Intra-VTA Deltorphin, But Not DPDPE, Induces Place Preference in Ethanol-Drinking Rats: Distinct DOR-1 and DOR-2 Mechanisms Control Ethanol Consumption and Reward

Mitchell, Jennifer; Margolis, Elyssa B.; Coker, Allison; Allen, Daicia C.

doi:10.1111/acer.12246

Cited by 21 publications

(18 citation statements)

References 31 publications

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“…Manipulating the fi ring rate of dopamine neurons either directly (Bass et al 2013) or indirectly via changes in γ-aminobutyric acid (GABA) neuronal activity in the VTA (Anstee et al, 2013;Mitchell et al, 2014) can alter ethanol intake. In addition, increases in glutamate, taurine, and glycine release in the NAc occur during operant responding for ethanol gelatin more so when rats have been exposed to high-dose ethanol treatment (Li et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Peris¹,

Rhodes²,

McCullough³

et al. 2015

J. Stud. Alcohol Drugs

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ABSTRACT. Objective: Alcohol use disorders have both high social and economic costs and are among the leading causes of preventable death in the United States. Understanding the factors that contribute to escalation of alcohol intake is important in developing effective treatments for this problem. This study further characterizes the effects of limited intermittent exposure to high levels of alcohol on the preference for alcohol consumption over other incentives. Method: Fourteen male, Sprague-Dawley rats were trained to consume ethanol in a gelatin vehicle. They were then given free access to both ethanol gelatin and plain gelatin during daily choice periods interspersed with nonchoice periods (only plain gelatin access). After baseline ethanol preference was established, half of the rats were given eight injections of 3 g/kg ethanol during nonchoice periods (spread out over about 2 months), and the other half received saline injections. Ethanol preference was measured during subsequent choice periods. Results: Intermittent ethanol injections increased ethanol preference from 21% (SEM = 2.3%) of their total gelatin consumption during the fi rst choice period to 46.8% (SEM = 3.4%) during the third choice period. The saline-treated rats had no signifi cant change in ethanol preference. In addition, the ethanoltreated rats exhibited higher ethanol intake than saline-treated rats when ethanol gelatin was the only choice available. Conclusions: The results indicate that intermittent exposure to sedative doses of ethanol leads to an increased ethanol preference in rats. This suggests that occasional high-dose alcohol exposure could be an important contributor to the development of enhanced ethanol intake, which may affect the incidence of chronic alcoholism. (J. Stud. Alcohol Drugs, 76, 165-173, 2015)

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Section: Discussionmentioning

confidence: 99%

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Peris¹,

Rhodes²,

McCullough³

et al. 2015

J. Stud. Alcohol Drugs

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“…Although immunohistochemical (Cahill et al, 2001a) and in situ hybridization studies (Mansour et al, 1994), as well as studies with DOPr-eGFP knock-in mice Scherrer et al, 2006), identify DOPr in mesolimbic brain structures important for reward and reinforcement, administration of DOPr agonists produced conflicting results in outcome measures of reward and addictive behaviors (Méndez and Morales-Mulia, 2008;Shippenberg et al, 2008;Rodríguez-Arias et al, 2010;Pradhan et al, 2011;Mitchell et al, 2014). Some studies report that DOPr agonists do not produce a place preference in otherwise drug-naïve animals (Hutcheson et al, 2001;Mitchell et al, 2014) but will after prolonged ethanol consumption (Mitchell et al, 2014). Similarly, negligible DOPr agonist abuse-related effects were evident in a monkey self-administration model (Negus et al, 1998) or in a rat model of intracranial self-stimulation (Do Carmo et al, 2009).…”

Section: Confoundsmentioning

confidence: 99%

“…Recently, the DOPr2 pharmacological profile was also associated with cardioprotection (Shen et al, 2012) and anxiolytic effects of KNT-127 (Sugiyama et al, 2014). DOPr1, on the other hand, could rather be a target to prevent alcohol abuse (Mitchell et al, 2014). Both subtypes were shown to be valid targets for the treatment of neuropathic pain (Mika et al, 2001).…”

Section: A Evidence For D-opioid Receptor Subtypesmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…Despite these molecular and cellular similarities, MOR and DOR agonists can generate different and often opposing effects on motivated behaviors (e.g. analgesia, reward, motivation) (Bals-Kubik et al, 1993; Farias et al, 2003; Hammond et al, 1998; Margolis et al, 2008a; Mitchell et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…Although DPDPE does not induce a conditioned place preference when infused into the VTA (Mitchell et al, 2014), animals will self-administer DPDPE directly into the VTA, suggesting that, like MOR activation, DOR1 activation in the VTA has a positive motivational effect (Devine and Wise, 1994). However, in long term alcohol drinking rats, while the MOR selective antagonist CTAP reduces alcohol consumption, the DOR selective antagonist TIPP- Ψ increases it (Margolis et al, 2008a).…”

Section: Introductionmentioning

confidence: 99%

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

et al. 2017

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The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling.

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Intra-VTA Deltorphin, But Not DPDPE, Induces Place Preference in Ethanol-Drinking Rats: Distinct DOR-1 and DOR-2 Mechanisms Control Ethanol Consumption and Reward

Abstract: These data indicate that the therapeutic potential of DOR agonists for alcohol abuse is through a selective action at the DOR-1 form of the receptor.

Cited by 21 publications

References 31 publications

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Molecular Pharmacology ofδ-Opioid Receptors

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

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