ReviewExtracellular Signal-Regulated Protein Kinases 1 and 2 Activation by Addictive Drugs: A Signal Toward Pathological Adaptation
Section snippets
ERK1/2 Signaling and Cocaine-Induced Behavioral Alterations
Activation of ERK1/2 induced by cocaine and other drugs of abuse is functionally relevant since pharmacologic blockade of ERK1/2 prevents subsequent behavioral adaptations, such as conditioned place preference (CPP) induced by cocaine (9), a form of Pavlovian learning used to study its rewarding properties (10), as well as the development of locomotor sensitization (11) (Table 1). In addition, ERK1/2 is involved in the retrieval of drug-associated memories since its activation by re-exposure to
Dopamine-Glutamate Receptor Interplay Controls ERK1/2 Activation by Cocaine
Medium-sized spiny neurons are segregated into two populations of about equal size depending on which subtype of DA receptor (dopamine D1 receptor [D1R] or dopamine D2 receptor [D2R]) they express. Expression of DA receptor subtype correlates with projection targets of MSNs, with significant differences between NAc and DS (16). The surge of DA induced by a single exposure to addictive drugs rapidly and transiently activates ERK1/2 in MSNs from the NAc and from the DS (8). Importantly,
Nuclear Functions of ERK1/2 in Response to Cocaine
The complex transcriptional response induced by cocaine in the striatum depends on the synergy between D1R and NMDAR-dependent signaling (40). This genetic program, which is essential for long-lasting behavioral changes induced by cocaine, is markedly altered upon blockade of the ERK1/2 pathway (9, 41) (Table 1). Acute cocaine triggers ERK1/2 translocation to the nucleus (42), where it acts as a key modulator of transcription. This cyto-nuclear shuttling of ERK1/2 involves its recruitment to a
Role of ERK1/2 in Cocaine-Induced Synaptic Plasticity
Drug-evoked synaptic plasticity, which refers to persistent alteration of synaptic transmission, is a major feature in the development of addiction (5, 55). The surge of dopamine evoked by drugs transiently activates intracellular cascades to induce long-lasting changes in neurons, such as alteration of synaptic transmission. Through the targeting of distinct substrates, ERK1/2 activity may control drug-evoked synaptic plasticity in MSNs.
By controlling the up and down states of MSNs, receptor
Role of ERK1/2 in Cocaine-Induced Structural Plasticity
Basic research into the relevance of dendritic spine changes in hippocampus and cerebral cortex indicates that the size and shape of individual spines correlates with forms of synaptic plasticity such as LTP and LTD (88). Unfortunately, causality between new dendritic spines in the striatum, the evolution of their size and shape during cocaine exposure, and synaptic transmission or behavior is poorly understood. A limitation in interpreting studies of structural plasticity of synapses is due to
Conclusions and Perspectives
Acute exposure to addictive drugs, including psychostimulants, nicotine, morphine, and tetrahydrocannabinol, activate ERK in common brain areas, including the striatum (8). Studies on activation of the ERK1/2 pathway in the striatum by psychostimulants have been instrumental in identifying mechanisms underlying genetic and epigenetic modifications, as well as synaptic plasticity and drug-evoked behavioral adaptations induced by noncontingent administration of cocaine. We identify the key role
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‘Ups, downs, and sideways’ of dopamine in drug addiction
2021, Trends in NeurosciencesHeteromerization of dopaminergic receptors in the brain: Pharmacological implications
2021, Pharmacological ResearchCitation Excerpt :The synergistic interaction of the D1 and NMDA receptors has a substantial role in drug abuse-mediated responses as well. The co-stimulation of D1 and NMDA receptors, therefore, relies on psychostimulant-derived activation of ERK1/2 that regulates long-term neuronal adaptations [133,134]. D1R-mediated phosphorylation of GluN2B-containing NMDA receptor on Tyr1472 via the tyrosine kinase was mandatory for the calcium-dependent activation of ERK1/2 that triggers cocaine-induced effects in drug abusers [134].
Dopamine and glutamate receptors control social stress-induced striatal ERK1/2 activation
2021, NeuropharmacologyFrom Signaling Molecules to Circuits and Behaviors: Cell-Type–Specific Adaptations to Psychostimulant Exposure in the Striatum
2020, Biological PsychiatryCitation Excerpt :Because DARPP-32 full knockout inhibits cocaine responses (89), cAMP/PKA/DARPP-32 signaling seems to prevail in D1R-SPNs over D2R-SPNs. Other possible pathways linking the D1R and cAMP/PKA pathways to ERK activation include the striatal-enriched protein phosphatase STEP, a phosphatase of ERK that is inhibited by PKA (85,89,92), and the neuritogenic cAMP sensor NCS-Rapgef2, for which ablation blocks cocaine-induced ERK activation in the NAc (93). Despite the importance of the crosstalk between striatal DA and glutamate signaling for drug-induced adaptations, targeting of cognate receptors in humans to alleviate addiction led to a lack of efficacy and/or side effects over time (86), likely due to perturbation of crucial physiological functions.
Glycogen Synthase Kinase 3β in the Ventral Hippocampus is Important for Cocaine Reward and Object Location Memory
2020, NeuroscienceCitation Excerpt :Hippocampal neuronal activity is associated with acquisition and expression of drug-induced conditioned place preference (Tan, 2008; Takano et al., 2010; Alvandi et al., 2017), and lesions or inactivation of the hippocampus, particularly the dentate gyrus sub-region, inhibits place preference acquisition and cue-induced drug-seeking behavior (Meyers et al., 2006; Hernández-Rabaza et al., 2008; Keleta and Martinez, 2012; Sikora et al., 2016). Glutamatergic ventral hippocampal projections to the nucleus accumbens shell contribute to drug-context memory formation and subsequent reinstatement of drug-seeking behavior (Taepavarapruk et al., 2014; Pascoli et al., 2014a,b, Sikora et al., 2016). Further, ventral hippocampal activity is necessary for drug primed-, cue- or context-induced reinstatement of drug-seeking behavior (Vorel et al., 2001; Taepavarapruk and Phillips, 2003; Taepavarapruk et al., 2014; Sun and Rebec, 2003; Atkins et al., 2008; Lasseter et al., 2010).
Modulation and functions of dopamine receptor heteromers in drugs of abuse-induced adaptations
2019, NeuropharmacologyCitation Excerpt :Based on these observations, it has been proposed that the imbalance between the activity of dMSN and iMSN evoked by drugs of abuse may drive towards compulsive drug intake and addiction (Lobo and Nestler, 2011; Volkow and Morales, 2015). We and others have started to identify the underlying cellular and molecular mechanisms (Girault et al., 2007; Cahill et al., 2014a; Pascoli et al., 2014a). We found that a single cocaine administration triggers a D1R-mediated facilitation of N-methyl-d-aspartate glutamate receptors (NMDAR) that activates in dMSN the extracellular signal-regulated kinase1/2 (ERK1/2), which controls epigenetic and genic responses that are mandatory for the development of long-term behavioral alterations (Pascoli et al., 2011a, 2014a,b).