Cocaine addicted to cytoskeletal change and a fibrosis high

Abstract

Cocaine is one of the most widely abused illicit drugs due to its euphoric and addictive properties. Cocaine‐mediated cognitive impairments are the result of dynamic cytoskeletal rearrangements involved in mediating structural and behavioural plasticity. Cytoskeletal changes initiated following cocaine abuse are regulated by the Rho family of GTPases with significant downstream activity in key actin binding proteins. Moreover, signalling via the endoplasmic reticulum chaperone protein, sigma‐1 receptor has highlighted the possibility of cocaine regulated pathology in other organ systems. However, the question of whether upstream stimulation of such a high affinity binding receptor is directly involved in cocaine‐mediated cytoskeletal changes at present remains unknown. In this review, we describe the functional role of key cytoskeletal regulators in response to cocaine‐induced signalling cues. In addition, we ascertain the extent of whether global cytoskeletal modulators involved in cocaine‐induced neurological stimulation can be used as a platform for future studies into elucidating its fibrotic potential within the hepatic microenvironment. A focus on aspects still poorly understood relating to the nonneuronal pathological impact of cocaine is discussed in the sphere of hepatic dysregulation. Lastly, we suggest that cocaine may mediate its pathological capacity via the sigma1 receptor in regulating hepatoxicity, hepatic stellate cells activity, cytoskeletal dynamics, and the transcriptional regulation of key hepato‐fibrogenic modulators.

Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation

“…It is well known that acute stress, chronic stress or cocaine exposure increase the locomotor response to an acute cocaine injection ( Esparza et al, 2012 ; Garcia-Keller et al, 2013 , 2016 ; Pacchioni et al, 2007 ), all leading to structural and functional synaptic alterations in NA MSNs ( Anderson and Self, 2017 ; Garcia-Keller et al, 2016 , 2019a , 2020 ; Khibnik et al, 2016 ; Qiao et al, 2016 ; Verma et al, 2019 ). However, several questions remain unanswered regarding how stress induces changes in the neuronal architecture and plasticity during cross-sensitization between stress and cocaine.…”

“…Moreover, changes in structural plasticity suggest a temporal sequence of cofilin activation and inactivation during LTP, relevant for initial spine enlargement and synaptic AMPAR accumulation (both dependent on cofilin activation), followed by consolidation of structural changes (dependent on cofilin inactivation) ( Gu et al, 2010 ; Noguchi et al, 2016 ; Stefen et al, 2016 ). Previous literature described that repeated cocaine changes in AMPAR surface expression are paralleled by increases in AMPA currents, AMPA/NMDA ratio and the density of dendritic spines in accumbens MSNs directed by cofilin-induced changes in actin dynamics ( Dietz et al, 2012 ; Kourrich et al, 2007 ; Robinson and Kolb, 2004 ; Shen et al, 2009 ; Verma et al, 2019 ). Here, we found that the reduced behavioral response to cocaine in pre-stress rats exposed to shcofilin with a smaller spine d h also showed reduced levels of AMPAR surface expression ( Fig.…”

“…Behavioral alterations associated with sensitization are mediated by enduring structural modifications in NA neurons. Indeed, long-term exposure to cocaine increases dendritic complexity and spine density and induces changes in the spine morphology of NA medium spiny neurons (MSNs) ( Russo et al, 2010 ) that are responsible, in part, for the enhanced cocaine reward and also promote behavioral responses ( Dietz et al, 2012 ; Shen et al, 2009 ; Toda et al, 2006 ; Verma et al, 2019 ). Modifications in dendritic spines depend on actin cytoskeleton remodeling ( Dietz et al, 2012 ; Matus, 2005 ; Russo et al, 2010 ; Shen et al, 2009 ; Toda et al, 2006 ; Wang et al, 2005 ).…”

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

“…[3][4][5]. For example, the structural changes in neurons induced by alcohol contribute to the long-lasting nature of alcohol use disorder (AUD) [6][7][8]. Repeated exposure to alcohol induces structural plasticity [9,10] in brain reward circuits and changes in the density and morphology of dendritic spines, which have significant consequences including cognitive deficits [11].…”

“…Importantly, hyperphosphorylation of tau, a microtubule-associated protein, leads to the development of major neurodegenerative diseases including AD and other AD-related disorders (ADRDs) [16,[18][19][20]. However, microtubule structure and functions are sufficiently complex that the sequence of events from microtubule disruption to the expression of disease largely remains unknown [1,7,21,22].…”