The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.
We consider the Kuramoto-Sakaguchi model of identical coupled phase oscillators with a common noisy forcing. While common noise always tends to synchronize the oscillators, a strong repulsive coupling prevents the fully synchronous state and leads to a nontrivial distribution of oscillator phases. In previous numerical simulations, a formation of stable multicluster states has been observed in this regime. However we argue here, that because identical phase oscillators in the Kuramoto-Sakaguchi model form a partially integrable system according to the Watanabe-Strogatz theory, the formation of clusters is impossible. Integrating with various time steps reveals that clustering is a numerical artifact, explained by the existence of higher order Fourier terms in the errors of the employed numerical integration schemes. Monitoring the induced change in certain integrals of motion we quantify these errors. We support these observations by showing, on the basis of the analysis of the corresponding Fokker-Planck equation, that two-cluster states are non-attractive. On the other hand, in ensembles of general limit cycle oscillators, such as Van der Pol oscillators, due to an anharmonic phase response function, as well as additional amplitude dynamics, multiclusters can occur naturally.a)
We show that a combined action of noise and delayed feedback on an excitable theta-neuron leads to rather coherent stochastic bursting. An idealized point process, valid if the characteristic time scales in the problem are well-separated, is used to describe statistical properties such as the power spectral density and the interspike interval distribution. We show how the main parameters of the point process, the spontaneous excitation rate and the probability to induce a spike during the delay action, can be calculated from the solutions of a stationary and a forced Fokker-Planck equation.
Repeated exposure to nicotine increases psychomotor activity. Long-lasting neural plasticity changes that contribute to the nicotine-induced development of locomotor sensitization have been identified. The mammalian target of rapamycin complex 1 (mTORC1) signalling pathway is involved in regulating the neuroplasticity of the central nervous system. In this study, we examined the role of mTORC1 in the amygdala in nicotine-induced locomotor sensitization. Rapamycin, an inhibitor of mTORC1, was infused into the basolateral amygdala (BLA) and central amygdala (CeA) or systemically administered to investigate the role of the mTORC1 in the development and expression of nicotine-induced locomotor sensitization. We found that locomotor activity progressively increased during the initiation of nicotine-induced locomotor sensitization and the expression of nicotine sensitization was induced by nicotine challenge injection (0.35 mg/kg s.c.) after five days of withdrawal. The initiation of nicotine-induced locomotor sensitization was accompanied by the increased phosphorylated level of mTORC1 downstream target proteins including p-p70s6k and p-4EBP in the BLA, but not CeA. Intra-BLA infusion or systemic administration of rapamycin blocked locomotor activity. Increased p-p70s6k and p-4EBP were also observed in the expression of nicotine sensitization, which was demonstrated to be inhibited by systemic rapamycin administration. Our findings indicated that mTORC1 activity in the BLA, but not the CeA, mediated the initiation and expression of nicotine-induced locomotor sensitization, and may become a potential target for the treatment of nicotine addiction.
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