference produced by morphine and cocaine. Administration of L-701,324 on the test day attenuated the expression of morphine-induced CPP, whereas it had no effect on cocaine CPP. When L-701,324 was given alone it did not affect dependent variables (i.e. time spent in non-preferred compartment) suggesting that L-701,324 did not display any reinforcing properties by itself. Our current data suggest that glycine site on the NMDA receptor complex may be involved in the mediation of the rewarding effects of drugs of abuse.     

L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats

  Rationale: It has recently been suggested that the overactivity of glutamatergic neurotransmission may contribute to the pathophysiology of Parkinson’s disease. Therefore, a search for new compounds which block glutamatergic receptors and show antiparkinsonian properties in animal models of this disease seems to be justified. Objective: The aim of this study was to determine whether L-701,324 [7-chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H)-one], a selective and full antagonist at the glycine site of the NMDA receptor, counteracts parkinsonian-like muscle rigidity and catalepsy induced by haloperidol in rats. Methods: The muscle tone was measured as the resistance developed to passive flexion and extension of the hind limb. Electromyographic (EMG) activity was additionally recorded in the gastrocnemius and tibialis anterior muscles. Results: L-701,324 (2.5–40 mg/kg IP) dose-dependently decreased the muscle tone enhanced by haloperidol (1–5 mg/kg IP). Likewise, the haloperidol-enhanced resting EMG activity and the EMG reflex response to passive movements were diminished by lower and almost abolished by higher doses of L-701,324. However, up to a dose of 20 mg/kg IP, L-701,324 did not influence haloperidol (0.5 mg/kg IP)-induced catalepsy. Moreover, L-701,324 (1.25–5 mg/kg IP) given alone or together with haloperidol (0.5–1 mg/kg IP) disturbed rotarod performance. Gross observation of behaviour indicated that rats injected with L-701,324 in doses equal to or higher than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic, i.e. rats showed signs of disturbed balance and loss of control over their hind limbs. Conclusions: The present study suggests that L-701,324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not that of parkinsonian akinesia. Nonetheless, this compound is not devoid of motor side-effects. Received: 1 February 1998 / Final version: 20 October 1998     

Effect of an NMDA receptor agonist on T-maze and passive avoidance test in 12-week streptozotocin-induced diabetic rats

This study examined behavioral effects mediated by NMDA (N-methyl-D-aspartic acid) receptors in 12-week streptozotocin (STZ)-induced diabetic rats. Effects of an NMDA receptor agonist on behavior in the open field test, passive avoidance test and T-maze were examined in control groups of rats and in rats with diabetes mellitus (DM). We have used 116 rats for experiments. Experimental type I diabetes was induced by a single intravenous injection of streptozotocin at a dose of 65 mg/kg, dissolved in citrate buffer. Stimulation with the NMDA receptor agonist at a dose of 15 mg/kg was performed 30 min before the experiments. In control rats, NMDA increased the number of crossing and rearings in the open field test, improved acquisition and consolidation processes and did not influence recall in the passive avoidance situation and was ineffective in the T-maze. Diabetes significantly inhibited locomotor and exploratory activity and profoundly impaired acquisition, consolidation and recalling in a passive avoidance, and significantly decreased working memory in T-maze. NMDA treatment of diabetic rats significantly improved memory in passive avoidance and T-maze. The NMDA receptor agonist increased locomotor activity in open field test. The obtained results suggested that stimulation of NMDA receptors had beneficial effects on learning and memory in type I diabetic rats.     

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     

The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission

In order to assess the role of excitatory amino acids (EAAs) in the reinforcing property of cocaine, the NMDA antagonist, dizocilpine, or the AMPA antagonist, DNQX, were administered to animals previously trained to self-administer cocaine (1.0, 0.4 or 0.16 mg/kg per infusion). The highest doses of dizocilpine (0.1 mg/kg, IP) and DNQX (30 mg/kg, IP) significantly reduced operant responding for cocaine maintained on a fixed ratio schedule of reinforcement. However, whereas dizocilpine had no influence operant responding for food, DNQX significantly decreased lever pressing for this reinforcer. These results indicate that an NMDA antagonist produces a relatively selective enhancement of cocaine reinforcement, while an AMPA antagonist decreases cocaine self-administration only at a dose that also impairs responding for an alternate reinforcer. A parallel in vivo microdialysis study performed in freely moving rats tested the effects of dizocilpine alone and in combination with cocaine on extracellular dopamine in the nucleus accumbens shell. The results revealed that dizocilpine alone (0.1 mg/kg, IP) did not alter basal extracellular dopamine levels in the nucleus accumbens or spontaneous behavior. In addition, 0.1 mg/kg dizocilpine did not alter the increase in dopamine in the accumbens shell or behavioral hyperactivity produced by cocaine (15 or 30 mg/kg). Collectively, these findings suggest that dizocilpine enhances the reinforcing effect of cocaine without influencing dopamine transmission in the nucleus accumbens shell. Received: 17 December 1996/Final version: 21 March 1997     

Characterization of the Interactive Effects of Glycine and -Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence

Reduced responses to N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in alcohol-dependent animals and humans provided evidence that chronic alcohol consumption increased NMDA receptor function. To further probe alterations in NMDA glutamate receptor function associated with human alcohol dependence, this study examined the interactive effects of agents acting at the glycine_B coagonist site of the NMDA receptor. In doing so, it tested the hypothesis that raising brain glycine concentrations would accentuate the antagonist-like effects of the glycine_B partial agonist, -cycloserine (DCS). Twenty-two alcohol-dependent men and 22 healthy individuals completed 4 test days, during which glycine 0.3 g/kg or saline were administered intravenously and DCS 1000 mg or placebo were administered orally. The study was conducted under double-blind conditions with randomized test day assignment. In this study, DCS produced alcohol-like effects in healthy subjects that were deemed similar to a single standard alcohol drink. The alcohol-like effects of DCS were blunted in alcohol-dependent patients, providing additional evidence of increased NMDA receptor function in this group. Although glycine administration reduced DCS plasma levels, glycine accentuated DCS effects previously associated with the NMDA receptor antagonists, ketamine and ethanol. Thus, this study provided evidence that raising glycine levels accentuated the NMDA receptor antagonist-like effects of DCS and that alcohol-dependent patients showed tolerance to these DCS effects.     

Chronic treatment with antidepressants affects glycine/NMDA receptor function: behavioral evidence

Like the clinically effective benzodiazepine anxiolytic, chlordiazepoxide, the glycine/NMDA receptor antagonist L-701,324 (3, 7.5 and 10 mg/kg), produces dose-related increases in the percentage of time spent in the open arms and the percentage of entries into the open arms of an elevated plus maze in mice. Consistent with its proposed mechanism of action, these anxiolytic effects of L-701,324 (7.5 mg/kg) are reversed by pretreatment with glycine (500 and 800 mg/kg). Chronic treatment with citalopram (20 mg/kg for 21 days), imipramine (15 mg/kg for 21 days) and electroconvulsive shock (ECS, for 8 days), produced a reduction in the anxiolytic-like actions of L-701,324 (7.5 mg/kg) such that they could not be reversed by glycine. In contrast, the anxiolytic effects of L-701,324 and reversal of these effects by glycine were unaffected by acute treatment with imipramine, chronic administration with placebo or the neuroleptic chlorpromazine, or sham ECS. Further, imipramine administered for 21 days did not affect the anxiolytic effect of 5 mg/kg of chlordiazepoxide. The apparent reduction in the anxiolytic-like actions of a specific glycine/NMDA receptor antagonist following chronic treatment with a variety of antidepressants is consistent with previous neurochemical and molecular studies indicating that chronic antidepressant treatment can affect NMDA receptor function.