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The transatlantic divide in the reception of law and economics is difficult to explain. Many factors have been mentioned without perfect success. The influence of legal theory has been unfortunately omitted. This article will show that European legal theory largely paved the way for an economic analysis of law through the clarification of legal language, EAL is certainly excluded as a theory of law, but it is recognized as a theory about law. Moreover, EAL through the lens of European legal theory is in part redefined.

In this paper, I argue that the “expanded” economic theory advocated in Calabresi’s book “The Future of Law and Economics” could be interpreted in at least three different ways, all of which are compatible. First, Calabresi’s book could be interpreted as an attempt to incentivize lawyer-economists to explore laws and regulations from different angles or perspectives rather than merely apply neoclassical theories. Second, it could be considered an attempt to justify the introduction of the notion of moral costs into law and economics to better explain some legal realities. Third, it could be considered an attempt to advocate, in a more normative way, the need to incorporate moral costs into real world analysis to better improve upon decision making. This paper will address and discuss each of these possible interpretations. It will be clear that, from an epistemological point of view, if the first interpretation might be more widely accepted because it is less controversial, the second and third interpretations remain more problematic. Admittedly, the concept of moral costs could obscure and even distort our understanding of some legal realities. Moreover, the introduction of such costs for decision making is raising questions which cannot be answered through economic theory alone.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α7 n-AChRs (Ki of 22±4 and 14±1 nM, respectively). Ex vivo 3[H]α-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID50=8 mg/kg p.o.). In functional studies performed with human α7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

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 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 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 microM) 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 CB1 receptors): it reversed the decrease in electrically evoked [3H]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.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K i of 22±4 and 14±1 nM, respectively). Ex vivo 3 [H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 =8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC 50 =4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.