Molecular Mechanisms Associated with Cocaine Effects

Ritz, Mary C.; Kuhar, Michael J.; George, Frank R.

doi:10.1007/978-1-4899-1648-8_13

Cited by 14 publications

(1 citation statement)

References 174 publications

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“…Many behavioral studies using lesion techniques and pharmacological manipulations have elucidated the neuronal mechanisms associated with the reinforcing effects of alcohol and psychostimulants and have been extensively reviewed elsewhere (Kuhar, Ritz, & Boja, 1991; Ritz, George, & Kuhar, 1992; Ritz & Kuhar, in press). The reinforcing effects of cocaine and its analogues in animal models of cocaine self-administration have been associated with their effects at dopamine transporters and, thus, with their potency to block dopamine uptake in mesolimbocortical nerve terminals (Bergman, Madras, Johnson, & Spealman, 1989; Kuhar et al, 1991; Ritz, Lamb, Goldberg, & Kuhar, 1987).…”

Section: Neuropharmacology Of Reward and Motivationmentioning

confidence: 99%

A psychopharmacology of motivation and reward related to substance abuse treatment.

George¹,

Ritz²

1993

Experimental and Clinical Psychopharmacology

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Section: Neuropharmacology Of Reward and Motivationmentioning

confidence: 99%

A psychopharmacology of motivation and reward related to substance abuse treatment.

George¹,

Ritz²

1993

Experimental and Clinical Psychopharmacology

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Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate

Rothman¹,

Silverthorn²,

Glowa³

et al. 1998

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[125I]RTI-55 is a cocaine analog with high affinity for dopamine (DA) and serotonin (5-HT) transporters. Quantitative ligand binding studies revealed a novel high affinity [125I]RTI-55 binding site assayed under 5-HT transporter (SERT) conditions which has low affinity for almost all classic biogenic amine transporter ligands, including high affinity 5-HT transporter inhibitors such as paroxetine, but which retains high affinity for cocaine analogs. This site, termed SERT(site2) for its detection under 5-HT transporter conditions (not for an association with the SERT) occurs in monkey caudate, human caudate, and guinea pig caudate membranes, but not in rat caudate membranes. SERT(site2) is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand-selectivity profile, the inability to detect SERT(site2) in cells stably expressing the cloned human DAT, and insensitivity to irreversible ligands which inhibit [125I]RTI-55 binding to the DAT and SERT. Perhaps the most striking finding about SERT(site2) is that a wide range of representative antidepressant agents have very low affinity for SERT(site2). The affinity of cocaine for this site is not very different from the concentration cocaine achieves in the brain at pharmacological doses. Viewed collectively with the observation that ligands with high affinity for SERT(site2) are mostly cocaine analogs, these data lead us to speculate that actions of cocaine which differ from those of classic biogenic amine uptake inhibitors may be mediated in part via SERT(site2).

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Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library

Rothman

Baumann

Dersch

et al. 1999

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The acute reinforcing effects of cocaine are thought by some to result from cocaine binding to the dopamine (DA) transporter, which inhibits DA uptake and increases synaptic DA levels in the mesolimbic system. Other data suggest that neurotransmitters other than DA contribute to cocaine reinforcement and addiction. These considerations illustrate the need to have additional research tools with which to test the "DA hypothesis." One strategy is to identify drugs which bind to the DA transporter (DAT ligands) but which do not inhibit DA uptake as effectively as cocaine. The purpose of the present study was to identify members of a novel structural class of DAT ligands and to characterize their interactions at the DA transporter. A positional scanning hexapeptide D-amino acid library was screened for inhibition of [(125)I]RTI-55 binding to rat caudate DA transporters. Based on the results, 12 peptides were synthesized. All 12 peptides inhibited [(125)I]RTI-55 binding to DA transporters with IC(50) values, which ranged from 1.8 microM to 12 microM. The two most potent peptides (TPI-669-1 and TPI-669-4) were prepared in larger quantities and were characterized further for activity at the DAT and 5-HT transporter. Both peptides inhibited DA and 5-HT uptake and transporter binding with IC(50)/K(i) values in the low micromolar range. In vivo microdialysis studies demonstrated that both peptides increase extracellular DA and 5-HT in the nucleus accumbens of rats. These data demonstrate that peptides can function as inhibitors of biogenic amine transport. Future work will focus on developing more potent and selective peptides. Published 1999 Wiley-Liss, Inc.

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Molecular Mechanisms Associated with Cocaine Effects

Cited by 14 publications

References 174 publications

A psychopharmacology of motivation and reward related to substance abuse treatment.

A psychopharmacology of motivation and reward related to substance abuse treatment.

Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate

Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library

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