The hypocretin–orexin system regulates cocaine self‐administration via actions on the mesolimbic dopamine system

España, Rodrigo A.; Oleson, Erik B.; Locke, Jason L.; Brookshire, Bethany R.; Roberts, David C. S.; Jones, Sara R.

doi:10.1111/j.1460-9568.2009.07065.x

Cited by 223 publications

(335 citation statements)

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“…Behavioral economic theory has been successfully applied to drug self-administration in general (Bickel et al, 1993;Hursh, 1991) and TH procedures in particular (Espana et al, 2010;Oleson et al, 2011;Oleson and Roberts, 2009). In the current TH procedure, the descending series of doses (listed above) resulted in rats receiving access to cocaine across the following 11 ascending unit-prices: 2.…”

Section: Discussionmentioning

confidence: 99%

“…4, 4.2, 7.5, 13.3, 23.7, 39.9, 75, 134, 242, 417, and 750 responses/mg. The primary dependent measure analyzed was the maximal price paid for cocaine (Pmax), which was determined to be the unit-price corresponding to the apex of the price-response function as previously described (Espana et al, 2010;Oleson et al, 2011). An example of the calculation of Pmax is shown in Figure 4a.…”

Section: Discussionmentioning

confidence: 99%

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The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

Zimmer

Oleson

Roberts

2012

Neuropsychopharmacol

138

205

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Recent attempts to model the addiction process in rodents have focused on cocaine self-administration procedures that provide extended daily access. Such procedures produce a characteristic loading phase during which blood levels rapidly rise and then are maintained within an elevated range for the duration of the session. The present experiments tested the hypothesis that multiple fastrising spikes in cocaine levels contribute to the addiction process more robustly than constant, maintained drug levels. Here, we compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic measure of the motivation to self-administer drug. Two groups received intermittent access (IntA) to cocaine during daily 6-h sessions. Access was limited to twelve 5-min trials that alternated with 25-min timeout periods, using either a hold-down procedure or a fixed ratio 1 (FR1). Cocaine levels could not be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long access and 2-h short access sessions and two other control groups. Here, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

Zimmer

Oleson

Roberts

2012

Neuropsychopharmacol

138

205

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“…However, the involvement of the hypocretin system in the rewarding properties of cocaine has mainly been revealed under conditions that require greater degrees of effort and motivation to obtain the drug (28,29). The present data point to a specific role for Hcrtr-1 in the modulation of the reinforcing properties of cannabinoids since the Hcrtr-2 antagonist TCSOX229 did not alter this behavior.…”

Section: The Enhanced Of Dopamine Extracellular Levels In the Nucleusmentioning

confidence: 46%

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

Flores

Maldonado

Berrendero

2014

Biological Psychiatry

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Table 1) 2 Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacological treatment is still available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction and the potential participation of this system in the addictive properties of cannabinoids is still unknown. Methods:We investigated the effects of hypocretins in the intravenous selfadministration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 (Hcrtr-2) antagonists, and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double label immunofluorescence of FosB/∆FosB with hypocretin-1.Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute ∆ 9 -tetrahydrocannabinol (THC) administration.Results: Systemic administration of the Hcrtr-1 antagonist SB334867, but not the Hctr-2 antagonist TCSOX229, reduced intravenous self-administration of WIN55,212-2 as well as the maximum effort to obtain a WIN55,212-2 infusion as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not non-contingent WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/∆FosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by THC was blocked in mice lacking the Hcrtr-1.Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest. 3 IntroductionCannabis is the most used illicit drug worldwide (1). It is estimated that about 9% of those who ever use this drug become daily users (2), rising to 16% when the consumption is initiated during the adolescence (2). Recent analysis of cannabis extracts has shown an increase in potency over the last years due to enhanced content of ∆ 9 -tetrahydrocannabinol (THC), its primary psychoactive constituent (3). A high THC content leads to an increase in the subjective effects of this drug probably enhancing the risk of dependence and psychotic symptoms of cannabis users (3). Treatment admissions for cannabis-use disorders have progressively increased in the past decade.Approximately 90% of those seeking treatment for these disorders have great difficulty achieving and sustaining periods of abstinence (4), and the majority relapse to use following therapeutic interventions (5). There are currently no effective pharmacotherapeutic approaches for this disorder (5). Therefore, the need for identifying specific medications to improve treatment outcomes for cannabis dependence becomes a major clinical priority.Several findin...

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“…Orexin A has been implicated in anxiety and reward-related behaviors (Buffalari and See, 2010;Dayas et al, 2008;Espana et al, 2010;Harris et al, 2005;Johnson et al, 2010;Lawrence et al, 2006;Richards et al, 2008), and the BNST receives dense orexinergic innervation (Baldo et al, 2003). To test the role of orexin signaling in the effects of yohimbine, we assessed the ability of OxR antagonists to block its actions.…”

Section: Orexin Receptor (Oxr) Antagonists Block Yohimbineinduced Depmentioning

confidence: 99%

“…The orexin system was first described in the late 1990s, when the orexin neuropeptides were shown to be important in feeding and arousal-related behaviors (de Lecea et al, 1998;Sakurai et al, 1998). Since then, studies have demonstrated an important role for the orexin system in anxiety and reward-related behaviors (Boutrel et al, 2005;Dayas et al, 2008;Espana et al, 2010;Harris et al, 2005;Johnson et al, 2010;Lawrence et al, 2006;Richards et al, 2008;Zhou et al, 2011). The BNST receives dense orexinergic inputs (Baldo et al, 2003) and has a high density of OX 1 R mRNA and protein expression (Hervieu et al, 2001;Marcus et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

Conrad

Davis

Silberman

et al. 2012

Neuropsychopharmacol

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The alpha2 adrenergic receptor (a 2 -AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of a 2 -AR signaling. Recent studies show yohimbineinduced drug-seeking behavior is attenuated by orexin receptor 1 (OX 1 R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR 1 ) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX 1 R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX 1 R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.

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The hypocretin–orexin system regulates cocaine self‐administration via actions on the mesolimbic dopamine system

Cited by 223 publications

References 62 publications

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

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