Delayed, context- and dopamine D1 receptor-dependent activation of ERK in morphine-sensitized mice
Introduction
Repeated intermittent administration of many drugs of abuse, including morphine, results in a progressive and persistent enhancement of locomotor activity called psychomotor sensitization (Robinson and Berridge, 1993, Vezina, 2004). Behavioral sensitization to opiates is strongly modulated by contextual cues (Badiani and Robinson, 2004, Paolone et al., 2007). Based on these observations, it was proposed that the environment and the drug synergistically contribute to the expression of this response (Anagnostaras et al., 2002, Badiani and Robinson, 2004). Interestingly, behavioral sensitization and drug craving appear to increase over time in the absence of drug (Lu et al., 2006). This incubation period indicates the existence of delayed neurochemical events in the brain that need to be identified in order to understand the long-lasting effects of drugs of abuse.
Expression of behavioral sensitization is critically dependent on the dopaminergic projections from the ventral tegmental area to the nucleus accumbens (NAc) (Vezina, 2004), a brain region particularly important for motivational control of motor activity (Mogenson et al., 1980, Voorn et al., 2004). Pharmacological blockade of dopamine D1 receptors (D1Rs) impairs behavioral sensitization in response to several drugs of abuse including morphine (Jeziorski and White, 1995). Although numerous studies have addressed the mechanisms involved in the expression of behavioral sensitization to morphine (Vanderschuren and Kalivas, 2000), the molecular substrates reflecting an association between this drug and the environment are not understood.
The extracellular signal-regulated kinases (ERK) play multiple roles in the activity-dependent regulation of neuronal function, including long-term synaptic plasticity, and ERK activation is crucial in various models of learning and memory (Thomas and Huganir, 2004). Recent evidence suggests that the ERK pathway is an important mediator of striatal plasticity and could therefore underlie some of the long-lasting changes induced by drugs of abuse (Girault et al., 2007, Nestler, 2001). Thus, ERK phosphorylation is increased in the NAc and other reward-related brain regions by various drugs of abuse, including psychostimulants and morphine (Valjent et al., 2004). Importantly, ERK is involved in the induction of long-lasting behavioral responses to these drugs, including psychomotor sensitization (Ferguson et al., 2006, Valjent et al., 2005), conditioned place preference (Miller and Marshall, 2005, Valjent et al., 2000) and cue-induced drug seeking (Lu et al., 2005, Shiflett et al., 2008). Moreover, re-exposure to context and/or drug in the presence of an inhibitor of the ERK pathway, can erase previously acquired cocaine or morphine conditioned place preference (Miller and Marshall, 2005, Valjent et al., 2006).
Previous work has shown that activation of ERK in the amygdala mediates cue-induced cocaine seeking after a prolonged period of withdrawal (Lu et al., 2005). In addition, ERK phosphorylation in the NAc has been implicated in cue-induced reward seeking (Shiflett et al., 2008). In the present study, we have investigated the time dependence and the role of contextual stimuli on ERK signaling in the NAc of morphine-sensitized mice. We show that the sensitized response to morphine is markedly increased after a period of withdrawal, suggesting that this phenomenon incubates over time. In parallel, exposure to the context previously paired to morphine increases ERK phosphorylation in the shell but not the core of the NAc. This effect occurs only in withdrawn mice and is exerted specifically at the level of D1R-expressing medium spiny neurons.
Section snippets
Animals
Male C57BL/6JBomTac mice (20–30 g) were from Taconic (Tornbjerg, Denmark). Bacterial artificial chromosomes (BAC) transgenic mice expressing EGFP under the control of the promoter for the D1R (Drd1a-EGFP) or the dopamine D2 receptor (Drd2-EGFP), were generated by the GENSAT (Gene Expression Nervous System Atlas) program at the Rockefeller University (Gong et al., 2003). Mice were housed in groups of 4–6 under standardized conditions, with lights on at 06:00 (12 h light/dark cycle) and an ambient
Increased morphine locomotor sensitization during withdrawal
As shown in Fig. 1b, repeated exposure to morphine (9 mg/kg, s.c. × 5 days) resulted in the development of a robust locomotor sensitization. Thus, a dose of morphine (2 mg/kg) unable to change motor activity in drug-naive mice [treatment effect: F(1, 14) = 0.291, n.s.] (Fig. 1b, gray bars) was capable, after sensitization, to elicit a large increase in locomotion [treatment effect: F(1, 16) = 23.960, p < 0.001] (Fig. 1b, filled bars). After 4 weeks of withdrawal there was a strong enhancement of the
Discussion
In this study we show that morphine psychomotor sensitization is enhanced by a prolonged drug-free period. This phenomenon has been previously described for other addictive substances, such as amphetamine (Kolta et al., 1985, Paulson and Robinson, 1991, Paulson and Robinson, 1995, Vanderschuren et al., 1999). Another critical factor involved in the expression of behavioral sensitization is the association with the environment paired to drug administration. The comparison of the responses
Acknowledgements
We thank Dr. Paul Greengard and Dr. Nathaniel Heintz for kindly providing the transgenic mice used in this study. This work was supported by Swedish Research Council Grants 13482, 14862 and 20715. EV was supported by Institut National de la Santé et de la Recherche Médicale (INSERM). JAG and DH were supported by a grant from Agence Nationale de la Recherche (ANR-05-NEUR-020).
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Context evoked morphine conditioned effects can be equivalent to morphine induced drug effects in terms of behavioral response and ERK activation in reward associated subcortical brain structures
2022, Pharmacology Biochemistry and BehaviorCitation Excerpt :In the present study we measured the effects of morphine on extracellular signal regulated protein kinase activity (ERK) to assess the effects of morphine on activation of subcortical brain areas implicated in dopaminergic related reward effects, namely the VTA and nucleus accumbens (NAc). The rationale for measuring ERK in these brain structures was based on findings that have reported increases in ERK activity in dopaminergic projection areas (Adams and Sweatt, 2002; Girault et al., 2007; Lu et al., 2006; Radwanska et al., 2005) including the NAc (Borgkvist et al., 2008; Valjent et al., 2004; Kim and Kim, 2008; Fricks-Gleason and Marshall, 2011) following treatment with psychostimulant drugs such as cocaine. Additionally, in previous studies (Sanguedo et al., 2014, 2016, 2017, 2019), we showed that apomorphine induced context specific behavioral stimulation was associated with a strong ERK signal in brain dopamine systems.
Repeated ventral midbrain neurotensin injections sensitize to amphetamine-induced locomotion and ERK activation: A role for NMDA receptors
2017, NeuropharmacologyCitation Excerpt :It is interesting to note that the other region in which we found a sensitize pERK1/2 level is the infralimbic cortex, a cortical area that sends glutamatergic efferents to the shell of the nucleus accumbens (Voorn et al., 2004). Drug associated context as been reported to produce pERK1/2 enhancement by itself (Borgkvist et al., 2008). In our experiments, the failure of systemic VEH to increase the level pERK1/2 in VM NT microinjected animals ruled out this possibility.
Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum
2013, NeuropharmacologyCitation Excerpt :Our study by adding complexity to the spectrum of MeCP2 functions suggests that this transcriptional regulator may be involved in the neuronal modifications, at both the somatodendritic and nuclear level, induced by opioid consumption and withdrawal. Moreover, by showing higher levels of epigenetic and transcriptional changes in the NAc shell compared to the NAc core (see Table 1), our findings underscores the centrality of the NAc shell in morphine withdrawal and strengthen the concept that differences exists between these areas in the neuronal modifications occurring in response to drugs of abuse (Borgkvist et al., 2008; Frenois et al., 2002; Hemby, 2004; Ito et al., 2004). While in this study we did not explore whether spontaneous morphine withdrawal may produce similar epigenetic modifications this will be an interesting issue for a future investigation.
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2009, PeptidesCitation Excerpt :Overexpression of plasminogen activators in the NAC enhanced cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization [44]. Delayed, context- and dopamine D1 receptor-dependent activation was observed for ERK in morphine-sensitized mice [84]. Chronic expression of the HIV-induced protein, transactivator of transcription and morphine decreased circadian activity rhythms as measured by wheel running independently [249].