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The behavioral sensitization produced by repeated cocaine treatment represents the neural adaptations underlying some of the features of addiction in humans. Cocaine administrations induce neural adaptations through regulation of gene expression. Several studies suggest that epigenetic modifications, including DNA methylation, are the critical regulators of gene expression in the adult central nervous system. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and consequent promoter region hypermethylation is associated with transcriptional silencing. In this study a potential role for DNA methylation in a cocaine-induced behavioral sensitization model in mice was explored. We report that acute cocaine treatment caused an upregulation of DNMT3A and DNMT3B gene expression in the nucleus accumbens (NAc). Using methylated DNA immunoprecipitation, DNA bisulfite modification, and chromatin immunoprecipitation assays, we observed that cocaine treatment resulted in DNA hypermethylation and increased binding of methyl CpG binding protein 2 (MeCP2) at the protein phosphatase-1 catalytic subunit (PP1c) promoter. These changes are associated with transcriptional downregulation of PP1c in NAc. In contrast, acute and repeated cocaine administrations induced hypomethylation and decreased binding of MeCP2 at the fosB promoter, and these are associated with transcriptional upregulation of fosB in NAc. We also found that pharmacological inhibition of DNMT by zebularine treatment decreased cocaine-induced DNA hypermethylation at the PP1c promoter and attenuated PP1c mRNA downregulation in NAc. Finally, zebularine and cocaine co-treatment delayed the development of cocaine-induced behavioral sensitization. Together, these results suggest that dynamic changes of DNA methylation may be an important gene regulation mechanism underlying cocaine-induced behavioral sensitization. [ABSTRACT FROM AUTHOR]

The CB1 cannabinoid receptor is implicated in the rewarding properties of many drugs of abuse, including cocaine. While CB1 receptor involvement in the acute rewarding properties of cocaine is controversial, CB1 antagonists such as SR141716 (rimonabant) have clearly been found to prevent cue- and cocaine-elicited reinstatement of cocaine self-administration in rodents. Here we demonstrate the novel involvement of CB1 receptors in the maintenance of behavioral sensitization to cocaine in C57BL/6 mice. Consistent with previous reports, the induction of locomotor sensitization following repeated daily cocaine was not prevented by systemic pretreatment of either rimonabant, D9-tetrahydrocannabinol (THC), or a 1:1 mixture of THC and cannabidiol (CBD). In contrast, established cocaine sensitization was markedly disrupted following subchronic treatment with rimonabant alone. This effect was notably context-dependent, in that rimonabant did not diminish established cocaine sensitization if delivered in the home cage, but only if the rimonabant-injected mice were exposed to activity chambers previously paired with cocaine. These findings are consistent with CB1 receptor involvement in conditioned cocaine-seeking behaviors, and further suggest that endocannabinoid (eCB)-mediated synaptic plasticity may act specifically within drug-paired environments to maintain cocaine-directed behavioral responses. [ABSTRACT FROM AUTHOR]

Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.Neuropsychopharmacology (2007) 32, 1995–2003; doi:10.1038/sj.npp.1301321; published online 24 January 2007 [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcriptional factor that regulates lipid metabolism and inflammation. Behavioral sensitization is an experimental model of psychostimulant psychosis; it is elicited by repeated administration of psychostimulants and has recently been implicated in brain inflammation. We examined the involvement of PPARγ, one of the isotypes of PPAR, in development of behavioral sensitization to the stimulant effect of methamphetamine (METH) (1 mg/kg, subcutaneously) in mice. Repeated administration of METH (once daily for 5 days) enhanced the locomotor-activating effect of METH, which was reproduced by METH challenge on withdrawal day 7 (test day 12). The protein level and the activity of PPARγ were significantly increased in the nuclear fraction of whole brain after 5 days of METH administration (test day 5) and on withdrawal day 7 (test day 12). Both pioglitazone and ciglitazone (PPARγ agonists; 0.5–5.0 μg, intracerebroventricularly (i.c.v.), once daily) prevented the expression of behavioral sensitization to METH challenge on withdrawal day 7, but not the sensitization that occurred during repeated administration of METH. In addition, the magnitude of expression of behavioral sensitization was augmented by treatments with GW9662 (a PPARγ antagonist; 0.5–5.0 μg i.c.v., once daily) during the withdrawal period. The pioglitazone-induced alleviation of behavioral sensitization was synergistically facilitated by simultaneous i.c.v. injection of 9-cis-retinoic acid (1.0 μg), an agonist for the retinoid X receptor which is a ligand-activated nuclear receptor that forms heterodimers with PPAR. These results suggest that PPARγ has a significant role in the expression of behavioral sensitization to METH in mice.Neuropsychopharmacology (2007) 32, 1133–1140. doi:10.1038/sj.npp.1301213; published online 4 October 2006 [ABSTRACT FROM AUTHOR]

To obtain an insight into the development of a new pharmacotherapy that prevents the treatment-resistant relapse of psychostimulant-induced psychosis and schizophrenia, we have investigated in the mouse the effects of selective serotonin reuptake inhibitors (SSRI), fluoxetine (FLX) and paroxetine (PRX), on the established sensitization induced by methamphetamine (MAP), a model of the relapse of these psychoses, because the modifications of the brain serotonergic transmission have been reported to antagonize the sensitization phenomenon. In agreement with previous reports, repeated MAP treatment (1.0 mg/kg a day, subcutaneously (s.c.)) for 10 days induced a long-lasting enhancement of the increasing effects of a challenge dose of MAP (0.24 mg/kg, s.c.) on motor activity on day 12 or 29 of withdrawal. The daily injection of FLX (10 mg/kg, s.c.) or PRX (8 mg/kg, s.c.) from 12 to 16 days of withdrawal of repeated MAP administration markedly attenuated the ability of the MAP pretreatment to augment the motor responses to the challenge dose of the stimulant 13 days after the SSRI injection. The repeated treatment with FLX or PRX alone failed to affect the motor stimulation following the challenge of saline and MAP 13 days later. These results suggest that the intermittent and repetitive elevation of serotonergic tone may inhibit the expression of the motor sensitization induced by pretreatment with MAP. It is proposed that clinically available serotonin reuptake inhibitors could be useful for preventing the recurrence of hallucinatory-paranoid state in drug-induced psychosis and schizophrenia.Neuropsychopharmacology (2007) 32, 658–664. doi:10.1038/sj.npp.1301111; published online 31 May 2006 [ABSTRACT FROM AUTHOR]

Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.Neuropsychopharmacology (2007) 32, 377–387. doi:10.1038/sj.npp.1301101; published online 14 June 2006 [ABSTRACT FROM AUTHOR]

Nonspecific blockade of opioid receptors has been found to prevent development of behavioral sensitization to ethanol. Whether this effect is achieved through a specific opioid receptor subtype, however, is not clear. The present study investigated, for the first time, the role of specific opioid receptor subtypes in the development of ethanol-(2.5 g/kg/day; six sessions) induced locomotor sensitization in mice. We confirmed previous results showing that the nonspecific antagonism of opioid receptors (naltrexone; 0–2 mg/kg) prevented the development of behavioral sensitization to ethanol, an effect attained at doses presumed to occupy only mu opioid receptors. This was confirmed by using the selective mu opioid receptor antagonist CTOP (0–1.5 mg/kg), which also blocked sensitization to ethanol. The selective delta receptor antagonist, naltrindole (0–10 mg/kg), however, did not alter sensitization. We further assessed the role of mu opioid receptors in sensitization to ethanol by exploring the involvement of mu1, mu1+2, and mu3 opioid receptor subtypes. Results of these experiments revealed that the blockade of mu1 (naloxonazine; 0–30 mg/kg) or mu3 opioid receptors (3-methoxynaltrexone; 0–6 mg/kg) did not prevent locomotor sensitization to ethanol. Using naloxonazine under treatment conditions that block mu1+2 opioid receptor subtypes we observed a retarded sensitization. The present data suggest that the concurrent inactivation of all mu opioid receptor subtypes may be required to prevent the neural adaptations underlying the development of behavioral sensitization to ethanol. In addition, these results support previous data suggesting a putative role for the mu opioid receptor endogenous ligand, β-endorphin, and the hypothalamic arcuate nucleus in ethanol sensitization.Neuropsychopharmacology (2006) 31, 1489–1499. doi:10.1038/sj.npp.1300928; published online 12 October 2005 [ABSTRACT FROM AUTHOR]

A rapid-onset type of behavioral sensitization (ROBS) has been demonstrated in rats treated with a single ‘priming’ injection of amphetamine (AMP). In that species, however, this phenomenon was restricted to AMP-induced stereotyped behavior (SB), not occurring for the locomotor-stimulant effect (LSE) of AMP and not reflecting environment-specific sensitization. In the present study, the ROBS was characterized in the mouse. Mice received a single ‘priming’ intraperitoneal injection of 5.0 mg/kg AMP which was paired or not with environment. At different intervals (3, 4 or 5 h) subgroups were tested for AMP (1.5 or 5.0 mg/kg)-induced SB or AMP (1.5 mg/kg)-induced open-field LSE. Results showed that: (1) in the absence of drug–environment association, a priming injection of AMP increased the SB induced by a 1.5 mg/kg AMP challenge injection given 3 h (but not 4 or 5 h) later; (2) when the dose of AMP challenge injection was increased to 5.0 mg/kg, an enhancement of SB was verified at all the intervals tested (3, 4, and 5 h); (3) when animals were tested in an open field, the priming injection of AMP produced an increase in the LSE of a 1.5 mg/kg AMP challenge injection, given 4 h later; (4) drug–environment association increased both SB and locomotion after a saline challenge injection and potentiated the rapid-onset sensitization of both behaviors in AMP-challenged mice. Collectively, these results demonstrate that the ROBS phenomenon also occurs in mice, is extended to AMP-induced LSE, and is markedly potentiated by (but does not depend on) environmental conditioning.Neuropsychopharmacology (2006) 31, 151–159. doi:10.1038/sj.npp.1300789; published online 8 June 2005 [ABSTRACT FROM AUTHOR]

The cyclin-dependent kinase Cdk5 and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of Mr 32 kDa)-dependent signaling have been implicated in the regulation of dopaminergic neurotransmission after chronic cocaine treatment. In this study, we examined if Cdk5 signaling participates in the behavioral and biochemical effect of acute and chronic methamphetamine (METH) treatment. We found that Cdk5 activity and the membrane fraction of p35 protein, a Cdk5 activator, in the ventral striatum increased transiently after an injection of 4 mg/kg METH, while intra-accumbens treatment with a Cdk5 inhibitor, roscovitine, prevented the acute METH induced locomotor activation. The phosphorylation of DARPP-32 at both Thr75 and Thr34 was differentially regulated after acute METH treatment, but the levels of total Cdk5, p35, and DARPP-32 remained the same. To determine if Cdk5 signaling was associated with behavior sensitization to METH, rats that received repetitive injections of METH (4 mg/kg) for 14 consecutive days were analyzed at withdrawal day 7. The results indicate that Cdk5 activity and p35 translocation in the ventral striatum were upregulated in METH-sensitized rats; treatment with roscovitine in the nucleus accumbens effectively suppressed the 1 mg/kg METH-induced behavioral sensitization. Concomitantly, a decrease in the amount of PP-2A and DARPP-32 phosphorylation at Thr34, but an increase in phosphorylation of DARPP-32/Thr75, was observed in the ventral striatum of sensitized rats. The overall results demonstrate that Cdk5/ p35 and downstream signaling in the ventral striatum play a critical role in the effects of acute METH treatment as well as the development of behavioral METH sensitization. [ABSTRACT FROM AUTHOR]

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine. [ABSTRACT FROM AUTHOR]

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A2A receptors in psychostimulant-induced locomotor sensitization using an A2A receptor knockout (A2A KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A2A KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D1 agonist SKF81297 (2.5 mg/kg) or the D2 agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A2A KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A2A KO and WT mice, suggesting normal D1 and D2 receptor responsiveness. Finally, at the cellular level A2A receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A2A KO mice suggests a critical role of the A2A receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A2A adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure. [ABSTRACT FROM AUTHOR]

The sensitizing properties of drugs of abuse have been proposed to play an important role in the persistence of drug seeking behavior. We decided to evaluate the temporal relationship of dopamine D2 receptor-mediated drug seeking behavior and behavioral sensitization in animals with a history of cocaine and heroin self-administration. During early phases of withdrawal (<1 week), activation of dopamine D2 receptors with quinpirole resulted in robust, dose-dependent, reinstatement of (non-reinforced) responding in both cocaine- and heroin-trained rats. Cocaine and heroin seeking induced by quinpirole was associated with a dramatic enhancement of the psychomotor stimulant effects of the D2 agonist, indicating that sensitization to D2-mediated events had developed. During the late phase of withdrawal (>3 weeks), reinstatement of cocaine seeking by quinpirole was still apparent, but less robust. In heroin-trained rats, increases of responding were no longer observed. Interestingly, behavioral sensitization to quinpirole was still observed in cocaine-trained rats, but was absent in heroin-trained rats. Thus, it appears that dopamine D2 receptors have a time-dependent role in relapse to cocaine and heroin seeking which is strongly associated with a behaviorally sensitized state. [ABSTRACT FROM AUTHOR]

We previously reported that ventral tegmental area (VTA) dopamine neurons are supersensitive to AMPA when recorded three days after discontinuing repeated amphetamine or cocaine administration. By increasing dopamine cell activity, this may contribute to the induction of behavioral sensitization. The goal of this study was to determine if increased sensitivity to AMPA reflects increased AMPA receptor expression in the midbrain. Immunolabeling for GluRT1, GluR2, GluR2/3, and GluR4 was quantified by immunohistochemistry with 35S-labeled secondary antibodies in VTA, substantia nigra, and a transitional area. First, rats were treated for five days with saline or amphetamine (5 mg/kg) and killed three or 14 days after the last injection. No significant changes in immunolabeling were observed for any subunit at either withdrawal time. GluR1 immunolabeling was further examined in rats killed 16-18 hrs or 24 hrs after a single injection of amphetamine or repeated injections of saline, amphetamine (5 mg/kg × 5 days) or cocaine (20 mg/kg × 7 days). No significant differences were observed in any region. Finally, neither repeated amphetamine or cocaine administration significantly altered GluR1 mRNA levels as quantified by reverse transcriptase-polymerase chain reaction. Our results suggest that enhanced responsiveness of VTA dopamine neurons to AMPA after withdrawal from repeated stimulant administration involves mechanisms more complex than increased expression of AMPA receptor subunits. [ABSTRACT FROM AUTHOR]