Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization

doi:10.1016/S0006-8993(96)01316-9

Brain Research

Volume 749, Issue 1, 21 February 1997, Pages 120-126

https://doi.org/10.1016/S0006-8993(96)01316-9 Get rights and content

Abstract

Expression in striatum of c-Fos, a 35 kDa Fos-related antigen (FRA) and the phosphorylated form of cyclic AMP response element binding protein (phosphoCREB) was assessed using Western blots in rats that developed behavioral sensitization following repeated amphetamine administration. Treatment with d-amphetamine (5 mg/kg) for 5 consecutive days produced behavioral sensitization. Similar to previous observations using chronic cocaine administration, amphetamine sensitized animals had decreased c-Fos and increased FRA proteins in striatum. Supershift analysis with antisera to c-Fos and FRA proteins demonstrated that c-Fos and the 35 kDa FRA are components of the striatal AP-1 binding complex from sensitized rats. Thus, amphetamine sensitization is accompanied by alterations in the composition of the AP-1 DNA binding complex. An increased amount of phosphoCREB protein was also present in the striatum of amphetamine sensitized rats. These results suggest that alterations in Fos, FRA and CREB transcription factors are common neuronal responses to chronic psychostimulant administration and may contribute to regulation of genes important to the neuroplastic changes underlying psychostimulant sensitization.

References (45)

A. Bonni et al.
Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals
Mol. Cell. Neurosci.
(1995)
D.M. Bronstein et al.
Role of a 35 kDa fos-related antigen (FRA) in the long-term induction of striatal dynorphin expression in the 6-hydroxydopamine lesioned rat
Mol. Brain Res.
(1994)
R.L. Cole et al.
Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum
Neuron
(1995)
J.B. Daunais et al.
Cocaine binges differentially alter striatal preprodynorphin and zif/268 mRNAs
Mol. Brain Res.
(1995)
D.J. Ennulat et al.
Persistent reduction of immediate early gene mRNA in rat forebrain following single or multiple doses of cocaine
Mol. Brain Res.
(1994)
G.A. Gonzalez et al.
Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133
Cell
(1989)
T. Hamamura et al.
Coadministration of a selective D1 or D2 dopamine agonist with methamphetamine prevents methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis
Brain Res.
(1991)
B. Hope et al.
Induction of a long-lasting AP-1 complex composed of altered fos-like proteins in brain by chronic cocaine and other chronic treatments
Neuron
(1994)
B.A. Horger et al.
Preexposure sensitizes rats to the rewarding effects of cocaine
Pharm. Biochem. Behav.
(1990)
Y.L. Hurd et al.
Amphetamine regulation of mesolimbic dopamine-cholecystokinin neurotransmission
Brain Res.
(1992)

Y.L. Hurd et al.

Cocaine reinforcement and extracellular dopamine overflow: an in vivo microdialysis study

Brain Res.

(1989)

M. Jaber et al.

Acute and chronic amphetamine treatments differentially regulate neuropeptide messenger RNA levels and Fos immunoreactivity in rat striatal neurons

Neuroscience

(1995)

R. Karler et al.

DNQX blockade of amphetamine behavioral sensitization

Brain Res.

(1991)

G.F. Koob

Drugs of abuse: anatomy, pharmacology and function of reward pathways

Trends Pharmacol. Sci.

(1992)

M.R. Montminy et al.

Regulation of cAMP-inducible genes by CREB

Trends Neurosci.

(1990)

E.R. Nestler et al.

Drug addiction: a model for the molecular basis of neural plasticity

Neuron

(1993)

T. Ohmori et al.

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

Pharmacol. Biochem. Behav.

(1994)

A.M. Persico et al.

Brain transcription factor expression: effects of acute and chronic amphetamine and injection stress

Mol. Brain Res.

(1993)

P.V. Piazza et al.

Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration

Brain Res.

(1990)

T.E. Robinson et al.

Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis

Brain Res. Rev.

(1986)

T.E. Robinson et al.

The neural basis of drug craving: an incentive-sensitization theory of addiction

Brain Res. Rev.

(1993)

T.E. Robinson et al.

Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)-amphetamine: a microdialysis study in freely moving rats

Brain Res.

(1988)

Cited by (116)

Neurobiological mechanisms underlying psychostimulant use
2023, Current Opinion in Neurobiology
Rates of individuals struggling with psychostimulant use disorder (PSUD), defined as chronic use of psychostimulants despite negative consequences, are growing rapidly over the last few decades. However, there are no current pharmacotherapeutics to aid individuals in maintaining drug abstinence. Identifying the underlying neurobiological mechanisms that promote persistent craving and taking of psychostimulants is critical to creating novel pharmacological treatments for PSUD. Psychostimulant use dysregulates processes within the brain that are responsible for decision-making, reward, and memory formation to drive future drug-seeking. Here, we describe novel findings and theories on how psychostimulants impact mechanisms related to transcription, mitochondrial function, and synaptic plasticity within the reward system to drive drug-seeking. We also highlight work examining how psychostimulants impact neural networks through rewiring circuitry to drive addiction-related behaviors. Overall, this review aims to feature the latest progress in understanding the biological basis of PSUD and promising mechanisms for PSUD pharmacotherapeutics.
Time-dependent changes in striatal monoamine levels and gene expression following single and repeated amphetamine administration in rats
2021, European Journal of Pharmacology
Citation Excerpt :
Furthermore, amphetamine downregulated the expression of CREB in the nucleus accumbens at 90 min. The CREB downregulation may appear discordant with the evidence that single or repeated exposures to psychostimulants induce CREB phosphorylation in the nucleus accumbens and the dorsal striatum without affecting total CREB levels (Konradi et al., 1994; Turgeon et al., 1997; Shi and McGinty, 2007). In fact, CREB activation has been posited to be necessary for acute cocaine administration to provoke expression changes in the striatum (Lemberger et al., 2008).
As drug addiction may result from pathological usurpations of learning and memory's neural mechanisms, we focused on the amphetamine-induced time-dependent neurochemical changes associated with neural plasticity. We used juvenile rats as the risk for drug abuse is higher during adolescence. Experiment 1 served to define the appropriate amphetamine dose and the neurochemical effects of a single administration. In experiment 2, rats received seven amphetamine or saline injections in the open-field test throughout a twelve-day period. We measured the mRNA levels of the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and monoamines and amino-acids contents in the nucleus accumbens and the dorsal striatum 45, 90, and 180 min after the last injection. We found that amphetamine changed gene expression only at certain time points and in a dose and region-dependent manner. Repeated but not single administrations upregulated accumbal and striatal BDNF (180 min) and striatal pri-miR-132 (90 min) expression, while downregulated accumbal CREB levels (90 min). As only some drug users develop addiction, we compared brain parameters between low and high amphetamine responders. Prone subjects characterized by having reduced striatal 5-HT metabolism, higher accumbal BDNF and TrkB expression, and lower levels of CREB in the dorsal striatum and p250GAP in both regions. Thus, individual differences in drug-induced changes in neurotransmission and gene expression in nigrostriatal and mesolimbic dopaminergic pathways may underlie the plasticity adaptations associated with behavioral sensitization to amphetamine.
Modulatory role of the intra-accumbal CB1 receptor in protein level of the c-fos and pCREB/CREB ratio in the nucleus accumbens and ventral tegmental area in extinction and morphine seeking in the rats
2018, Brain Research Bulletin
Brain reward and motivation circuit begin from the ventral tegmental area (VTA) that its dopaminergic terminals project to various regions of the brain including the nucleus accumbens (NAc). This reward circuit is influenced by drugs of abuse such as morphine and cannabinoid. The present study tried to investigate the role of the intra-accumbal CB1 receptor in the c-fos level and pCREB/CREB ratio in the NAc and the VTA during reinstatement phase of morphine-induced conditioned place preference (CPP) by western blotting. The present data reveals that intra-accumbal administration of CB1 agonist, WIN55,212-2 (0.5, 1 and 2 mM/0.5 μl DMSO) before/during extinction period of morphine-induced CPP, significantly decreased the NAc and the VTA c-fos protein level in the reinstatement phase; whereas the pre-reinstatement administration of the CB1 agonist, increased the c-fos protein level. Intra-accumbal administration of the CB1 agonist during the extinction period of morphine-induced CPP reduced the pCREB/CREB ratio in the NAc. Also, the present data show that intra-accumbal administration of CB1 antagonist, AM251 (15, 45 and 90 μM/0.5 μl DMSO) during/after extinction period of morphine-induced CPP affects the NAc and the VTA c-fos protein level in the reinstatement phase. Also, intra-NAc microinjection of AM251 during the extinction period reduced pCREB/CREB ratio in these regions. In conclusion, the results presented here provide compelling evidence of the modulation and involvement of the c-fos and the CREB molecules in the cannabinoid-opioid interaction of the brain reward system in the CPP paradigm.
The Effects of Amphetamine and Methamphetamine on Brain Activity-Related Immediate Early Gene Expression
2016, Neuropathology of Drug Addictions and Substance Misuse
Widespread abuse of amphetamine and methamphetamine remains a significant global health problem. Intervention efforts to reduce its use have focused on developing treatments that reverse or mitigate the neurological effects of these drugs that support addictive behaviors. Exposing rodents to amphetamine or methamphetamine and analyzing their brain tissue for genetic responses has proven to be a valuable tool for identifying the most relevant brain circuits for targeted treatment of drug abuse. Immediate early genes (IEGs), including transcription factors that coordinate stimulus-driven effects across a range of genes and signaling pathways, have been widely studied in efforts to map the neural responses to psychoactive drugs. This chapter provides an overview of studies that have examined the effects of amphetamine and methamphetamine treatment on expression patterns of the IEGs c-fos, arc, zif/268, and bdnf to characterize the neural effects of acute and chronic drug exposure.
The Effects of Amphetamine and Methamphetamine on Brain Activity-Related Immediate Early Gene Expression
2016, Neuropathology of Drug Addictions and Substance Misuse Volume 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects
Widespread abuse of amphetamine and methamphetamine remains a significant global health problem. Intervention efforts to reduce its use have focused on developing treatments that reverse or mitigate the neurological effects of these drugs that support addictive behaviors. Exposing rodents to amphetamine or methamphetamine and analyzing their brain tissue for genetic responses has proven to be a valuable tool for identifying the most relevant brain circuits for targeted treatment of drug abuse. Immediate early genes (IEGs), including transcription factors that coordinate stimulus-driven effects across a range of genes and signaling pathways, have been widely studied in efforts to map the neural responses to psychoactive drugs. This chapter provides an overview of studies that have examined the effects of amphetamine and methamphetamine treatment on expression patterns of the IEGs c-fos, arc, zif/268, and bdnf to characterize the neural effects of acute and chronic drug exposure.
Susceptibility to ethanol sensitization is differentially associated with changes in pCREB, trkB and BDNF mRNA expression in the mouse brain
2013, Behavioural Brain Research
Repeated exposure to ethanol in mice induces behavioural sensitization, a progressive increase in locomotor activity that is common to drugs of abuse. Not all mice however show sensitization to ethanol. The goal of the present study was to examine whether variability in the sensitization response to ethanol (EtOH) is differentially associated with regional brain changes in specific molecular markers associated with neuroplasticity, namely BDNF and its receptor trkB, and levels of phosphorylated cyclic AMP-regulated element-binding protein (pCREB), 14 days after withdrawal from chronic, intermittent EtOH exposure.
Male DBA/2NCrl mice received 7 biweekly EtOH (2.2 g/kg, i.p.) or saline (SAL) injections and were classified as Sensitized or Non-sensitized on the basis of final locomotor activity (LMA) scores. Brains were removed two weeks later for immunohistochemical and in situ hybridization analyses.
Compared to SAL-treated and Non-sensitized mice, Sensitized animals showed a higher number of pCREB-immunoreactive cells in the nucleus accumbens shell (+68% and +50%, respectively) and in the bed nucleus of the stria terminalis (+61% and 46%, respectively), whereas SAL and Non-sensitized groups did not differ from each other. A different pattern was seen when BDNF and trkB mRNA levels were analyzed in the same groups. Non-sensitized mice displayed lower BDNF mRNA in several brain areas and significantly lower trkB levels throughout the brain when compared to either the Sensitized or to SAL groups, which did not differ from each other.
These results indicate that sensitization to EtOH is differentially associated with increased pCREB levels in specific brain areas. The observed decrease in BDNF and trkB mRNA in the Non-sensitized group suggests the possibility that EtOH may have neurotoxic effects in a subpopulation of mice, which might in turn prevent the development of behavioural sensitization. The lack of a difference in BDNF and trkB mRNA expression between Sensitized and SAL mice suggests that EtOH sensitization may be mediated by mechanisms different from those mediating sensitization to other psychostimulants.

View all citing articles on Scopus

¹: Present address: Department of Psychology, Amherst College, Amherst, MA 01002, USA.

²: Present address: Department of Psychology, Brown University, Box 1853, Providence, RI 02912, USA.

View full text

Research reportEnhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization

Abstract

Mol. Cell. Neurosci.

Mol. Brain Res.

Neuron

Mol. Brain Res.

Mol. Brain Res.

Cell

Brain Res.

Neuron

Pharm. Biochem. Behav.

Brain Res.

Brain Res.

Neuroscience

Brain Res.

Trends Pharmacol. Sci.

Trends Neurosci.

Neuron

Pharmacol. Biochem. Behav.

Mol. Brain Res.

Brain Res.

Brain Res. Rev.

Brain Res. Rev.

Brain Res.

Research report
Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization