Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor.

The endogenous polyamines spermine and spermidine increase the binding of [3H]MK-801 to NMDA receptors. This effect is antagonized by diethylenetriamine (DET). We report here that spermine increases the rates of both association and dissociation of binding of [3H]MK-801, suggesting that it increases the accessibility of the binding site for MK-801 within the ion channel of the receptor complex. 1,10-Diaminodecane (DA10) inhibited the binding of [3H]MK-801. This effect was due to a decrease in the rate of association with no change in the rate of dissociation of [3H]MK-801. The effect of DA10 was not mediated by an action of DA10 at the binding sites for glutamate, glycine, Mg2+, or Zn2+, and was attenuated by DET. This suggests that DA10 acts at the polyamine recognition site. In hippocampal neurons the NMDA-elicited current was decreased by DA10, an effect opposite to that of spermine. The effects of spermine and DA10 were selectively blocked by DET. It is concluded that DA10 acts as a negative allosteric modulator or inverse agonist at the polyamine recognition site of the NMDA receptor.

Regional neuroprotective effects of the NMDA receptor antagonist MK-801 (dizocilpine) in hypoglycemic brain damage.

Current evidence points to an important role of N-methyl-D-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 [dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5H-di[a,d]cyclohepten-5,10-imine] is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood-brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5-5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5-2.0 mM) at the stage of delta-wave (1-4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of delta-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.

D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia.

D-Serine, a selective agonist at the strychnine-insensitive glycine binding site, antagonized PCP-induction of stereotyped behavior and ataxia in a dose-dependent manner. At intraventricular doses of 0.1, 0.5 and 1 mumol/rat, D-serine significantly attenuated PCP-induction of stereotyped behavior in rats. Only doses of 0.5 and 1.0 mumol/rat of D-serine antagonized PCP-induction of ataxia. D-Serine (0.5 mumol/rat) also antagonized MK-801 induced stereotyped behavior and ataxia. These results suggest that agonists at the strychnine-insensitive glycine site may be clinically useful as a novel class of atypical antipsychotic agents.

Electrophysiological effects of amineptine on neurones of the rat substantia nigra pars compacta: evidence for an inhibition of the dopamine uptake system.

1. Intracellular recordings were made from substantia nigra pars compacta neurones of the rat maintained in vitro in order to study the effects of the tricyclic antidepressant drug, amineptine. 2. Amineptine hydrochloride (1-30 microM) decreased spontaneous firing and slightly hyperpolarized the membrane potential. In neurones voltage-clamped at -50 or -60 mV, amineptine produced an outward membrane current. These actions were concentration-dependent and were completely antagonized by (-)-sulpiride. 3. The amineptine-induced hyperpolarization was resistant to tetrodotoxin (1 microM) but it was abolished in 0 mM Ca2+ (plus 13 mM MgCl2) solutions. 4. Amineptine (300 nM-30 microM) and cocaine (10-30 microM) increased the amplitude and duration of responses to exogenously applied dopamine. The effects of dopamine were potentiated about 5 fold by 10 microM amineptine; this potentiation persisted in calcium-free solutions. 5. Cocaine (10 microM) had no additional effect on the dopamine-induced responses in the presence of amineptine (30 microM). Amineptine (10 microM) produced no detectable effects in the presence of cocaine (30 microM). 6. It is concluded that amineptine acts as a dopamine uptake blocker in slices of rat substantia nigra.

Ascorbic acid and atypical antipsychotic drugs: modulation of amineptine-induced behavior in mice.

To provide a detailed characterization of individual kinds of behavior produced by ascorbic acid in combination with typical (haloperidol) or atypical (clozapine, sulpiride and remoxipride) antipsychotic drugs, the 'open-field' test was selected. Amineptine, an indirect dopamine agonist, was used as an explicit model of dopaminergic activity. Results showed that amineptine (5-10-20 mg/kg i.p.), dose-dependently, increased ambulation and rearing. Ascorbic acid (62.5-125-250 mg/kg i.p.) markedly inhibited the behavior of mice as well as the amineptine-induced hyperactivity. A combination of each typical or atypical antipsychotic drug (except clozapine 2.5 mg/kg i.p.) with amineptine (20 mg/kg i.p.) induced a significant increase in ambulation and rearing over that seen with the antipsychotic drugs alone. The combination of antipsychotic drugs with ascorbic acid 250 mg/kg i.p. led to a decrease in open-field parameters when compared with controls. In conclusion, these data provide further in vivo support for the effect of ascorbic acid on dopaminergic system and demonstrate that the antidopaminergic effects of both typical and atypical antipsychotic drugs may be enhanced with concurrent administration of ascorbic acid.

Blockade of MK-801 induced ipsiversive turning in 6-OHDA lesioned rats by alpha 1-adrenoceptor antagonists.

Previously the ipsiversive turning response elicited by MK-801 in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra has been shown to be reduced by the alpha 1-receptor antagonist, prazosin. In these experiments the effects of additional alpha 1-adrenoceptor antagonists were examined to verify the involvement of alpha 1-adrenoceptors in the elucidation of the ipsiversive turning response elicited by MK-801. Both aceperone and azapetine did significantly reduce the ipsiversive turning evoked by MK-801. In contrast, neither agent produced a statistically significant reduction in the contraversive turning evoked by the direct acting dopamine agonist, apomorphine. In addition, aceperone also produced a weak but dose-related inhibition of amphetamine-induced ipsiversive rotation, whereas azapetine partially reduced amphetamine-induced turning a non-dose related manner. These data suggest alpha 1-adrenoceptors may be partially involved in the ipsiversive turning response caused by MK-801 and to a lesser extent by amphetamine. This theory was further supported by the finding that reduction of endogenous norepinephrine levels, via administration of the dopamine-beta-hydroxylase inhibitor FLA-63, markedly reduced the turning evoked by MK-801 and to a lesser degree that produced by amphetamine.