Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the infor- mation storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.

Synaptic plasticity and memory: an evaluation of the hypothesis

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitiveN-methyl-d-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.

Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors.

The objective of this study was to characterize the behavior induced by the N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine maleate) in rats as a model of psychosis. The temporal profile, dose dependence, age, and sex differences of the behavior are described. A gas chromatographic method for the analysis of MK-801 in plasma and brain was developed. Female rats showed 4 to 10 times more MK-801-induced behavior and displayed around 25 times higher serum and brain concentrations of MK-801 than male rats. Twenty-one neuroactive compounds, including a number of excitatory amino acid-active substances, were tested for the effect on MK-801-induced behavior. Neuroleptics blocked MK-801-induced behavior in a dose-dependent manner that correlated to their antipsychotic potency in humans. Adenosine receptor agonists and an N-methyl-D-aspartate receptor-associated glycine site antagonist showed putative antipsychotic effects. In conclusion, MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.

Characterization of MK-801-Induced Behavior as a Putative Rat Model of Psychosis

NCS-1 in the Dentate Gyrus Promotes Exploration, Synaptic Plasticity, and Rapid Acquisition of Spatial Memory

An integrated view of pathophysiological models of schizophrenia.

MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclo-hepten-5, 10-imine hydrogen maleate], which blocks glutamatergic transmission at the NMDA-receptor-gated ion chanel, induced stereotypies which are similar to those found after intrastriatal injections of AP-5, e.g. sniffing and locomotion. Tests in familiar or unfamiliar environment (non-stressful or stressful situation) did not qualitatively change MK-801-induced effects. Haloperidol (0.1mg/kg, IP) delayed the onset and shortened the duration of MK-801 (0.16; 0.33mg/ kg, IP)-induced stereotypy whereas clozapine (5 mg/kg, SC) potently antagonized it. However, exact quantification of sniffing, measured in an experimental chamber designed for this purpose, revealed an antagonism by both drugs, haloperidol as well as clozapine. Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.

C. Bischoff

Papers

MK-801-induced stereotypy and its antagonism by neuroleptic drugs.