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Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms. Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.

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Prenatal stress (PS) can produce profound and long-lasting perturbations of individual adaptive capacities, which in turn can result in an increased proneness to behavioural disorders. Indeed, in PS rats there is evidence of impaired social play behaviour, disturbances in a variety of circadian rhythms, enhanced anxiety and increased hypothalamic-pituitary-adrenal (HPA) axis reactivity. This study was designed to experimentally investigate the degree of reversibility of PS-induced disturbances of social play and HPA reactivity by assessing the effect of the enrichment of the physical environment on PS rats during periadolescence. PS subjects showed a reduced expression of social play behaviour and a prolonged corticosterone secretion in response to restraint stress, but both these effects were markedly reversed following environmental enrichment. Interestingly, the enrichment procedure increased social behaviour but had no effect on corticosterone secretion in nonstressed animals, indicating a differential impact of the postnatal environment as a function of prenatal background. As a whole, results clearly indicate that rats prenatally exposed to stress can benefit during periadolescence from the modulatory effects of an enriched environment. Moreover, they confirm that PS may well represent a suitable animal model for the design and testing of new therapeutic strategies for behavioural disorders produced by early insults.

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(10 mg/l). After a 6-day period, a fading study was carried out, in which nicotine concentration was reduced to 7 mg/l (days 7-9) and 5 mg/l (days 10-12), to assess whether animals would compensate by increasing their intake from the nicotine solution. In Experiment 2, psychopharmacological effects on locomotion induced by the nicotine solution (0, 10, 30 mg/l) Recent research has emphasized that adolescence is associated with patterns of temporary deviance (Arnett 1992) and the use of various kinds of psychoactive agents (Mathias 1996). Drug abuse in adolescents ranging from 11-12 to 17-18 years of age is likely to start with tobacco smoking, which can be followed by marijuana and/or 1991;Breslau et al. 1993;Nides et al. 1995;Kandel and Chen 2000). Despite the social and scientific importance of deepening our knowledge of this issue (see e.g. Colby et al. 2000), there have been very few investigations on the psychobiological factors contributing to the specific adolescence-related willingness to experience various psychoactive drugs (for a review, see Laviola et al. 1999;Spear 2000). For the purpose of laboratory studies, a suitable animal model of human adolescence is available in rodents. Namely, periadolescence is classically defined as the ontogenetic period that encompasses the week preceding the onset of puberty and the first few days thereafter (Spear and Brake 1983). Periadolescent rodents differ markedly from adults in their spontaneous behavioral repertoire (Cirulli et al. 1996;Terranova et al. 1993;Meaney and Stewart 1981;Panksepp 1981). In fact, elevated levels of novelty seeking and a reduced behavioral and hormonal response to stress (Adriani et al. 1998;Adriani and Laviola 2000) are exhibited by animals around this age. A characteristic hyporesponsivity to the effects of an acute administration of psychostimulants (Spear and Brake 1983;Laviola et al. 1995;Bolanos et al. 1998;Adriani and Laviola 2000), a peculiar pattern of behavioral sensitization following repeated drug exposure (Laviola et al. 1995(Laviola et al. , 2001Adriani et al. 1998), as well as a weak drug-induced place conditioning profile (Adriani et al. 1998;Bolanos et al. 1996Bolanos et al. , 1998 but see Campbell and Spear 2000), are also reported. Based on these findings, an increased vulnerability to the addictive properties of abused drugs has been suggested to be typical of adolescence in both humans and animals models (see Laviola et al. 1999).In the present study, we were interested in nicotine, which beside being the main psychoactive compound implied in tobacco smoking, also shares most of the characteristics of other addictive drugs (Corrigall et al. 1992(Corrigall et al. ,1994Pontieri et al. 1996;Merlo-Pich et al. 1997;Stolerman 1999). Nicotine's effects in mice have been shown to be highly dependent on the genetic background (see Marks et al. 1989;Robinson et al. 1996). However, the interaction between the pharmacological effects and the incentive properties of nicotine during the adolescent period has been largel...