Some central effects of CGP 37849 and CGP 39551, the competitive NMDA receptor antagonists: potential antiparkinsonian activity

Summary Two new competitive NMDA receptor antagonists with oral activity CGP 37849 (D,L-E-amino-methyl-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551 were studied in rats. CGP 37849 did not change the locomotor activity or increased it. The hyperactivity induced by CGP 37849 was antagonized by haloperidol but not idazoxan or prazosin. CGP 39551 decreased the locomotor activity. The studied compounds did not increase the locomotion in monoamine-depleted (pretreated with reserpine and -methyl-p-tyrosine) rats. Clonidine induced antiakinetic effect in monoamine-depleted rats. This effect was more pronounced after joint administration of clonidine and CGP 37849 or CGP 39551. The locomotor hyperactivity induced by joint dministration of CGP 37849 and clonidine was inhibited by haloperidol but not prazosin or idazoxan. CGP 37849 but not CGP 39551 also enhanced antiakinetic effect of L-DOPA (given together with benserazide) in monoamine-depleted rats. CGP 37849 antagonized the spiperone- and fluphenazine-induced catalepsy; CGP 39551 had considerably weaker antagonistic effect. The reserpine-induced catalepsy was attenuated by CGP 37849. MK-801, a non-competitive NMDA antagonist inhibited spiperone- but not reserpine-induced catalepsy. The obtained results indicate that CGP 37849 administered alone or in combination with L-DOPA or clonidine may be a potential antiparkinsonian drug.     

Reciprocal inhibition between seizures induced by intermittent light stimulation and premotor cortical stimulation in Senegalese baboons, Papio papio

The temporal relationship between the degree of photosensitivity and the intensity of kindling stimulus response was examined in four Senegalese baboons, Papio papio, kindled at the premotor cortical area. When fully kindled, the intensity of photosensitivity diminished significantly in all the animals. With successive daily intermittent light stimulation, two animals showed partial recovery and the other two showed complete recovery to the prekindling level of photosensitivity. When premotor cortical kindling stimulation was subsequently reapplied, three-quarters of the animals failed to respond with kindled seizures and additional stimulations were necessary to reestablish kindled seizure. Two of these three animals also required increased stimulus intensity before the previously established generalized seizure threshold could be reinstated. The frontorolandic cortex is known as the most epileptogenic area in photosensitive Papio papio. In this species, spontaneous generalized convulsive seizures, intermittent light stimulation-induced seizures, and kindled generalized convulsive seizures are all known to share a common electroclinical phenomenology. The reciprocal inhibition observed in this study between generalized seizures induced by either intermittent light stimulation or by premotor cortical kindling stimulation further strengthens the possibility that they also share a common neuronal mechanism.     

Effects of some excitatory amino acid antagonists on imipenem-induced seizures in DBA/2 mice

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABA_A agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (±)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((±)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) . 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 ? Msc ? (−)-2-amino-7-phosphonic acid (AP7) > γ-D-glutamylaminomethylsulphonate (γ-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABA_A agonist, was able to protect against seizures induced by Imi.     

Effects of isolation on activity,reactivity, excitability and aggressive behavior in two inbred strains of mice

In order to investigate mechanisms of isolation-induced aggressive behavior, inbred mice of the C57BL/6 and DBA/2 strains were individually housed over a period of 8 weeks. In the DBA/2 strain only, isolation was followed by a clear increase in activity (Animex), reactivity (reactions upon tactile body stimulation), excitability (duration of EEG desynchronization elicited by tactile stimulation of the thorax area under urethane anesthesia) and intermale aggression (biting and fighting responses). The use of inbred strains of mice proved to be a useful tool for the examination of the relationship between various parameters. It is concluded that there are no clear correlations between activity, reactivity and aggressive behavior and that the resulting aggressive responses in the DBA/2 strain are likely due to the increase of excitability.     

Serotonin transporter, 5‐HT1A receptor,and behavior in DBA/2J mice in comparison with four inbred mouse strains

Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5‐HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5‐HT transporter (5‐HTT) mRNA level, 5‐HT_1A receptor mRNA level, and 5‐HT_1A receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5‐HTT mRNA level in the midbrain and a reduced density of 5‐HT_1A receptors in the frontal cortex without significant changes in 5‐HT_1A receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light‐dark box and elevated plus‐maze tests, were found. The results suggested the involvement of decreased 5‐HTT gene expression and 5‐HT_1A receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive‐like behaviors. © 2009 Wiley‐Liss, Inc.