CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects (original) (raw)
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Frontiers in behavioral neuroscience, 2014
It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. Th behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. e Keywords: CREB, dominant negative CREB, dopamine receptor D1, activity-dependent gene expression, cocaine-related behavior, addiction Frontiers in Behavioral Neuroscience www.frontiersin.org
Neuroreport, 2000
Central effects of psychostimulants such as cocaine are predominantly mediated by dopamine receptors. We have used mice with a targeted deletion of the D3 dopamine receptor subtype to investigate the role of this receptor in the regulation of gene expression in striatal neurons and behavior by acute and repeated treatment with cocaine (25 mg/kg). In mice lacking D3 receptors, acute administration of cocaine has more pronounced stimulatory effects on c-fos and dynorphin expression in the dorsal and ventral striatum. The behavioral response to cocaine is also increased in these mice. These ®ndings indicate that the D3 receptor plays an inhibitory role in the action of cocaine on behavior and gene regulation in the striatum. NeuroReport 11:2395±2399 & 2000 Lippincott Williams & Wilkins.
Cocaine effects on gene regulation in the striatum and behavior
NeuroReport, 2000
Central effects of psychostimulants such as cocaine are predominantly mediated by dopamine receptors. We have used mice with a targeted deletion of the D3 dopamine receptor subtype to investigate the role of this receptor in the regulation of gene expression in striatal neurons and behavior by acute and repeated treatment with cocaine (25 mg/kg). In mice lacking D3 receptors, acute administration of cocaine has more pronounced stimulatory effects on c-fos and dynorphin expression in the dorsal and ventral striatum. The behavioral response to cocaine is also increased in these mice. These ®ndings indicate that the D3 receptor plays an inhibitory role in the action of cocaine on behavior and gene regulation in the striatum. NeuroReport 11:2395±2399 & 2000 Lippincott Williams & Wilkins.
European Journal of Neuroscience, 2003
Psychostimulants alter gene expression in projection neurons of the striatum, and such neuroplasticity is implicated in drug addiction and dependence. Evidence indicates that excitatory inputs from the cortex and thalamus are critical for these molecular changes. In the present study, we determined the topography of cocaine-induced changes in gene expression in the rat striatum and investigated whether these molecular alterations are associated with particular cortical inputs. Acute induction of c-fos (by 25 mg/kg of cocaine), and the c-fos response and dynorphin expression after repeated cocaine treatment (25 mg/kg, 4 days) were assessed as examples for short-term and longer-term molecular changes, respectively. In addition, we examined whether these molecular effects were in¯uenced by the behaviour performed during cocaine action (running-wheel training vs. open ®eld). Our results demonstrate that the overall topography of cocaine-induced gene regulation in the striatum is remarkably stable. Both acute and longer-term molecular changes were maximal in caudal dorsal striatal sectors that receive convergent inputs from the medial agranular and the sensorimotor cortex. In contrast, relatively minor or no effects were found in rostral and ventral striatal sectors. However, running-wheel training under the in¯uence of cocaine enhanced the c-fos response to a subsequent cocaine challenge selectively in parts of the caudal sensorimotor striatum. These results indicate that cocaine produces molecular adaptations preferentially in cortico-basal ganglia circuits through the sensorimotor striatum, and that some of these neuronal changes are in¯uenced by the behaviour performed during drug exposure.
PLoS ONE, 2010
Background: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Repeated exposure to psychomotor stimulants produces a striking behavioral syndrome involving repetitive, stereotypic behaviors that occur if an additional exposure to the stimulant is experienced. The same stimulant exposure produces specific alterations in gene expression patterns in the striatum. To identify the dopamine receptor subtypes required for the parallel expression of these acquired neural and behavioral responses, we treated rats with different D1-class and D2-class dopamine receptor agonists and compared the responses of drug-naive rats with those of rats given previous intermittent treatment with cocaine. In rats exposed to repeated cocaine treatment, the effects of a subsequent challenge treatment with either a D1-class agonist (SKF 81297) or a D2-class agonist (quinpirole) were not significantly different from those observed in drug-naive animals: the drugs administered singly did not induce robust stereotyped motor behaviors nor produce significantly striosome-pre...
Scientific Reports
Previous evidence pointed out a role for the striatal-enriched protein Rhes in modulating dopaminergic transmission. Based on the knowledge that cocaine induces both addiction and motor stimulation, through its ability to enhance dopaminergic signaling in the corpus striatum, we have now explored the involvement of Rhes in the effects associated with this psychostimulant. Our behavioral data showed that a lack of Rhes in knockout animals caused profound alterations in motor stimulation following cocaine exposure, eliciting a significant leftward shift in the dose-response curve and triggering a dramatic hyperactivity. We also found that Rhes modulated either short- or long-term motor sensitization induced by cocaine, since lack of this protein prevents both of them in mutants. Consistent with this in vivo observation, we found that lack of Rhes in mice caused a greater increase in striatal cocaine-dependent D1R/cAMP/PKA signaling, along with considerable enhancement of Arc, zif268, ...
Neuroscience, 1996
Psychomotor stimulants such as cocaine alter gene expression in neurons of the striatum. Whereas many of these effects are mediated by D1 dopamine receptors, the involvement of other dopamine receptor subtypes or neurotransmitters is likely. To distinguish between these possibilities, regulation by cocaine of immediate-early genes and genes encoding neuropeptides was analysed in mice that lack functional D1 receptors. Gene expression was examined with in situ hybridization histochemistry. In these animals, cocaine failed to induce the immediate-early genes c-fos and zif 268. In contrast, substance P expression was abnormally increased by this drug.
Cocaine binding sites in mouse striatum, dopamine autoreceptors, and cocaine-induced locomotion
Pharmacology Biochemistry and Behavior, 1992
REITH, M. E. A. AND G. SELMECI. Cocaine binding sites in mouse striatum, dopamine autoreceptors, and cocaine-induced locomotion. PHARMACOL BIOCHEM BEHAV 41(1) 227-230, 1992.-BALB/cByJ mice received cocaine (25 mg/kg IP) once a day for 3 days, resulting in a greater locomotor response to cocaine on day 3 than on day 1. On day 4, a dose (0.03 mg/kg SC) of apomorphine, targeted at dopamine autoreceptors, caused the same degree of locomotor depression in cocaine-as in saiinepretreated mice. In addition, no change was found in either the affinity or density of cocaine binding sites in their striatum as measured by the binding of [3H]CFr. C57BL/6ByJ mice displayed a greater locomotor response to cocaine than BALB/cByJ mice, but had the same number of striatal [3H]CFF binding sites with the same affinity. Factors other than striatal cocaine binding sites, or dopamine autoreceptors as measured by apomorphine-indueed depression of locomotion, should be considered for the explanation of the enhancement of the locomotor response upon daily cocaine administration in BALB/cByJ mice, or for the different locomotor response to cocaine of this strain compared with the C57BL/6ByJ strain of mice. Cocaine Locomotion Cocaine binding Dopamine autoreceptors Mouse striatum COCAINE administration to rodents stimulates locomotor behavior, and this effect increases over time with repeated intermittent doses of moderate size (11, 14, 15). The locomotor response to acute administration of cocaine varies in different strains of rats (5) and mice (6, 21, 22, 24). In addition, different mouse strains respond differently to subchronic treatment with cocaine (19,22). Current theories implicate mesencephalic dopaminergic systems in cocaine's stimulatory activity (4,25); this effect is associated with blockade of the neuronal uptake of dopamine by binding of cocaine to the dopamine transporter (12, 16, 20). Therefore, cocaine binding sites are potential candidates for mediators of the differences in the responsiveness to cocaine between strains, or the sensitization following repeated cocaine administration. Additional candidates are dopamine autoreceptors, known to be subject to regulation by cocaine administration depending on the dosage schedule and functional assay employed (1, 3, 9, 26). The present study focusses on cocaine binding sites and dopamine autoreceptors in two mouse strains, the BALB/cByJ and C57BL/6ByJ. Enhancement of the locomotor effect of cocaine is produced by daily injection of cocaine for three days according to our previously described model (15); on day 4 the animals are examined for either the binding of [3H]2[3-carbomethoxy
2020
D1 dopamine receptors play an important role in the effects of cocaine. Here we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupled designer receptor exclusively activated by designer drugs (Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the induction of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in non-transgenic mice. Inhibition of D1-neurons during the first cocaine administration reduced the sensitization of the locomotor response in response to a second cocaine administration ten days later. At day 11, inhibit...