Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice

Abstract

The behavioral effects of cocaine are affected by gene knockout of the dopamine transporter (DAT), the serotonin transporter (SERT) and the norepinephrine transporter (NET). The relative involvement of each of these transporters varies depending on the particular behavioral response to cocaine considered, as well as on other factors such as genetic background of the subjects. Interestingly, the effects of these gene knockouts on cocaine induced locomotion are quite different from those on reward assessed in the conditioned place preference paradigm. To further explore the role of these genes in the rewarding effects of cocaine, the ability of five daily injections of cocaine to induce conditioned locomotion was assessed in DAT, SERT and NET knockout (KO) mice. Cocaine increased locomotor activity acutely during the initial conditioning session in SERT KO and NET KO, but not DAT KO, mice. Surprisingly, locomotor responses in the cocaine-paired subjects diminished over the 5 conditioning sessions in SERT KO mice, while locomotor responses increased in DAT KO mice, despite the fact that they did not demonstrate any initial locomotor responses to cocaine. Cocaine-induced locomotion was unchanged over the course of conditioning in NET KO mice. In the post-conditioning assessment, conditioned locomotion was not observed in DAT KO mice, and was reduced in SERT KO and NET KO mice. These data reaffirm the central role of dopamine and DAT in the behavioral effects of cocaine. Furthermore, they emphasize the polygenic basis of cocaine mediated behavior and the non-unitary nature of drug reward mechanisms, particularly in the context of previous studies that have shown normal cocaine conditioned place preference in DAT KO mice.

Development of Hyperactivity and Anxiety Responses in Dopamine Transporter-Deficient Mice

“…This is consistent with previous work [4,8,31,32,33,34]. The extent of the hyperlocomotion is very impressive and sustained in multiple environmental contexts.…”

Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

“…However, depending on the behavioral effect of cocaine, enhanced NE and 5-HT release (upon blockade of NET and SERT) may also play a role (Drouin et al, 2002;Homberg et al, 2008;Hall et al, 2009 Since an inhibitory effect of insulin on electrically evoked monoamine release in brain slices was associated with potentiation of the release-enhancing effect of monoamine transporter blockers, our study reveals that insulin presynaptically enhances the function of monoamine transporters in frontal cortical and striatal rat brain regions.…”

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

“…Higher dopamine concentrations in the synaptic cleft can be simulated by knock-out of the dopamine transporter (DAT). Such mice have been classified as models of schizophrenia as they are hyperactive in novel environments, express excessive stereotypic behaviour, reduced reward learning, deficits in sensorimotor gating, working and declarative memory, and show circadian rhythm impairments [96][97][98][99] . The modified neuron-oscillatory properties caused by DAT knock-out have also been shown to influence the serotonergic system, possibly as compensation for the hyperdopaminergia 100,101 .…”