Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D 3 versus D 2 receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D 3 receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D 2 receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+)S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D 3 receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D 3 receptors as a target for treatment of disorders in which cognitive function is compromised.

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano [3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D 3 versus D 2 receptors and does not interact with histamine H 1 and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16 -2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04 -2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04 -0.63 g/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04 -0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16 -2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0 -40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D 3 versus D 2 receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.We have recently described a novel benzopyranopyrrolidine derivative, S33138 (Millan et al., 2008a,b) that behaves as a preferential antagonist at cloned, human, and native cerebral dopaminergic D 3 versus D 2 receptors. In addition, it displays modest antagonist properties at serotonin (5-HT) 2A receptors, 5-HT 7 receptors, and ␣ 2C -adrenoceptors (ARs), blockade of which may also be useful in the treatment of schizophrenia Svensson, 2003). In contrast, S33138 does not interact with histamine H 1 , muscarinic, or ␣ 1 -adrenoceptors, antagonism of which provokes cardiovascular-autonomic side effects (Kroeze et al., 2003;Lieberman, 2005). This distinctive receptor-binding profile differentiates S33138 from clinically employed antipsychotics like the neuroleptic and D 2 /D 3 receptor antagonist, haloperidol; the "atypical" agent, clozapine; and two further mulArticle, publication date, and citation information can be found at

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The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specific in vitro models represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establish in vitro models that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases.

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