A cocaine analog, 2β-propanoyl-3β-(4-tolyl)-tropane (PTT), reduces tyrosine hydroxylase in the mesolimbic dopamine pathway

Willard M. Freeman, George J. Yohrling IV, James B. Daunais, Lynda Gioia, Stephanie L. Hart, Linda J. Porrino, Huw M.L. Davies, Kent Vrana

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Previously published results have established that chronic cocaine administration (30-45 mg/kg per day, 10-14 days) resulted in an upregulation of TH gene expression in dopaminergic pathways of rats. The present studies tested the effects of a tropane analog, PTT (2β-propanoyl-3β-(4-tolyl)-tropane), on TH expression. This drug has similar actions to cocaine, but possesses markedly different pharmacokinetics (20 times more potent at binding the dopamine transporter, markedly increased metabolic stability, and 10-20 times more potent in behavioral measures). Moreover, PTT demonstrates an increased selectivity for the dopamine (DA) and norepinephrine (NE) transporters compared with cocaine. In direct contrast to the previously reported effects of cocaine, 10 days of PTT administration (3.0 mg/kg per day, i.p.) produced a uniform downregulation of TH protein and activity gene expression. TH activity and immunoreactive protein where decreased by 54 and 69%, respectively in the nucleus accumbens. Within the ventral tegmental area, TH activity and protein were decreased by 33 and 19%, respectively. The underlying mechanisms for these fundamental differences are unclear, but likely reflect varying and selective affinities and lengths of occupancy at biogenic amine transporters.(C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)15-21
Number of pages7
JournalDrug and Alcohol Dependence
Volume61
Issue number1
DOIs
StatePublished - Dec 22 2000

Fingerprint

Tyrosine 3-Monooxygenase
Cocaine
Dopamine
Dopamine Plasma Membrane Transport Proteins
Gene expression
Tropanes
Norepinephrine Plasma Membrane Transport Proteins
Gene Expression
Ventral Tegmental Area
Proteins
Biogenic Amines
Pharmacokinetics
Biosynthesis
Nucleus Accumbens
Catecholamines
2-propanoyl-3-(4-tolyl)tropane
Rats
Up-Regulation
Down-Regulation
Enzymes

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Freeman, Willard M. ; Yohrling IV, George J. ; Daunais, James B. ; Gioia, Lynda ; Hart, Stephanie L. ; Porrino, Linda J. ; Davies, Huw M.L. ; Vrana, Kent. / A cocaine analog, 2β-propanoyl-3β-(4-tolyl)-tropane (PTT), reduces tyrosine hydroxylase in the mesolimbic dopamine pathway. In: Drug and Alcohol Dependence. 2000 ; Vol. 61, No. 1. pp. 15-21.
@article{9df3b43666d94761b68f54ad68b2b427,
title = "A cocaine analog, 2β-propanoyl-3β-(4-tolyl)-tropane (PTT), reduces tyrosine hydroxylase in the mesolimbic dopamine pathway",
abstract = "Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Previously published results have established that chronic cocaine administration (30-45 mg/kg per day, 10-14 days) resulted in an upregulation of TH gene expression in dopaminergic pathways of rats. The present studies tested the effects of a tropane analog, PTT (2β-propanoyl-3β-(4-tolyl)-tropane), on TH expression. This drug has similar actions to cocaine, but possesses markedly different pharmacokinetics (20 times more potent at binding the dopamine transporter, markedly increased metabolic stability, and 10-20 times more potent in behavioral measures). Moreover, PTT demonstrates an increased selectivity for the dopamine (DA) and norepinephrine (NE) transporters compared with cocaine. In direct contrast to the previously reported effects of cocaine, 10 days of PTT administration (3.0 mg/kg per day, i.p.) produced a uniform downregulation of TH protein and activity gene expression. TH activity and immunoreactive protein where decreased by 54 and 69{\%}, respectively in the nucleus accumbens. Within the ventral tegmental area, TH activity and protein were decreased by 33 and 19{\%}, respectively. The underlying mechanisms for these fundamental differences are unclear, but likely reflect varying and selective affinities and lengths of occupancy at biogenic amine transporters.(C) 2000 Elsevier Science Ireland Ltd.",
author = "Freeman, {Willard M.} and {Yohrling IV}, {George J.} and Daunais, {James B.} and Lynda Gioia and Hart, {Stephanie L.} and Porrino, {Linda J.} and Davies, {Huw M.L.} and Kent Vrana",
year = "2000",
month = "12",
day = "22",
doi = "10.1016/S0376-8716(00)00119-8",
language = "English (US)",
volume = "61",
pages = "15--21",
journal = "Drug and Alcohol Dependence",
issn = "0376-8716",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

A cocaine analog, 2β-propanoyl-3β-(4-tolyl)-tropane (PTT), reduces tyrosine hydroxylase in the mesolimbic dopamine pathway. / Freeman, Willard M.; Yohrling IV, George J.; Daunais, James B.; Gioia, Lynda; Hart, Stephanie L.; Porrino, Linda J.; Davies, Huw M.L.; Vrana, Kent.

In: Drug and Alcohol Dependence, Vol. 61, No. 1, 22.12.2000, p. 15-21.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A cocaine analog, 2β-propanoyl-3β-(4-tolyl)-tropane (PTT), reduces tyrosine hydroxylase in the mesolimbic dopamine pathway

AU - Freeman, Willard M.

AU - Yohrling IV, George J.

AU - Daunais, James B.

AU - Gioia, Lynda

AU - Hart, Stephanie L.

AU - Porrino, Linda J.

AU - Davies, Huw M.L.

AU - Vrana, Kent

PY - 2000/12/22

Y1 - 2000/12/22

N2 - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Previously published results have established that chronic cocaine administration (30-45 mg/kg per day, 10-14 days) resulted in an upregulation of TH gene expression in dopaminergic pathways of rats. The present studies tested the effects of a tropane analog, PTT (2β-propanoyl-3β-(4-tolyl)-tropane), on TH expression. This drug has similar actions to cocaine, but possesses markedly different pharmacokinetics (20 times more potent at binding the dopamine transporter, markedly increased metabolic stability, and 10-20 times more potent in behavioral measures). Moreover, PTT demonstrates an increased selectivity for the dopamine (DA) and norepinephrine (NE) transporters compared with cocaine. In direct contrast to the previously reported effects of cocaine, 10 days of PTT administration (3.0 mg/kg per day, i.p.) produced a uniform downregulation of TH protein and activity gene expression. TH activity and immunoreactive protein where decreased by 54 and 69%, respectively in the nucleus accumbens. Within the ventral tegmental area, TH activity and protein were decreased by 33 and 19%, respectively. The underlying mechanisms for these fundamental differences are unclear, but likely reflect varying and selective affinities and lengths of occupancy at biogenic amine transporters.(C) 2000 Elsevier Science Ireland Ltd.

AB - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Previously published results have established that chronic cocaine administration (30-45 mg/kg per day, 10-14 days) resulted in an upregulation of TH gene expression in dopaminergic pathways of rats. The present studies tested the effects of a tropane analog, PTT (2β-propanoyl-3β-(4-tolyl)-tropane), on TH expression. This drug has similar actions to cocaine, but possesses markedly different pharmacokinetics (20 times more potent at binding the dopamine transporter, markedly increased metabolic stability, and 10-20 times more potent in behavioral measures). Moreover, PTT demonstrates an increased selectivity for the dopamine (DA) and norepinephrine (NE) transporters compared with cocaine. In direct contrast to the previously reported effects of cocaine, 10 days of PTT administration (3.0 mg/kg per day, i.p.) produced a uniform downregulation of TH protein and activity gene expression. TH activity and immunoreactive protein where decreased by 54 and 69%, respectively in the nucleus accumbens. Within the ventral tegmental area, TH activity and protein were decreased by 33 and 19%, respectively. The underlying mechanisms for these fundamental differences are unclear, but likely reflect varying and selective affinities and lengths of occupancy at biogenic amine transporters.(C) 2000 Elsevier Science Ireland Ltd.

UR - http://www.scopus.com/inward/record.url?scp=0034703982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034703982&partnerID=8YFLogxK

U2 - 10.1016/S0376-8716(00)00119-8

DO - 10.1016/S0376-8716(00)00119-8

M3 - Article

VL - 61

SP - 15

EP - 21

JO - Drug and Alcohol Dependence

JF - Drug and Alcohol Dependence

SN - 0376-8716

IS - 1

ER -