Acute amphetamine or methamphetamine alters opioid peptide mRNA expression in rat striatum

doi:10.1016/0169-328X(94)90268-2

Molecular Brain Research

Volume 21, Issues 3–4, February 1994, Pages 359-362

https://doi.org/10.1016/0169-328X(94)90268-2 Get rights and content

Abstract

The effects of a single dose of amphetamine or methamphetamine on opioid peptide gene expression in the dorsal and ventral striatum of rats were investigated by quantitative in situ hybridization 3, 6, or 18 h after injection. Although amphetamine-treated rats exhibited significantly different behaviors than those treated with methamphetamine, both drugs caused a patchy increase in preprodynorphin, but not preproenkephalin, mRNA in the caudate at all 3 time points. No changes were detected in the nucleus accumbens. These data indicate that prolonged elevation of preprodynorphin expression may alter the responsiveness of striatonigral neurons to subsequent amphetamine exposure.

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In situ hybridization studies revealed a prominent increase of the proDYN mRNA in ventral and medial aspects of the rostral-middle striatum three hours after 10 mg/kg MDMA administration [14]. In 1994, it has been reported that a single dose of amphetamine or methamphetamine increased the proDYN gene expression in the caudate but no changes were reported in the NAc [68]. This latter result is not consistent with our and previous data showing that in the neostriatum, NAc and substantia nigra the dynorphinergic system is already augmented after a single MDMA injection [13,15,66].
The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ)-NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8 mg/kg) or repeated (8 mg/kg twice daily for seven days) MDMA exposure.
MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure.
Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up-regulation.
Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse.
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Citation Excerpt :
Many nonopioid drugs of abuse, including ATS, are also known to interact with the endogenous opioid system (for a review, see Trigo et al., 2010), and this interaction may mediate some of the rewarding properties associated with acute ATS use (Boutrel, 2008). For example, acute amphetamine administration has been linked with increased β-endorphin levels in the NAcc (Olive et al., 2001), increased striatonigral dynorphin-like immunoreactivity (Bustamante et al., 2002; Hanson et al., 1988), and changes in the endogenous opioid mRNA expression in the striatum (Hurd and Herkenham, 1992; Smith and McGinty, 1994; Wang and McGinty, 1995). Further, preclinical data suggest that the endogenous opioid system is involved in the induction and expression of methamphetamine-induced behavioral (locomotor) sensitization (Chiu et al., 2006), analogous to compulsive drug-seeking behavior in humans (i.e., drug craving; Itzhak and Ali, 2002), through its modulatory actions of the mesolimbic dopamine system (Ford et al., 2006).
Abuse of amphetamine-type stimulants (ATS) poses a significant public health concern with known neurotoxic and neurocognitive effects to the user. In this chapter, we seek to integrate the latest research on ATS, particularly methamphetamine, by covering areas of pharmacology, neurocognitive effects, and the treatment of ATS use disorders with the goal of advancing the clinical neuroscience of ATS and highlighting avenues for future research.
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Psychostimulants alter the expression of hundreds of genes in the basal ganglia. This review discusses mechanisms of psychostimulant-induced gene regulation in the striatum (receptors involved, cell types, and functional domains affected), with focus on examples of effector genes such as neuropeptides, and neuroplasticity-related molecules such as transcription factors and others. Studies show that psychostimulants alter gene regulation predominantly in neurons of the direct striatal output pathway, with lesser effects in the indirect pathway. These changes are caused by excessive stimulation of D1 dopamine receptors (in interaction with glutamate inputs) and are modulated by D2, D3, and serotonin receptors. Some gene regulation occurs in limbic domains, which mediate reward processes. However, these drug-induced molecular changes are most pronounced in associative and sensorimotor domains, which mediate switching functions (motor acts, thoughts), procedural learning, and other functions. Limbic effects likely underlie motivational aspects of drug taking. Sensorimotor changes may be responsible for aberrant habit formation and compulsive behavior that signify drug addiction.
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Despite initial reports of a decline in use in the early 2000s, methamphetamine remains a significant public health concern with known neurotoxic and neurocognitive effects to the user. The goal of this review is to update the literature on methamphetamine use and addiction since its assent to peak popularity in 1990s.
We first review recent epidemiological reports with a focus on methamphetamine accessibility, changes in use and disorder prevalence rates over time, and accurate estimates of the associated burden of care to the individual and society. Second, we review methamphetamine pharmacology literature with emphasis on the structural and functional neurotoxic effects associated with repeated use of the drug. Third, we briefly outline the findings on methamphetamine-related neurocognitive deficits as assessed via behavioral and neuroimaging paradigms. Lastly, we review the clinical presentation of methamphetamine addiction and the evidence supporting the available psychosocial and pharmacological treatments within the context of an addiction biology framework.
Taken together, this review provides a broad-based update of the available literature covering methamphetamine research over the past two decades and concludes with recommendations for future research.
Addiction-related gene regulation: Risks of exposure to cognitive enhancers vs. other psychostimulants
2013, Progress in Neurobiology
Citation Excerpt :
Notably, increased dynorphin expression has also been found in human cocaine addicts (Hurd and Herkenham, 1993; Frankel et al., 2008). After a single psychostimulant administration, elevated dynorphin mRNA levels persist in the rat for at least 18–30 h (Smith and McGinty, 1994; Wang and McGinty, 1995a,b). Thus, this mRNA accumulates with daily drug treatments.
The psychostimulants methylphenidate (Ritalin, Concerta), amphetamine (Adderall), and modafinil (Provigil) are widely used in the treatment of medical conditions such as attention-deficit hyperactivity disorder and narcolepsy and, increasingly, as “cognitive enhancers” by healthy people. The long-term neuronal effects of these drugs, however, are poorly understood. A substantial amount of research over the past two decades has investigated the effects of psychostimulants such as cocaine and amphetamines on gene regulation in the brain because these molecular changes are considered critical for psychostimulant addiction. This work has determined in some detail the neurochemical and cellular mechanisms that mediate psychostimulant-induced gene regulation and has also identified the neuronal systems altered by these drugs. Among the most affected brain systems are corticostriatal circuits, which are part of cortico-basal ganglia-cortical loops that mediate motivated behavior. The neurotransmitters critical for such gene regulation are dopamine in interaction with glutamate, while other neurotransmitters (e.g., serotonin) play modulatory roles. This review presents (1) an overview of the main findings on cocaine- and amphetamine-induced gene regulation in corticostriatal circuits in an effort to provide a cellular framework for (2) an assessment of the molecular changes produced by methylphenidate, medical amphetamine (Adderall), and modafinil. The findings lead to the conclusion that protracted exposure to these cognitive enhancers can induce gene regulation effects in corticostriatal circuits that are qualitatively similar to those of cocaine and other amphetamines. These neuronal changes may contribute to the addiction liability of the psychostimulant cognitive enhancers.
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^☆: This research was supported by DA03982.

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Short communicationAcute amphetamine or methamphetamine alters opioid peptide mRNA expression in rat striatum☆

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Mol. Brain Res.

Mol. Brain Res.

Brain Res.

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Acute amphetamine or methamphetamine alters opioid peptide mRNA expression in rat striatum☆