PubMed · 7978611
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R O Bischof, G Buchalter. 1994. TAC Gel defined.. https://doi.org/10.1016/s0196-0644(94)70257-8
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Previously we found that inhibitors of noradrenaline (NA) and/or 5-HT reuptake are able to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) in the CNS most probably by a channel blocker-type mechanism. The aim of our study was to clarify whether selective dopamine uptake inhibitors also possess this property, therefore we investigated the effect of GBR-12909 on the nicotine-evoked release of [3H]NA from rat hippocampal slices. GBR-12909, similar to selective NA and 5-HT uptake blockers, inhibited the nicotine-evoked release with an IC50 of 2.32 microM. The ability of monoamine uptake blockers to inhibit nicotine-evoked [3H]NA release (IC50) and NA reuptake (Ki) showed no correlation, indicating that the NA uptake system is not involved in the inhibition of the response to nicotine. Previously we have shown in whole cell patch clamp experiments, that GBR-12909, depending on the stimulation pattern, inhibits Na+-currents with an IC50 in the 6-35 microM concentration range [Mike A, Karoly R, Vizi ES, Kiss JP (2003) Inhibitory effect of the DA uptake blocker GBR-12909 on sodium channels of hippocampal neurons. Neuroreport 14:1945-1949]. To study whether the inhibition of Na+-channels is involved in the action of GBR-12909 on the nicotine-evoked [(3)H]NA release, we compared the effect of GBR-12909 and the Na(+)-channel blocker tetrodotoxin (TTX) on the electrical stimulation- and nicotine-evoked response. TTX prevented the release of [3H]NA induced by both types of stimulation, whereas GBR-12909 inhibited only the nicotine-induced response, indicating that under our experimental conditions the target of GBR-12909 is not the Na+-channel. These data indicate that the selective DA uptake inhibitor GBR-12909 is able to inhibit nAChRs, that is, the nAChR antagonistic property of monoamine uptake inhibitors is independent of their selectivity. The fact that monoamine uptake inhibitors with different chemical structure and selectivity are able to inhibit nAChRs may reveal some common properties of nicotinic receptors and monoamine uptake carriers.
Synaptic long-term depression (LTD) is thought to be important for various brain functions such as learning, memory, and development. Although anterior cingulated cortex (ACC) has been demonstrated to contribute to learning and memory, no studies has been reported about the synaptic mechanisms for cingulate LTD. Here, we used integrative genetic, pharmacological and electrophysiological approaches to demonstrate that AMPA GluR2, but not GluR3, subunit is critical for cingulate LTD. We found that LTD was absent in adult cingulate slices of GluR2 knockout mice. Furthermore, postsynaptic injections of peptides that inhibit AMPA GluR2-PDZ interactions blocked the induction of LTD. To determine if the requirement for AMPA receptor-PDZ interaction is time-dependent, we injected the same inhibiting peptide into the postsynaptic cells 5 min after the induction of LTD. We found that LTD was not affected by the peptide, providing the first evidence that postsynaptic AMPA GluR2-mediated depression occurs rapidly (within t = 5 min). Genetic deletion of GluR3 did not affect cingulate LTD. Our results provide the first study of cingulate LTD mechanism using whole-cell patch-clamp recording in adult cortical slices and demonstrate that postsynaptic AMPA GluR2 subunit is crucial for synaptic depression in the ACC of adult mice.
Synapse competition and elimination are a general developmental process both in central and in peripheral nervous systems that is strongly activity dependent. Some common features regulate synapse competition, and one of these is an application to development of the Hebb's postulate of learning: repeated coincident spike activity in competing presynaptic inputs on the same target cell inhibits competition, whereas noncoincident activity promotes weakening of some of the inputs and ultimately their elimination. Here we report experiments that indicate that the development of muscle innervation (initial polyneuronal innervation and subsequent synapse elimination) follows the Hebb's paradigm. We utilized two different models of muscle reinnervation in the adult rat: 1) we crushed nerves going to soleus or extensor digitorum longus muscles, to activate regeneration of the presynaptic component of the neuromuscular junctions (NMJ), or 2) we injected the soleus muscle with Marcaine (a myotoxic agent) to activate regeneration of the postsynaptic component, the muscle fiber. A condition of transient polyneuronal innervation occurs during NMJ regeneration in both cases, although the two models differ insofar as the relative strength of the competing inputs is concerned. During the period of competition (a few days or weeks, in Marcaine or crush experiments, respectively), we imposed a synchronous firing pattern on the competing inputs by stimulating motor axons distal to a chronic conduction block and demonstrated that this procedure strongly inhibits synapse elimination, with respect to control muscles in which regeneration occurs under natural impulse activity of motoneurons.