Disposition and metabolism of [3H] cocaine in acutely and chronically treated monkeys

Misra, Aditi; Giri, Varun; Patel, Mehul; Alluri, V.R.; Mulé, S. J.

doi:10.1016/0376-8716(77)90004-7

Cited by 39 publications

(26 citation statements)

References 13 publications

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“…Norcocaine, the N-demethylated metabolite of cocaine in rat (e.g. Nayak et al, 1976) dog (Misra, Patel, Alluri, Mule, Najak, 1976), monkey (Hawks, Kopin, Colburn & Thoa, 1974;Misra, Giri, Patel, Alluri & Mule, 1977) and possibly also in man (Inaba, Stewart & Kalow, 1978), was about 2.5 times more potent than cocaine. The potency relationships were fairly similar at both the 15 and 60 min tests indicating only slight differences in the rate of decay of the stimulus effects of these compounds during this time interval.…”

Section: Discussionmentioning

confidence: 99%

“…The potency order of the cocaine analogues in our pigeons was WIN 35,428>WIN 35,065-2 > cocaine, which is consonant with previously reported rankings (Clarke et al, 1973;Heikkila et al, 1979;Spealman etal., 1977) although the magnitude of the potency differences appears to be related to both the dependent variable and the species used. Since cocaine is extensively metabolized, primarily by hydrolysis of the ester groups, to more polar metabolites in vivo (Archer & Hawks, 1976;Nayak, Misra & Mule, 1976) it has been suggested (Spealman et al, 1977; that the metabolism of the WIN compounds, where the benzene ring is attached directly to the tropane configuration, may be slowed down because of the elimination of the esteratic link and as a consequence, may result in a more prolonged duration of action.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Järbe

1981

British J Pharmacology

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1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,. Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), A9-tetrahydrocannabinol (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively. 4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus. 5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Järbe

1981

British J Pharmacology

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“…Three studies assessed the pharmacokinetic and behavioral effects of i.v. cocaine in male and female rhesus monkeys (Misra et al, 1977;Saady et al, 1994Saady et al, , 1995, but they did not directly compare males and females and did not control for menstrual cycle phase. Mello, Mendelson and co-workers have conducted a series of elegant studies investigating the effects of cocaine on gonadal and pituitary hormones in rhesus monkeys.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys

Evans

Foltin

2004

Neuropsychopharmacol

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Several studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Female rhesus monkeys have menstrual cycles that are remarkably similar to human menstrual cycles in both duration and hormonal variations. Therefore, data obtained in monkeys should be an ideal model for assessing the effects of cocaine across the menstrual cycle in humans. The present study assessed the acute effects of intravenous cocaine (0, 0.25, 0.50, and 1.00 mg/kg) in five female rhesus monkeys during four phases of the menstrual cycle: menses, midfollicular, periovulatory, and midluteal. To reduce the effects of stress that can occur from sedation, all animals were trained to enter primate chairs so that repeated blood samples could be obtained in awake animals. Hormone levels for estradiol and progesterone were measured each session before cocaine administration. Cocaine and cocaine metabolite plasma levels were measured at 5, 15, 30, 45, 60, and 90 min after cocaine administration. Similarly, levels of luteinizing hormone (LH) were measured before, 15, 30, 45, 60, and 90 min after cocaine administration. Within 5 min of cocaine administration, cocaine plasma levels peaked and dose-dependent behavioral changes (ie increased motor activity, mydriasis, and refusal of treats) were observed. These effects typically resolved in 15-30 min. There were few differences in the pharmacokinetic profile of cocaine across the menstrual cycle. However, the cocaine metabolites, BZE and EME, did vary across the menstrual cycle, with both being increased in the luteal phase, particularly following the highest dose of cocaine. In addition, unlike previous studies, cocaine did not produce consistent increases in LH levels. Rather, the change in LH levels depended on menstrual cycle phase and cocaine dose. In summary, there is little evidence that the pharmacokinetics of cocaine vary as a function of menstrual cycle phase.

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“…cocaine resulted in hyperactivity and agitated behavior, and because the convulsant dose range for cocaine is 3 to 8 mg/kg i.v. (Matsuzaki et al, 1976;Misra et al, 1977). Cocaine or placebococaine was administered over 10 s into the saphenous vein of the leg opposite the exfusion catheter.…”

Section: Cocaine Administrationmentioning

confidence: 99%

Ovarian Steroid Hormone Modulation of the Acute Effects of Cocaine on Luteinizing Hormone and Prolactin Levels in Ovariectomized Rhesus Monkeys

Mello

Mendelson²,

Negus³

et al. 2003

J Pharmacol Exp Ther

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Cocaine stimulates significant increases in luteinizing hormone (LH) and decreases prolactin levels in gonadally intact rhesus monkeys, but cocaine did not alter plasma levels of these anterior pituitary hormones in ovariectomized females. These findings suggested that ovarian steroid hormones may contribute to the endocrine effects of acute cocaine administration. To test this hypothesis, the acute effects of cocaine and placebococaine on plasma LH and prolactin levels were examined in five ovariectomized rhesus females during three chronic hormone replacement conditions: 1) estradiol (E 2 ␤) treatment (0.0015-0.006 mg/kg/day i.m.), 2) progesterone treatment (0.32 mg/kg/day i.m.), and 3) combinations of progesterone (0.32 mg/ kg/day i.m.) and E 2 ␤ (0.002 and 0.004 mg/kg/day i.m.). Cocaine (0.8 mg/kg i.v.) did not alter prolactin or LH in ovariectomized monkeys without ovarian steroid replacement. During chronic estradiol treatment, cocaine produced an estradiol dosedependent decrease in prolactin. Cocaine also decreased prolactin during treatment with progesterone alone and progesterone ϩ E 2 ␤ (0.004 mg/kg/day i.m.). Cocaine stimulated a significant increase in LH during treatment with progesterone alone, but not during treatment with progesterone ϩ E 2 ␤, or three of four estradiol treatment doses. Cocaine pharmacokinetics did not differ as a function of hormone replacement conditions. Together, these data suggest that both E 2 ␤ and progesterone modulate cocaine's effects on prolactin, whereas E 2 ␤ alone and in combination with progesterone, do not facilitate LH release in response to cocaine in ovariectomized rhesus females.

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Disposition and metabolism of [3H] cocaine in acutely and chronically treated monkeys

Cited by 39 publications

References 13 publications

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys

Ovarian Steroid Hormone Modulation of the Acute Effects of Cocaine on Luteinizing Hormone and Prolactin Levels in Ovariectomized Rhesus Monkeys

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