Associative learning performance is impaired in zebrafish (Danio rerio) by the NMDA-R antagonist MK-801

The zebrafish is gaining popularity in behavioral neuroscience perhaps because of a promise of efficient large scale mutagenesis and drug screens that could identify a substantial number of yet undiscovered molecular players involved in complex traits. Learning and memory are complex functions of the brain and the analysis of their mechanisms may benefit from such large scale zebrafish screens. One bottleneck in this research is the paucity of appropriate behavioral screening paradigms, which may be due to the relatively uncharacterized nature of the behavior of this species. Here we show that zebrafish exhibit good learning performance in a task adapted from the mammalian literature, a plus maze in which zebrafish are required to associate a neutral visual stimulus with the presence of conspecifics, the rewarding unconditioned stimulus. Furthermore, we show that MK-801, a non-competitive NMDA-R antagonist, impairs memory performance in this maze when administered right after training or just before recall but not when given before training at a dose that does not impair motor function, perception or motivation. These results suggest that the plus maze associative learning paradigm has face and construct validity and that zebrafish may become an appropriate and translationally relevant study species for the analysis of the mechanisms of vertebrate, including mammalian, learning and memory.     

Effects of NMDA receptor channel blockade on aggression in isolated male mice

N‐Methyl‐D ‐aspartate (NMDA) receptor antagonists are perspective candidates for medication development for a number of diseases/states that are associated with increased aggressiveness (e.g., opioid withdrawal). The prototypic NMDA receptor antagonist phencyclidine (PCP) itself is a widely abused substance and is known to elevate levels of aggression in drug users. The present study was aimed at testing several drugs that share with PCP the ability to block NMDA receptor–associated channel. The resident‐intruder procedure was used to assess drug effects on aggressive behavior in isolated male mice. Resident aggressive mice were administered NMDA channel blockers (PCP; 0.3–10 mg/kg), dizocilpine (MK‐801; 0.01–0.3 mg/kg), memantine (1–30 mg/kg), and MRZ 2/579 (0.1–5.6 mg/kg). The competitive NMDA receptor antagonist D CPPene (0.1–5.6 mg/kg) was also tested as a compound representing an alternative approach to reduce activity of NMDA receptor complex. PCP, dizocilpine, and memantine inhibited expression of aggressive behaviors only at doses that produced ataxia. The novel channel blocker MRZ 2/579 also produced ataxia at the highest dose level but failed to affect aggressiveness. Reduction in aggression with a corresponding increase in sociability was observed after administration of D ‐CPPene. Overall, the present results suggest that NMDA receptor channel blockers do not exert selective effects on aggressive behavior. Aggr. Behav. 25:381–396, 1999. © 1999 Wiley‐Liss, Inc.     

EFFECTS OF DRUGS AND DRUG COMBINATIONS IN PIGEONS TRAINED TO DISCRIMINAT AMONG PENTOBARBITAL,DIZOCILPINE, A COMBINATION OF THESE DRUGS,AND SALIN

Drugs with multiple actions can have complex discriminative‐stimulus properties. An approach to studying such drugs is to train subjects to discriminate among drug combinations and individual drugs in the combination so that all of the complex discriminative stimuli are present during training. In the current experiments, a four‐choice procedure was used to train pigeons to discriminate among dizocilpine (noncompetitive NMDA receptor blocker), pentobarbital (GABA_A receptor agonist), a fixed‐dose combination of these two drugs, and saline. Following extended training, low doses of pentobarbital or dizocilpine administered alone produced saline‐appropriate responding. Higher doses of pentobarbital produced responding on the pentobarbital‐appropriate key and higher doses of dizocilpine produced responding on the dizocilpine key. Administering the lowest doses of pentobarbital and dizocilpine together resulted in responding on the saline‐appropriate key. Increasing the dose of pentobarbital in the presence of low doses of dizocilpine produced responding primarily on the pentobarbital‐appropriate key; increasing the dose of dizocilpine in the presence of the lowest dose of pentobarbital produced responding primarily on the dizocilpine‐appropriate key. Combining the higher doses of pentobarbital and dizocilpine resulted in responding primarily on the drug‐combination key. Low doses of phencyclidine or ethanol produced responding on the saline‐appropriate key, but intermediate doses resulted in individual subjects responding predominately on either the pentobarbital key, the dizocilpine key, or the drug‐combination key depending on the subject. After the highest dose of phencyclidine or ethanol, most subjects responded predominantly on the drug‐combination key. Low doses of other drugs tested produced responding on the saline‐appropriate key. With the highest diazepam doses responding was largely confined to the pentobarbital‐appropriate key. The highest doses of dextromethorphan or dextrorphan resulted in responding on the dizocilpine key more frequently than on other keys. Across a range of doses, morphine produced responding predominantly on the saline key. The results using the four‐key procedure emphasized the role of both GABA_A and NMDA receptors in the complex discriminative stimulus properties of phencyclidine and of ethanol.     

5HT antagonists attenuate MK801-impaired radial arm maze performance in rats

Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a noncompetitive blocker of glutamate N-methyl-D-aspartate receptors, was used to disrupt the cognitive performance of rats trained on a delayed nonmatching to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairment produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antagonist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive benefit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritanserin, ondansetron, or arecoline in combination with MK801 did not result in a cognitive impairment, indicating that these drugs attenuated the MK801 impairment. The combination of buspirone and MK801 resulted in an inability of the animals to complete the task. These results suggest that interactions between 5-HT and glutamate may mediate the beneficial effects of reducing cognitive impairment and that 5-HT antagonists, especially selective 5-HT1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of tools available to predict treatment efficacy in AD.