Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method

Emmett‐Oglesby, M. W.; Peltier, Rachel; Depoortère, R.; Pickering, Chris; Hooper, M.; Gong, Yu; Lane, John D.

doi:10.1016/0376-8716(93)90089-9

Cited by 70 publications

(44 citation statements)

References 15 publications

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“…Addiction-related changes in cocaine self-administration dose-response curves may reflect increased motivation for drugs (incentive sensitization), but reduced pharmacological impact of drugs on reward processes (tolerance) leading to compensatory increases in drug intake (Emmett-Oglesby et al, 1993;Piazza et al, 2000). Our results suggest that such changes, whether due to higher cocaine exposure or an inherent disposition, could result in enhancing D 2 and reducing D 1 receptor responsiveness, respectively.…”

Section: Brain Cocaine Levelsmentioning

confidence: 78%

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

Edwards

Whisler

Fuller

et al. 2006

Neuropsychopharmacol

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The cocaine-addicted phenotype can be modeled in rats based on individual differences in preferred levels of cocaine intake and a propensity for relapse in withdrawal. These cocaine-taking and -seeking behaviors are strongly but differentially regulated by postsynaptic D 1 and D 2 receptors in the mesolimbic dopamine system. Thus, we determined whether addiction-related differences in cocaine selfadministration would be related to differential sensitivity in functional D 1 and D 2 receptor responses. Using a population of 40 outbred Sprague-Dawley rats trained to self-administer cocaine for 3 weeks, we found that animals with higher preferred levels of cocaine intake exhibited a vertical and rightward shift in the self-administration dose-response function, and were more resistant to extinction from cocaine self-administration, similar to phenotypic changes reported in other models of cocaine addiction. After 3 weeks of withdrawal from cocaine self-administration, high intake rats were subsensitive to the ability of the D 1 agonist SKF 81297 to inhibit cocaine-seeking behavior elicited by cocaine priming, but supersensitive to cocaine seeking triggered by the D 2 agonist quinpirole, when compared to low intake rats. Additionally, high intake rats developed profound increases in locomotor responses to D 2 receptor challenge from early to late withdrawal times, whereas low intake rats developed increased responsiveness to D 1 receptor challenge. In a second experiment, responses to the mixed D 1 /D 2 agonist apomorphine and the NMDA glutamate receptor antagonist MK-801 failed to differ between low and high intake rats. These findings suggest that cocaine addiction is related specifically to differential alterations in functional D 1 and D 2 receptors and their ability to modulate cocaine-seeking behavior.

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Section: Brain Cocaine Levelsmentioning

confidence: 78%

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

Edwards

Whisler

Fuller

et al. 2006

Neuropsychopharmacol

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“…The present hypothesis is that an escalation in cocaine intake predicts an increase in the hedonic set-point accompanied by an increased motivation for the drug, rather than the development of tolerance, which is generally indicated by a rightward shift in the curve (Ahmed et al, 2000;Emmett-Oglesby et al, 1993;Li et al, 1994). In this context, escalating vertical shifts in the dose-response curve may reflect changes in the self-injection of the drug reward with an increase in the motivation to take the drug (increased peak or maximum rate of behavior).…”

Section: Discussionmentioning

confidence: 90%

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Wang

et al. 2009

Neuropsychopharmacol

161

156

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The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIa, but not CaMKIIb, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIa, but not CaMKIIb, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIa, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. Neuropsychopharmacology (2010) 35, 913-928; doi:10.1038/npp.2009; published online 9 December 2009 Keywords: histone acetylation; nucleus accumbens; motivation; cocaine self-administration; addiction; CaMKIIa INTRODUCTIONDrug addiction is a debilitating psychiatric disorder characterized by (1) a compulsion to seek and take the drug, (2) a loss of control in limiting intake, and (3) the emergence of a negative emotional state when access to the drug is prevented (Hyman et al, 2006;Kalivas et al, 2005;Koob and Kreek, 2007). The complex behavioral changes leading to drug addiction are thought to result from molecular and cellular adaptation in specific brain regions (Brami-Cherrier et al, 2005). One area of intensive research to clarify neuroadaptation addresses the regulation of gene expression induced by the drug (Nestler, 2001). The drug induces changes in gene expression in key brain reward regions, such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral tegmental area (VTA). For instance, the expression of the immediate early gene c-Fos and several other Fos family proteins is upregulated in the nucleus accumbens, striatum (Courtin et al, 2006) and frontal cortex (Thiriet et al, 2000) after acute cocaine treatment. T...

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“…These observations also suggest that pharmacological tolerance is not responsible for the decrease in responding. Tolerance is more likely to be expressed as an increase in responding in self-administration experi- ments using a fixed ratio schedules of reinforcement (Yokel 1987;Emmett-Oglesby et al 1993).…”

Section: Intravenous Cocaine Self-administration In Balb/cbyjmentioning

confidence: 99%

Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

David

Gold

Koob

et al. 2001

Neuropsychopharmacology

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Previous studies have reported intravenous cocaine selfadministration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/ kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a rewardrelevant brain region might support consistent cocaineseeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) The reinforcing effect of cocaine has long been demonstrated in several species including humans, (Pickens and Thompson 1968;Woods and Schuster 1968;Deneau et al. 1969;Goldberg 1973;Fischman and Schuster 1982). However, in studies using monkeys as well as rats, not all individual subjects exhibit acquisition of self-administration, and data from subjects that fail to acquire selfadministration are usually excluded (Davis and Smith 1987). Consistent with these observations, many humans experiencing psychostimulant drugs do not develop compulsive drug-seeking behavior (Siegel 1984;O'Brien et al. 1986). Recently, an increasing number of studies have investigated the biological basis of the vulnerability to drug abuse in outbred rats. From this work, it is possible to define a vulnerability profile based on a number of behavioral, neurochemical, and endocrinological features (Hooks et al. 1991;Piazza and Le Moal 1996). Importantly, traits associated with a vulnerable phenotype in rats, such as novelty-induced activity, can be compared to psychological dimensions measured in humans, such as novelty-seeking behavior (see Bardo et al. 1996). It is of special interest to note here that novelty- Cocaine Self-Administration in BALB/cByJ Mice 301 seeking and drug-seeking behaviors co-vary in humans as well as laboratory animals (Bardo et al. 1996). These behaviors are also expressed differentially in inbred strains of mice making these mice a potentially important model for further examining the relationship between behavioral traits, their underlying biological basis, and drug-seeking behavior (Crabbe et al. 1994).Of particular interest in this context is the difficulty of demonstrating intravenous cocaine self-administration in BALB/cByJ mice (Deroche et al. 1997;Roberts et al. 1997;Yu et al. 1997), using doses known to maintain self-administration in C57BL/6 or several other strains (Carney et al. 1991;Grahame et al. 1995;Deroche et al. 1997;Rocha et al. 1998). This observation cannot be accounted for by pharmacokinetic differences (Ruth et al. 1988), capacity to learn operant tasks (Cazala 1976;Deroche et al. 1997;Heyser et al. 199...

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Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method

Cited by 70 publications

References 15 publications

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

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