Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference

Learned associations between environmental cues and morphine use play an important role in the maintenance and/or relapse of opioid addiction. Although previous studies suggest that context-dependent morphine treatment alters glutamatergic transmission and synaptic plasticity in the hippocampus, their role in morphine conditioned place preference (CPP) and reinstatement remains unknown. We investigated changes in synaptic plasticity and NMDAR expression in the hippocampus after the expression, extinction, and reinstatement of morphine CPP. Here we report that morphine CPP is associated with increased basal synaptic transmission, impaired hippocampal long-term potentiation (LTP), and increased synaptic expression of the NR1 and NR2b NMDAR subunits. Changes in synaptic plasticity, synaptic NR1 and NR2b expression, and morphine CPP were absent when morphine was not paired with a specific context. Furthermore, hippocampal LTP was impaired and synaptic NR2b expression was increased after extinction of morphine CPP, indicating that these alterations in plasticity may be involved in the mechanisms underlying the learning of drug–environment associations. After extinction of morphine CPP, a priming dose of morphine was sufficient to reinstate morphine CPP and was associated with LTP that was indistinguishable from saline control groups. In contrast, morphine CPP extinguished mice that received a saline priming dose did not show CPP and had disrupted hippocampal LTP. Finally, we found that reinstatement of morphine CPP was prevented by the selective blockade of the NR2b subunit in the hippocampus. Together, these data suggest that alterations in synaptic plasticity and glutamatergic transmission play an important role in the reinstatement of morphine CPP

Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus.

International audienceExcessive maternal caffeine consumption can lead to fetal and neonatal pathology, but the underlying mechanisms have not been determined. Here, we report that low doses of caffeine generate seizures when applied in conjunction with brief anoxic episodes in the hippocampus of neonatal rats in vitro. In control conditions, brief (4-6 minutes) anoxic episodes reversibly depressed evoked synaptic responses and blocked the physiological pattern of network activity. In the presence of caffeine (50 microM), similar anoxic episodes generated ictal (29%) or interictal (33%) epileptiform activities often followed during reoxygenation by recurrent spontaneous seizure activity that persisted for several hours. These effects are likely mediated by a blockade of adenosine receptors by caffeine because (1) in control conditions, caffeine antagonized the inhibitory effect of selective A1 receptor agonist N6-cyclopentyladenosine on excitatory synaptic responses, and (2) epileptogenic effects of caffeine were reproduced by selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and theophylline. Our findings suggest that endogenous adenosine released during anoxia acting via A1 receptors prevents seizures in the neonatal hippocampus and that the antagonism of these receptors by caffeine leads to epileptogenesis. This study suggests concerns about the safety of caffeine in the fetus and newborn

Increased Small Conductance Calcium-Activated Potassium Type 2 Channel-Mediated Negative Feedback on N-methyl-D-aspartate Receptors Impairs Synaptic Plasticity Following Context-Dependent Sensitization to Morphine

This paper addresses the comparison between two techniques for the optimization under parametric uncertainty of multiproduct batch plants integrating design and production planning decisions. This problem has been conceived as a two-stage stochastic mixed integer linear programming (MILP) in which the first-stage decisions consist of design variables that allow determining the batch plant structure, and the second-stage decisions consist of production planning continuous variables in a multiperiod context. The objective function maximizes the expected net present value. In the first solving approach, the problem has been tackled through mathematical programming considering a discrete set of scenarios. In the second solving approach, the multi-scenario MILP problem has been reformulated by adopting a simulation-based optimization scheme to accommodate the variables belonging to different management levels. Advantages and disadvantages of both approaches are demonstrated through a case study. Results allow concluding that a simulation-based optimization strategy may be a suitable technique to afford two-stage stochastic programming problems.Sociedad Argentina de Informática e Investigación Operativ