Potencies of Cocaine Methiodide on Major Cocaine Targets in Mice

Hill, Emily B.; Tian, Jin Bin; Tilley, Michael R.; Zhu, Michael X.; Gu, Howard H.

doi:10.1371/journal.pone.0007578

Cited by 11 publications

(11 citation statements)

References 22 publications

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“…The results presented here indicate that DIR can occur at much lower concentrations of DA in the presence of 100 nM cocaine than with DA alone. As the EC 50 of cocaine for monoamine transporters is between 10 À7 and 10 À6 M (Hill et al, 2009), low concentrations of cocaine may increase the likelihood that DA in the VTA can cause activation of PKC, and subsequently decrease responsiveness to DA autoinhibition. This would result in less autoregulation, and excitatory inputs to the VTA would produce more increases in firing and more DA release in terminal fields receiving DA innervation.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area is Mediated by Protein Kinase C

Nimitvilai

Arora

Brodie

2011

Neuropsychopharmacol

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Adaptation of putative dopaminergic (pDA) neurons in the ventral tegmental area (VTA) to drugs of abuse may alter information processing related to reward and reinforcement and is an important factor in the development of addiction. We have demonstrated that prolonged increases in the concentration of dopamine (DA) result in a time-dependent decrease in sensitivity of pDA neurons to DA, which we termed DA inhibition reversal (DIR). In this study, we used extracellular recordings to examine factors mediating DIR. A 40 min administration of DA (2.5-10 mM), but not the DA D2 receptor agonist quinpirole (50-200 nM), resulted in inhibition of neuronal firing followed by DIR. In the presence of 100 nM cocaine, inhibition followed by DIR was seen with much lower DA concentrations. Reversal of quinpirole inhibition could be induced by an activator of protein kinase C, but not of protein kinase A. Inhibitors of protein kinase C or phospholipase C blocked the development of DIR. Disruption of intracellular calcium release also prevented DIR. Reduction of extracellular calcium or inhibition of store-operated calcium entry blocked DIR, but the L-type calcium channel blocker nifedipine did not. DIR was age-dependent and not seen in pDA VTA neurons from rat pups younger than 15 days postnatally. Our data indicate that DIR is mediated by protein kinase C, and implicate a conventional protein kinase C. This characterization of DIR gives insight into the regulation of autoinhibition of pDA VTA neurons, and the resulting long-term alteration in information processing related to reward and reinforcement.

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Section: Discussionmentioning

confidence: 99%

Reversal of Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area is Mediated by Protein Kinase C

Nimitvilai

Arora

Brodie

2011

Neuropsychopharmacol

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“…About 20–24 h after transfection, HeLa cells were assayed for substrate uptake in 96-well plates using the PBS/Ca/Mg buffer as described (Hill et al, 2009). For the determination of Km and Vmax values, cells were incubated in PBS/Ca/Mg buffer containing 60 nM [ 3 H]-labeled dopamine or norepinephrine in the presence of increasing concentrations of unlabeled monoamine substrates (0.1–20 μM) for 10 min at room temperature.…”

Section: 0 Materials and Methodsmentioning

confidence: 99%

Interaction of tyrosine 151 in norepinephrine transporter with the 2β group of cocaine analog RTI-113

Hill¹,

Huang²,

Chen³

et al. 2011

Neuropharmacology

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Cocaine binds and inhibits dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter. The residues forming cocaine binding sites are unknown. RTI-113, a cocaine analog, is 100x more potent at inhibiting DAT than inhibiting NET. Here we show that removing the hydroxyl group from residue Tyr151 in NET by replacing it with Phe, the corresponding residue in DAT, increased the sensitivity of NET to RTI-113, while the reverse mutation in DAT decreased the sensitivity of DAT to RTI-113. In contrast, RTI-31, another cocaine analog having the same structure as RTI-113 but with the phenyl group at the 2β position replaced by a methyl group, inhibits the transporter mutants equally well whether a hydroxyl group is present at the residue or not. The data suggest that this residue contributes to cocaine binding site and is close to the 2β position of cocaine analogs. These results are consistent with our previously proposed cocaine-DAT binding model where cocaine initially binds to a site that does not overlap with, but is close to, the dopamine-binding site. Computational modeling and molecular docking yielded a binding model that explains the observed changes in RTI-113 inhibition potencies.

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“…It remains an interesting observation that almorexant only showed a trend but did not significantly attenuate the CPP expression related to a low dose of cocaine (5 mg/kg). Cocaine is often viewed as a ' dirty drug', affecting not only dopamine, but also serotonin and noradrenaline uptake, and, in addition, sodium channels function at high dose (Hill et al 2009). Thus, one may speculate that a slightly different activation of neurocircuits during conditioning with a low dose as opposed to high dose cocaine may have led to a different extent of OX recruitment upon context reexposure at the CPP test.…”

Section: Acute Almorexant In Combination With Morphine Cocaine and Amentioning

confidence: 99%

The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat

Steiner

Lecourt

Jenck

2012

International Journal of Neuropsychopharmacology

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Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used γ-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared almorexant to the GABA metabolite γ-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with almorexant did not. Second, we tested the potential of almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after almorexant washout. Our findings suggest that almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates).

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Potencies of Cocaine Methiodide on Major Cocaine Targets in Mice

Cited by 11 publications

References 22 publications

Reversal of Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area is Mediated by Protein Kinase C

Reversal of Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area is Mediated by Protein Kinase C

Interaction of tyrosine 151 in norepinephrine transporter with the 2β group of cocaine analog RTI-113

The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat

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