|คาสิโนไทย||Memory Consolidation and Drug Addiction||Memory|
Drug addiction is a disease of learning and memory, that is, the brain remembers too much or too powerfully the pleasure associated with the drug (Hyman, 2005; Nestler, 2013). Compelling evidence suggests that the powerful recall could be due to excessive memory strengthening, rather than impairment in memory extinction. As discussed in Chapter 22, long-term memory extinction may result from deficiency in brain-derived neurotrophic factor (BDNF). However, cocaine has been shown to increase BDNF expression (McCarthy et al., 2012). On the other hand, virtually all drugs of abuse (cocaine, amphetamine, morphine, marijuana, nicotine and alcohol) have the capacity to induce two pathways implicated in memory strengthening: (1) a truncated form of the FosB protein known as ?FosB and (2) mechanistic target of rapamycin (mTOR). The underlying mechanism is discussed in this chapter.
Cocaine Causes Spine Shrinkage
In the nucleus accumbens (NAc, located in the striatum), chronic exposure to cocaine results in a time-dependent structural changes in the spine head of medium spiny neurons (MSNs) (Nestler, 2013). At early withdrawal time points (0 - 1 day), the spine shrinks, akin to long-term depression (LTD). During more prolonged withdrawal, the spine grows to mushroom-shape, resembling long-term potentiation (LTP). Exposure to cocaine again causes rapid spine shrinkage (Figure 30-1). These results can be explained by the finding that cocaine blocks dopamine reuptake (Hummel and Unterwald, 2002), thereby elevating the concentration of dopamine in the synaptic cleft, and leading to over-stimulation of the dopamine receptors on MSNs. Activation of D1 receptors can trigger the phospholipase C (PLC)/Ca2+ cascade (Abraham et al., 2014, Figure 1), which may induce PIP2 hydrolysis to release membrane-associated cofilin into the cytosol. The large amount of cofilin in the cytosol would cause dramatic F-actin depolymerization, consequently resulting in spine shrinkage (Chapter 20).
The spine shrinkage does not account for addictive behavior, which instead arises from memory consolidation during more prolonged withdrawal (> 2 weeks). ?FosB and mTOR have been demonstrated to play crucial roles in memory consolidation that leads to addiction.
?FosB and NF-κB
?FosB is a transcriptional factor with long lifetime. It persists in neurons for at least several weeks after the cessation of drug exposure (Nestler, 2008; Nestler, 2015). The targets of ?FosB include nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (Cdk5). NF-κB is also a transcription factor, regulating many genes involved in synaptic plasticity (Engelmann and Haenold, 2016). It has been shown to be essential for consolidation and reconsolidation of persistent memories (de la Fuente et al., 2015). CaMKII is known to play a critical role in LTP (Chapter 6). Cdk5 may regulate dendritic spine development by phosphorylating CRMP2 (Jin et al., 2016).
mTOR and CRMP2
mTOR is a protein kinase that catalyzes protein phosphorylation. Upon activation, it can phosphorylate two major targets, p70 ribosome S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), to initiate protein synthesis from mRNA to a globular protein. A variety of signals may activate mTOR, including the BDNF-TrkB and Dopamine-D3R pathways which can lead to addiction (Figure 30-2). Depending on the regulatory proteins associated with mTOR, two complexes have been identified: mTORC1 and mTORC2. mTORC1 is involved in cell growth such as the elongation and branching of neurites (dendrites and axon).
Mounting evidence demonstrates that the ERK signaling pathway is implicated in drug addiction (คาสิโนไทยSun et al., 2016; Schafe et al., 2000; Lu et al., 2006; Zamora-Martinez and Edwards, 2014; Papale et al., 2016). The dopamine D3 receptor also plays an important role in drug seeking (Payer et al., 2014; Le Foll and Di Ciano, 2015; Sokoloff and Le Foll, 2017). They converge to the activation of mTORC1 (Figure 30-2), which has emerged as a key player in drug addiction. Virtually all drugs of abuse induce the activation of mTORC1 including cocaine, methamphetamine, morphine, THC (a component of marijuana), alcohol and nicotine (Neasta et al., 2014; Bergman et al., 2012). CRMP2 plays a critical role in the formation of enduring memory by orchestrating the elongation and branching of neurites (Chapter 27). Strikingly, CRMP2 expression is regulated by mTORC1 (คาสิโนไทย). The mTORC1-dependent translation of CRMP2 has been demonstrated to drive the excessive alcohol-drinking behavior (Liu et al., 2017).
Author: Frank Lee