Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

Robinson, J. Elliott; Chen, Meng; Stamatakis, Alice M.; Krouse, Michael C.; Howard, Elaina C.; Faccidomo, Sara; Hodge, Clyde W.; Fish, Eric W.; Malanga, C. J.

doi:10.1038/npp.2013.30

Cited by 11 publications

(13 citation statements)

References 73 publications

(92 reference statements)

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“…h/mOPRM1-118AA and 118GG mice were implanted with stimulating electrodes in the medial forebrain bundle at the level of the lateral hypothalamus and were conditioned to perform ICSS as previously described (Robinson et al, 2013). After baseline testing, mice were removed from the operant chambers, injected with vehicle (i.p.…”

Section: Intracranial Self-stimulation (Icss)mentioning

confidence: 99%

“…Dialysate DA concentrations were analyzed using high-pressure liquid chromatography (HPLC) with electrochemical detection as previously described (Chefer et al, 2013). In the fentanyl/β-funaltrexamine experiment, locomotion was measured in MedAssociates locomotor activity chambers (St Albans, VT) as previously described (Robinson et al, 2013).…”

Section: Microdialysis and Locomotor Activitymentioning

confidence: 99%

“…Acute horizontal midbrain slices were prepared, and wholecell patch clamp recordings from VTA dopaminergic neurons were obtained as previously described (Robinson et al, 2013). Miniature inhibitory postsynaptic currents (mIPSCs) were recorded in oxygenated aCSF that contained tetrodotoxin (500 nM) and kynurenic acid (1 μM).…”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

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Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Robinson

Vardy

DiBerto

et al. 2015

Neuropsychopharmacol

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The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function.

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Section: Intracranial Self-stimulation (Icss)mentioning

confidence: 99%

Section: Microdialysis and Locomotor Activitymentioning

confidence: 99%

Section: Electrophysiological Recordingsmentioning

confidence: 99%

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Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Robinson

Vardy

DiBerto

et al. 2015

Neuropsychopharmacol

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“…Levetiracetam (LEV) is an antiepileptic drug that alters glutamate and possibly GABA neurotransmission (Meehan et al, 2011; Meehan et al, 2012; Robinson et al, 2013) by interfering with the activity of synaptic vesicle protein 2A (SV2A), which has been identified as the sole binding site for LEV in the brain (Lynch et al, 2004). In addition to its efficacy in the treatment of epilepsy, LEV has been proposed for use in the treatment of several neuropsychiatric disorders (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Repeated LEV administration has been shown to reduce alcohol intake in female alcohol-preferring rats (Zalewska-Kaszubska et al, 2011) and acute LEV administration has been shown to alleviate the anxiety-like behaviors produced by benzodiazepine withdrawal in mice (Lamberty et al, 2002). Acute LEV has been also shown to reduce the effects of acute alcohol on both locomotor activation and the potentiation of intracranial self-stimulation (ICSS), and independently reduces both the induction and expression of locomotor sensitization to repeated alcohol exposure in male C57BL/6J mice (Robinson et al, 2013). Most preclinical studies of LEV have focused on its anti-seizure efficacy.…”

Section: Introductionmentioning

confidence: 99%

Levetiracetam results in increased and decreased alcohol drinking with different access procedures in C57BL/6J mice

Fish

Agoglia²,

Krouse³

et al. 2014

Behavioural Pharmacology

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The antiepileptic, levetiracetam (LEV), has been investigated for the treatment of alcohol abuse. However, little is known about how LEV alters the behavioral effects of alcohol in laboratory animals. The acute effects of LEV on alcohol drinking by male C57BL/6J mice were investigated using two different drinking procedures, limited access (drinking-in-the-dark, or DID) and intermittent access (IA) drinking. In the first experiment (DID), mice had access to a single bottle containing alcohol or sucrose for four hours every-other day. In the second experiment (IA), mice had intermittent access to two bottles, one containing alcohol or sucrose and one containing water, for 24 h on Mon/Wed/Fri. In both experiments, mice were administered LEV (0.3 – 100 mg/kg i.p.) or vehicle 30 min before access to the drinking solutions. In the DID mice, LEV increased alcohol intake from 4.3 to 5.4 g/kg, while in the IA mice LEV decreased alcohol intake from 4.8 to 3.0 g/kg in the first 4 h of access and decreased 24 h alcohol intake from 20 g/kg to approximately 15 g/kg. These effects appear specific to alcohol, as LEV did not affect sucrose intake in either experiment. LEV appears to differentially affect drinking in animal models of moderate and heavier alcohol consumption.

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Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J Mice

Fish

DiBerto

et al. 2014

Psychopharmacology

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Rationale The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. Objective to examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. Methods Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward, BSR). Mice received cocaine (n=11, 3.0 – 30.0 mg/kg, i.p.) or the neuroactive steroid allopregnanolone (n=11, 3.0 – 17.0 mg/kg, i.p.). BSR thresholds (θ0) and maximum operant response rates (MAX) after drug treatments were compared to those after vehicle injections. Results Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 minutes following the 30 mg/kg dose, while allopregnanolone was maximally effective (30% reduction) 15-45 minutes after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. Conclusions The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice.

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Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

Cited by 11 publications

References 73 publications

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Levetiracetam results in increased and decreased alcohol drinking with different access procedures in C57BL/6J mice

Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J Mice

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