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.

Females exhibit greater susceptibility to trauma-and stress-related disorders compared to males; therefore, it is imperative to study sex differences in the mode and magnitude of defensive responses in the face of threat. To test for sex differences in defensive behavior, we used a modified Pavlovian fear conditioning paradigm that elicits clear transitions between freezing and flight behaviors within individual subjects. Female mice subjected to this paradigm exhibited higher percentages of freezing behavior compared to males, especially during the intertrial interval period. Female mice also exhibited more cued freezing in response to the conditioned stimuli in the last block of extinction training. Furthermore, there were sex differences in the expression of other adaptive behaviors during fear conditioning. Assaying rearing, grooming, and tail rattling behaviors during the conditioned flight paradigm yielded measurable differences across sessions and between males and females. Overall, these results provide insight into sexdependent alterations in mouse behavior induced by fear conditioning.

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AbstractFemales exhibit greater susceptibility to trauma- and stress-related disorders compared to males; therefore, it is imperative to study sex differences in the mode and magnitude of defensive responses in the face of threat. To test for sex differences in defensive behavior, we used a modified Pavlovian fear conditioning paradigm that elicits clear transitions between freezing and flight behaviors within individual subjects. Female mice subjected to this paradigm exhibited higher percentages of freezing behavior compared to males, especially during the intertrial interval period. Female mice also exhibited more cued freezing in response to the conditioned stimuli in the last block of extinction training. Furthermore, there were sex differences in the expression of other adaptive behaviors during fear conditioning. Assaying rearing, grooming, and tail rattling behaviors during the conditioned flight paradigm yielded measurable differences across sessions and between males and females. Overall, these results provide insight into sex-dependent alterations in mouse behavior induced by fear conditioning.HighlightsMale and female mice do not differ in conditioned flight behavior.Female mice exhibit more freezing behavior.Rearing, self-grooming, and tail rattling behavior changes across days.Male mice exhibit more rearing and grooming behavior.Female mice exhibit more tail rattling behavior.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for addiction treatments because it affects dopamine transmission in the mesolimbic pathway. TAAR1 is involved in the effects of addictive drugs, such as amphetamines, cocaine and ethanol, but the impact of TAAR1 on the effects of nicotine, the psychoactive drug responsible for the development and maintenance of tobacco smoking, has not yet been studied. This study was performed to investigate the possible modulatory action of TAAR1 on the effects of nicotine on locomotor behaviors in rats and mice. Pretreatment with the TAAR1 agonist RO5263397 dose-dependently decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes, prevented the development of nicotine sensitization and blocked hypermotility in nicotine-sensitized rats at the highest tested dose (10 mg/kg). The lack of TAAR1 failed to affect the effects of nicotine on the locomotion of mutant mice. Based on the results of the present study, TAAR1 activation attenuates the locomotion-stimulating effects of nicotine on rats. These results further support the previously proposed hypothesis that TAAR1 is a promising target for the prevention and treatment of drug addiction. Further studies aimed at analyzing the effects of TAAR1 agonists on animal models of nicotine addiction are warranted.