D2 Receptor-Mediated Regulation of Vesicular Dopamine Uptake

Fleckenstein, Annette E.; Brown, Jeffrey M.; Sandoval, Verónica; Riddle, Evan L.; Hansen, J. Paul; Ugarte, Yvette V.; Gibb, James W.; Hanson, Glen R.

doi:10.1007/978-1-4757-3538-3_6

Cited by 2 publications

(1 citation statement)

References 12 publications

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“…Acting as a substrate for the monoamine transporters, MDMA also enters the neuron and interacts with the vesicular monoamine transporter 2 (VMAT-2), preventing the repackaging of cytosolic monoamines into vesicles whilst displacing monoamines from the vesicles into the cytosol (Bogen, Haug, Myhre, & Fonnum, 2003;Eiden & Weihe, 2011;J. L. Fitzgerald & Reid, 1990;Fleckenstein et al, 2002;Gu & Azmitia, 1993;Rudnick & Wall, 1992;Sabol & Seiden, 1998;Schuldiner, Steiner-Mordoch, Yelin, Wall, & Rudnick, 1993;Sulzer & Rayport, 1990). Transporter reversal then results in the substantial efflux of cytosolic monoamines into the synapse (Crespi, Mennini, & Gobbi, 1997;Gudelsky & Nash, 2002;Rudnick & Wall, 1992).…”

Section: Pharmacology Of Mdmamentioning

confidence: 99%

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

Wetering¹

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<p>Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.</p>

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Section: Pharmacology Of Mdmamentioning

confidence: 99%

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

Wetering¹

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Vesicular monoamine transporters: Structure‐function, pharmacology, and medicinal chemistry

Wimalasena

2011

Medicinal Research Reviews

165

140

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Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor tetrabenazine has long been used for the treatment of chorea associated with Huntington's disease in UK, Canada and Australia and recently approved in the US. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, since VMAT2 is also expressed in the β-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structurefunction relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I are also discussed.

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D2 Receptor-Mediated Regulation of Vesicular Dopamine Uptake

Cited by 2 publications

References 12 publications

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

Vesicular monoamine transporters: Structure‐function, pharmacology, and medicinal chemistry

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