Eated mice than in CTX-na e mice (P 0.05 at 10 and 50 min post-injection; P 0.001 at 20 and 30 min post-injection; and P 0.01 at 40 min post-injection). For cumulative locomotorNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptNeurosci Lett. Author manuscript; readily available in PMC 2014 November 27.Tallarida et al.Pageactivity over the entire 60-min period following cocaine injection (Fig. 2B, box), locomotor activity was drastically reduced inside the CTX-COC group (P 0.01, Student’s t-test).NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptDiscussionCTX attenuated hypersensitivity towards the locomotor-stimulant effects of cocaine in two dosing regimens, a single in which it was co-administered with cocaine through improvement of locomotor sensitization and a single in which it was administered only in the course of the period of forced absence following discontinuation of repeated cocaine exposure. The mechanism by which CTX attenuated the locomotor-stimulant effects brought on by repeated cocaine exposure is unclear, but a glutamate-based mechanism may have contributed. CTX enhances cellular glutamate uptake by means of GLT-1 transporter activation [3, 7, 21, 23, 27, 32-33 40, 43]. In addition, repeated cocaine administration produces GLT-1 transporter dysfunction in brain reward and motor substrates that contributes to its locomotor-activating properties [18-19, 28, 37, 40]. Extracellular glutamate in the nucleus accumbens, a limbic structure that mediates the locomotor response to cocaine [9, 42], follows a distinctive profile across different stages of cocaine exposure, with glutamate levels declining in the course of cocaine absence and growing following reintroduction to cocaine [1, 24, 39]. CTX, by means of activation of GLT-1 transporters, reduces extracellular glutamate levels within the nucleus accumbens of otherwise drug-na e rats [29].56946-65-7 Purity Taken collectively, probably the most parsimonious explanation for CTX efficacy observed right here is that enhanced cellular glutamate uptake capacity following repeated CTX treatment normalizes part of the glutamate dysfunction that facilitates the sensitized locomotor response to cocaine, particularly the elevation in extracellular glutamate that is created by cocaine challenge. A caveat related with this interpretation is the fact that CTX therapy may well be predicted to exacerbate the reduction in extracellular glutamate that happens inside the nucleus accumbens of cocaine-withdrawn rats [1], thereby enhancing, as an alternative to suppressing, a triggering mechanism for the expression of behavioral sensitization. However, due to the fact CTX does attenuate the behavioral-sensitizing effects of cocaine in our paradigm, and in a different paradigm and species [37], it is actually a lot more most likely that cocaine-withdrawn rats show a nearmaximal reduction in basal extracellular glutamate that’s not further reduced by means of GLT-1 transporter activation by CTX.1-Bromo-3-methylnaphthalene web Cross-talk among glutamate uptake and antiport systems may perhaps be one particular reason for this; for instance, enhancement of glutamate reuptake by GLT-1 activation is offset to a degree by compensatory upregulation of glutamate efflux into the extrasynaptic space through activation of cystine-glutamate exchange, thereby preventing much more extensive reductions in basal glutamate levels of cocaine-withdrawn rats [40].PMID:31085260 Analysis with the time course data also reveal that sensitization to cocaine was modest and short, occurring more than the initial ten min following cocaine challenge, and that it was this initial element.
