Withdrawal duration differentially affects c-fos expression in the medial prefrontal cortex and discrete subregions of the nucleus accumbens in cocaine-sensitized rats

Todtenkopf, Mark S.; Mihalakopoulos, A; Stellar, James R.

doi:10.1016/s0306-4522(02)00272-5

Cited by 55 publications

(58 citation statements)

References 53 publications

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“…While fos induction is generally associated with cocaine administration, there have been reported decreases in mPFC fos with forced abstinence (Todtenkopf et al, 2002). The suppression of fos mRNA levels was similar in both the mPFC and NAc and occurred by 1 day of abstinence with no return toward control levels at 10 or 100 days of abstinence.…”

Section: Discussionmentioning

confidence: 86%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

Neuropsychopharmacol

110

126

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Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine selfadministration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens cfos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence.Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.

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Section: Discussionmentioning

confidence: 86%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

Neuropsychopharmacol

110

126

View full text Add to dashboard Cite

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“…It is possible that in OvxϩE females treated repeatedly with cocaine, basal metabolic activity was reduced after a 7 d abstinence period, and this could partially explain the greater magnitude change in BOLD signal intensity. Repeated cocaine administration induces longterm adaptations within mesocorticolimbic circuits, such as changes in c-fos expression (Hiroi et al, 1997;Canales and Graybiel, 2000;Todtenkopf et al, 2002) and dendritic spine density (Robinson and Kolb, 1999) that consequently affect synaptic transmission (Thomas et al, 2001;Beurrier and Malenka, 2002). These changes have also been reported in the female after estrogen administration (Segarra and McEwen, 1991;Woolley et al, 1997;Priest and Roberts, 2000).…”

Section: Discussionmentioning

confidence: 95%

Estrogen Influences Cocaine-Induced Blood Oxygen Level-Dependent Signal Changes in Female Rats

Febo¹,

Ferris²,

Segarra³

2005

J. Neurosci.

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We investigated the effect of estrogen on cocaine-induced brain activity using blood oxygen level-dependent (BOLD) magnetic resonance imaging. Ovariectomized (Ovx) rats without estrogen and Ovx rats with estrogen (OvxϩE) were given a single saline or cocaine injection (15 mg/kg, i.p.) for 5 d. After 7 d of withdrawal from injections, rats were challenged with cocaine during functional imaging. Acute cocaine administration produced positive BOLD activation in the prefrontal cortex, nucleus accumbens, striatum, ventral tegmental area, and hippocampus, among other brain regions. Positive BOLD signal changes were lower in OvxϩE than in Ovx rats. With repeated cocaine administration, OvxϩE rats showed enhanced BOLD signal changes in the nucleus accumbens, ventral tegmental area, and hippocampus compared with acutely treated animals. Our results indicate that estrogen influences the effects of acute and repeated cocaine administration on BOLD signal changes. The data suggest that in females with estrogen, cocaine-induced neuronal activity is enhanced after repeated cocaine administration. It is possible that the actions of estrogen within the aforementioned brain regions potentiate the behavioral response to cocaine observed in female rats.

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“…Activation of such neurons may control the particular motor qualities of the stereotypic motifs elicited on challenge, a suggestion also in accord with the observation (Tremblay et al, 2003) that focal stimulation of the external pallidum can induce persistent stereotypies. We did not analyze responses to drug challenges given after different time points after the post-treatment period of abstinence, but in rodents it is known that repeated cocaine treatments downregulate early-gene inducibility in the striatum, after which inducibility recovers during subsequent drug-free periods (Hope et al, 1992;Persico et al, 1993;Steiner and Gerfen, 1993;Ennulat et al, 1994;Moratalla et al, 1996;Todtenkopf et al, 2002). If these dynamics hold in primates, as our experiments suggest, the dorsal zone of strong matrix and striosome labeling could represent the last region in a gradient of downregulation producing striosomal predominance moving from ventral to dorsal or the first region to recover balanced striosome-matrix activation in a reverse gradient of upregulation.…”

Section: Discussionmentioning

confidence: 99%

Repetitive Behaviors in Monkeys Are Linked to Specific Striatal Activation Patterns

Saka¹,

Goodrich²,

Harlan³

et al. 2004

J. Neurosci.

130

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The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.

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Withdrawal duration differentially affects c-fos expression in the medial prefrontal cortex and discrete subregions of the nucleus accumbens in cocaine-sensitized rats

Cited by 55 publications

References 53 publications

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Estrogen Influences Cocaine-Induced Blood Oxygen Level-Dependent Signal Changes in Female Rats

Repetitive Behaviors in Monkeys Are Linked to Specific Striatal Activation Patterns

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