Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective a7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the a7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801-or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective a7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

Social short-term memory in rodents is based on the recognition of a juvenile by an adult conspecific when the juvenile is presented on two successive occasions. Cannabimimetics are claimed to induce memory deficits in both humans and animals. In the brain, they mainly bind to CB1 receptors for which anandamide is a purported endogenous ligand. SR 141716, a specific antagonist of CB1 receptors, dose-dependently reverses biochemical and pharmacological effects of cannabimimetics. More particularly, it antagonizes the inhibition of hippocampal long-term potentiation induced by WIN 55,212-2 and anandamide, and it increases arousal when given alone. The present experiments study the ability of SR 141716 (from 0.03 to 3 mg/kg SC) to facilitate short-term olfactory memory in the social recognition test in rodents. SR 141716 improved social recognition in a long intertrial paradigm with a threshold dose of 0.1 mg/kg SC. At 1 mg/kg, it antagonized the memory disturbance elicited by retroactive inhibition. Scopolamine (0.06 mg/kg IP) partially reversed its memory-enhancing effect. Moreover, SR 141716 reduced memory deficit in aged rats (0.03-0.1 mg/kg) and mice (0.3-1 mg/kg). As SR 141716 is not known to exhibit any pharmacological activity which is not mediated by CB1 receptors, the results strongly support the concept that blockade of CB1 receptors plays an important role in consolidation of short-term memory in rodents and suggest there may be a role for an endogenous cannabinoid agonist tone (anandaminergic) in forgetting.

Rr I PhDrm. .,I (flflAn 11X icr242-A Dr. j. r-armout 77't, Here, we show that, in contrast to its antagonistic action on NT-induced hypomotility in the rat, SR 48692 failed to antagonize NT-induced hypothermia and analgesia in the mouse and rat. We suggest that these effects might be mediated through a subtype of SR 48692-insensitive NT receptor.