Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys

Nicholson, Katherine L.; Hayes, Belinda A.; Balster, Robert L.

doi:10.1007/s002130051087

Cited by 46 publications

(28 citation statements)

References 41 publications

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“…These results are consistent with and extend the results of a recently published study in which a 30 mg/kg dose of dextromethorphan (s.c.) did not substitute for nicotine and did not antagonize nicotine's discriminative stimulus effects (Zakharova et al, 2005). Other research has shown that dextromethorphan and dextrorphan, both administered i.p., fully and dose-dependently substituted for the noncompetitive NMDA open channel blocker phencyclidine in rats (Nicholson et al, 1999). With s.c. administration, however, only dextrorphan substituted fully for phencyclidine, with dextromethorphan producing only partial substitution (Nicholson et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Other research has shown that dextromethorphan and dextrorphan, both administered i.p., fully and dose-dependently substituted for the noncompetitive NMDA open channel blocker phencyclidine in rats (Nicholson et al, 1999). With s.c. administration, however, only dextrorphan substituted fully for phencyclidine, with dextromethorphan producing only partial substitution (Nicholson et al, 1999). These results suggest that NMDA antagonism cannot fully account for the stimulus properties of dextromethorphan when metabolism to dextrorphan is attenuated.…”

Section: Discussionmentioning

confidence: 99%

“…In rats, three times as much dextrorphan is formed from dextromethorphan after intraperitoneal injection than after s.c. injection (Wu et al, 1995). Indeed, there is evidence that most of the observed effects of dextromethorphan in behavioral paradigms that are sensitive to NMDA receptor antagonism are mediated by dextrorphan (Nicholson et al, 1999;Szekely et al, 1991), although there are also contradictory findings (Holtzman, 1994).…”

Section: Methodsmentioning

confidence: 99%

“…Dextromethorphan and dextrorphan share a number of in vivo pharmacological effects in rodents, including phencyclidine-like discriminative stimulus effects (Nicholson et al, 1999), suppression of self-administration of abused substances (Glick et al, 2001), antinociception (France et al, 1989), neuroprotective properties (Steinberg et al, 1993), disruption of prepulse inhibition of acoustic startle (Wiley et al, 2003), and anticonvulsant effects (Tortella & Musacchio, 1986). The degree to which these similar effects are produced by a common mechanism is uncertain, however, because the two drugs have somewhat divergent profiles in receptor binding and functional in vitro assays.…”

Section: Introductionmentioning

confidence: 99%

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Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

Wright

Vann

Gamage

et al. 2006

Pharmacology Biochemistry and Behavior

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While the role of dextrorphan and dextromethorphan as N-methyl-D-aspartate (NMDA) receptor antagonists has received considerable research attention, their effects on nicotinic acetylcholine receptors (nAChR) has been less well characterized. Recent in vitro and in vivo research has suggested that these drugs noncompetitively block α3β4*, α4β2, and α7 nAChR subtypes and antagonize nicotine's antinociceptive and reinforcing effects. Both drugs were most potent at blocking α3β4* AChR. This study investigated the effects of dextrorphan and dextromethorphan on nicotine's discriminative stimulus effects. Three groups of rats were trained in a two-lever drug discrimination procedure to discriminate 0.4 mg/kg s.c. nicotine from saline. Nicotine dose-dependently substituted for itself in all three groups. In contrast, when dextrorphan (group 1) or dextromethorphan (group 2) were injected i.p., neither substitution for nor antagonism of nicotine was observed for either drug. Since i.p. administration allows substantial metabolism of dextromethorphan to its parent compound dextrorphan, the two drugs were also tested following s.c. administration (group 3). Discrimination results were similar across both routes of administration, in that neither substitution nor antagonism occurred, however, s.c. administration reduced response rates to a much greater extent than did i.p. administration. Previous work suggests that β2 subunits are crucial for mediation of nicotine's discriminative stimulus effects and may play a role in its reinforcing effects, albeit other research suggests a role for α3β4* nicotinic receptors in the latter. Our results suggest that α3β4* nicotinic receptors do not play a major role in nicotine's discriminative stimulus effects. Further, they suggest that the role of cholinergic mediation of the behavioral effects of dextrorphan and dextromethorphan related to the abuse properties of nicotine may be minimal.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

Wright

Vann

Gamage

et al. 2006

Pharmacology Biochemistry and Behavior

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“…For example, dextromethorphan is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (Church et al, 1985;Church et al, 1989;Franklin and Murray, 1992). In rats and monkeys, dextromethorphan produces discriminate stimuli that generalize to phencyclidine (PCP) and other noncompetitive NMDA receptor antagonists (Holtzman, 1994;Nicholson et al, 1999). Like other noncompetitive NMDA receptor antagonists, such as PCP, dextromethorphan produces ataxia, and stereotypy in rats (Székely et al, 1991;Ishmael et al, 1998) and psychotomimetic and ethanollike effects and is subject to abuse in humans (Jasinski et al, 1971;Fleming, 1986;Orrell and Campbell, 1986;Mortimer et al, 1989;Bem and Peck, 1992;Steinberg et al, 1996;Soyka et al, 2000).…”

mentioning

confidence: 99%

Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis

Pechnick¹,

Poland²

2004

J Pharmacol Exp Ther

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Dextromethorphan is a weak noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is metabolized in vivo to dextrorphan, a more potent noncompetitive NMDA antagonist that is the dextrorotatory enantiomer of the opioid agonist levorphanol. The present study characterized the effects of the acute administration of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal (HPA) axis in the rat and tested the involvement of opioid receptors in the responses produced by dextrorphan and levorphanol. Although both dextromethorphan and dextrorphan increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, the dextromethorphan-induced responses occurred more rapidly than the dextrorphan-induced responses. The analysis of plasma levels of dextrorphan produced after the administration of dextromethorphan indicates that the concentration of dextrorphan formed was too low to be pharmacologically relevant, suggesting that at least some of the effects on the HPA axis are due to the parent compound, and not the metabolite. Naloxone (2 mg/kg) had no effect on the dextrorphan-induced increases in plasma levels of ACTH and corticosterone, but it blocked the levorphanol-induced increases. These results support the hypothesis that dextromethorphan has pharmacological activity aside from its biotransformation to dextrorphan and demonstrate that the effects of dextrorphan are not mediated by opioid receptors.

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Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling – A case study of dextromethorphan modified release tablets

Gundeti,

Murthy,

Jamdade

et al. 2024

Biopharm & Drug Disp

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The United States Food and Drug Administration guidelines for the bioequivalence (BE) testing of the generic drug products suggests that there should be an equal proportion of male and female population in the BE study. Despite this requirement, many generic drug companies do not maintain the suggested proportion of female population in their studies. Several socio‐economic and cultural factors lead to lower participation of the females in the BE studies. More recently, the regulatory agencies across the globe are requesting the generic drug companies to demonstrate the performance of their drug products in the under‐represented sex via additional studies. In this work, we describe the case of Dextromethorphan modified release tablets where the gender effect on the product performance was evaluated by physiologically based pharmacokinetic (PBPK) modeling approach. We have compared the drug product's performance by population simulations considering four different scenarios. The data from all‐male population (from in house Pharmacokinetic [PK] BE studies) was considered as a reference and other scenarios were compared against the all‐male population data. In the first scenario, we made a comparison between all‐male (100% male) vs all‐female (100% female) population. Second scenario was as per agency’s requirements—equal proportion of male and female in the BE study. As an extreme scenario, 100% male vs 30:70 male:female was considered (higher females than males in the BE studies). Finally, as a more realistic scenario, 100% male versus 70:30 male:female was considered (lower females than males in the BE studies). Population PK followed by virtual BE was employed to demonstrate the similarity/differences in the drug product performance between the sexes. This approach can be potentially utilized to seek BE study waivers thus saving cost and accelerating the entry of the generic products to the market.

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Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys

Cited by 46 publications

References 41 publications

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis

Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling – A case study of dextromethorphan modified release tablets

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