Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons - PubMed (original) (raw)

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Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons

Yanhua H Huang et al. Behav Brain Res. 2011.

Abstract

Homeostatic response is an endowed self-correcting/maintaining property for living units, ranging from subcellular domains, single cells, and organs to the whole organism. Homeostatic responses maintain stable function through the ever-changing internal and external environments. In central neurons, several forms of homeostatic regulation have been identified, all of which tend to stabilize the functional output of neurons toward their prior "set-point." Medium spiny neurons (MSNs) within the forebrain region the nucleus accumbens (NAc) play a central role in gating/regulating emotional and motivational behaviors including craving and seeking drugs of abuse. Exposure to highly salient stimuli such as cocaine administration not only acutely activates a certain population of NAc MSNs, but also induces long-lasting changes in these neurons. It is these long-lasting cellular alterations that are speculated to mediate the increasingly strong cocaine-craving and cocaine-seeking behaviors. Why do the potentially powerful homeostatic mechanisms fail to correct or compensate for these drug-induced maladaptations in neurons? Based on recent experimental results, this review proposes a hypothesis of homeostatic dysregulation induced by exposure to cocaine. Specifically, we hypothesize that exposure to cocaine generates false molecular signals which misleads the homeostatic regulation process, resulting in maladaptive changes in NAc MSNs. Thus, many molecular and cellular alterations observed in the addicted brain may indeed result from homeostatic dysregulation. This review is among the first to introduce the concept of homeostatic neuroplasticity to understanding the molecular and cellular maladaptations following exposure to drugs of abuse.

Copyright © 2010 Elsevier B.V. All rights reserved.

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Figures

Figure 1

Figure 1

Using synaptic plasticity as an example, the diagram shows the differences between regulated and homeostatic plasticity. A A postsynaptic neuron receives multiple presynaptic inputs (1, 2, and 3). These presynaptic terminals may project from different neurons and thus may also represent synapses from different pathways. B Regulated synaptic plasticity exhibits two defining properties, contingency and specificity. A successful induction of regulated synaptic plasticity requires a contingent activation of pre- and postsynaptic terminals (diagramed as action potential firing at both presynaptic and postsynaptic terminals at synapse 2; affected synapse is in shade), and is only expressed in the affected pathway (e.g., only synapse 2 is potentiated by enhanced postsynaptic responsiveness). Other synapses (1 and 3), although located on the same postsynaptic neuron, are not altered because they are not within the contingently activated pathway. C Homeostatic synaptic plasticity is induced and expressed “globally”. Chronic decrease of postsynaptic receptor sensitivity induces a global increase in presynaptic release such that the action potential firing of postsynaptic neurons is restored.

Figure 2

Figure 2

A schematic view of homeostatic synapse-driven membrane plasticity in NAc neurons. On the postsynaptic membrane, AMPARs mediate most of postsynaptic current, and NMDARs are also activated during synaptic transmission. The activity of synaptic NMDARs is positively correlated with the activity level of excitatory synapses. As such, the constitutively active NMDAR-coupled intracellular signaling (e.g., the CaMKII-mediated signaling) can be up- or down-regulated accordingly on a real-time base, which in turn modulates ion channels (e.g., SK channels) located on the somatic membrane.

Figure 3

Figure 3

Summary of synaptic and membrane alterations in NAc neurons following non-contingent exposure to cocaine. A typical non-contingent cocaine procedure is to treat the animal with 5-day i.p. injections of cocaine (15–20 mg/kg/day), followed by different withdrawal periods. An important synaptic alteration in NAc neurons during the late phase of cocaine exposure and short-term withdrawal is the appearance of silent synapses enriched in NR2B-containing NMDARs. These silent synapses decrease over time during long-term withdrawal. Synaptic/surface AMPARs in NAc neurons are altered minimally if any (i.e., a slight decrease) during short-term withdrawal, but are greatly up-regulated during long-term withdrawal. The intrinsic membrane excitability of NAc neurons is decreased throughout short- and long-term withdrawal. Based on the timing of these cocaine-induced synaptic and membrane alterations, we hypothesize that these cellular alterations are homeostatically linked. For example, although synaptic AMPARs are not up-regulated during short-term withdrawal, the increased NMDAR-mediated activity may create a false signal of increased synaptic strength to trigger hSMP, resulting in observed decrease in membrane excitability (?1). Furthermore, newly generated silent synapses provide extra synaptic lots that may facilitate synaptic recruitment of new AMPARs during long-tem withdrawal (?2). The synaptic recruitment of AMPARs during long-term withdrawal may result from regulated or homeostatic plasticity. For homeostatic plasticity, a potential mechanism is that the decreased membrane excitability may trigger another round of membrane-to-synapse homeostatic response, resulting in an increase in excitatory synaptic strength in NAc neurons (?3).

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