Effects of (+) SKF 10,047, a sigma-1 receptor agonist, on anxiety,tested in two laboratory models in mice.

Recently, sigma-1 receptor modulators have been considered drugs with an interesting therapeutic potential for the treatment of anxiety. However, there is no clear information in preclinical studies about the possible effects of sigma-1 ligands on anxiety in experimental animal models. Therefore, the present study examined the effects of (+)SKF 10,047 (2-8 mg/kg, ip), a sigma-1 agonist, on anxiety, tested in two classical laboratory models (social interaction test and elevated plus maze). (+)SKF 10,047 (8 mg/kg) produced a significant decrease of social investigation in the "social interaction test", whereas in the "elevated plus maze", the drug (4 and 8 mg/kg) provoked a significant reduction in the number of entries into open arms, as well as in the time spent in this area, as compared with the control group, without affecting motor activity. Overall, these findings indicate that (+)SKF 10,047 exhibits an anxiogenic-like profile in mice. It is suggested that anxiogenic effects of this sigma-1 ligand could be related to its potent ability to modulate diverse neurotransmitter systems involved in anxiety regulation.

Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.

NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.

Spike and wave complexes produced by four hallucinogenic compounds in the cat.

The ability of four hallucinogenic compounds: ketamine, phencyclidine, quipazine and SKF-10,047 to produce spike and wave activity in the limbic system, was studied in cats with permanently implanted electrodes. Electronic frequency integrators were used to analyze the results and the percent of change in electrographic alterations was calculated. All the compounds studied, produced trains of 6/sec spike and waves complexes in the cingulum, rapid synchronous discharges in the amygdaloid complex, and slow wave synchronous activity and spiking in the septal areas. At low but hallucinatory concentrations of these drugs, the cortical EEG was not affected. Exploratory movements directed toward non-existent objects, classified as hallucinatory-like behavior, appeared simultaneous with these changes in the EEG recordings. It was concluded that there could exist a relationship between the appearance of 6/sec spike and wave complexes in the cingulum and the presence of hallucinations, produced by some synthetic drugs in the cat, this activity could be interpreted as the spreading of altered function of limbic and non-limbic nuclei related with this bundle which explain unspecificity of action.

The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice.

1. The administration of either iproniazid or tranylcypromine to mice potentiates the acute toxicity of pethidine, morphine, pentazocine and phenazocine.2. Blood levels of pentazocine in mice pretreated with tranylcypromine do not differ from the levels in animals not receiving the monoamine oxidase (MAO) inhibitor.3. There is no correlation between changes in brain and liver MAO activity and the increased pethidine toxicity.4. A comparison is made between the change in pethidine toxicity and the changes in the concentration of cerebral noradrenaline, dopamine and 5-hydroxytryptamine following the injection of tranylcypromine.5. It is concluded that the increased toxicity of potent analgesics in combination with MAO inhibitors is not due to a decelerated metabolism of the analgesic drug, but is related to an increased concentration of cerebral 5-hydroxytryptamine. A critical level of this monoamine, in the brain, may be necessary before the drug interaction will take place.