Modulation of the discriminative stimulus effects of triazolam across the menstrual cycle phase in healthy pre-menopausal women

Babalonis, Shanna; Emurian, Cleeve S.; Martin, Catherine A.; Lile, Joshua A.; Kelly, Thomas C.

doi:10.1016/j.drugalcdep.2007.11.007

Cited by 7 publications

(9 citation statements)

References 33 publications

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“…This experiment used well-established drug-discrimination procedures in which subjects learn to discriminate between a Drug condition (i.e., 25 mg Δ 9 -THC) and a Not Drug condition (i.e., placebo) (e.g., Babalonis et al, 2008; Griffiths et al, 1990; Heishman and Henningfield, 1991; Lile et al, 2004, 2005a,b, 2006, 2007; Stoops et al, 2005, 2006; Rush et al, 2000, 2003). We chose to use a Drug versus Not Drug discrimination because instructing subjects to discriminate these conditions have yielded results that are more consistent with the pharmacology of drugs compared to studies that instruct subjects to discriminate between Drug A and Drug B (e.g., active versus placebo) as the training conditions.…”

Section: Methodsmentioning

confidence: 99%

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

et al. 2008

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Rationale Preclinical evidence suggests that non-cannabinoid neurotransmitter systems are involved in the behavioral and physiological effects of cannabinoids, but relatively little research has been conducted in humans. Objectives The aims of this study were to assess whether oral Δ 9 -tetrahydrocannabinol (Δ 9 -THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Methods Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Δ 9 -THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., ≥80% drug-appropriate responding for four consecutive sessions), multiple doses of Δ 9 -THC, the GABA A positive modulator triazolam, the µ-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Δ 9 -THC. Results Eight subjects (N=8) accurately discriminated Δ 9 -THC and completed the study. The training dose of Δ 9 -THC functioned as a discriminative stimulus and produced prototypical subject-rated drug effects. All of the drugs Psychopharmacology (2009) 203:241-250 DOI 10.1007/s00213-008-1393 This research and the preparation of this manuscript were supported by grants from the National Institute on Drug Abuse (K01 DA018772) and the University tested produced significant effects on the self-report questionnaires, but only Δ 9 -THC substituted for the training dose. Conclusion These results suggest that the discriminativestimulus effects of Δ 9 -THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study.

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Section: Methodsmentioning

confidence: 99%

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

et al. 2008

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“…Finally, the behavioral effects of GABAergic drugs are enhanced during menstrual cycle phases in which progesterone levels are elevated. For example, the discriminative stimulus effects of ethanol in nonhuman primates (Grant et al 1997; Green et al 1999) and triazolam in humans (Babalonis et al 2008) are enhanced during the mid-luteal phase of the menstrual cycle when progesterone levels surge. However, menstrual cycle modulation of GABAergic drug effects have not been replicated across all studies (Rukstalis and de Wit 1999; Holdstock and de Wit 2000) and may depend on the experimental conditions (e.g., behavioral measures, drugs, and/or doses that are tested).…”

Section: Introductionmentioning

confidence: 99%

“…The moderate dose of triazolam (0.12 mg/70 kg) was selected because it is minimally behaviorally active when administered alone, but is sensitive to hormonal variations (Babalonis et al 2008). The high dose of triazolam (0.25 mg/70 kg) was selected because it is a standard therapeutic dose that has measurable behavioral effects in isolation.…”

Section: Introductionmentioning

confidence: 99%

Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women

et al. 2011

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Rationale Gender plays a critical role in the effects of drugs and drug abuse liability. Biological factors, including ovarian hormones, may contribute to gender differences in drug abuse. Preclinical and some clinical research suggests that progesterone and its metabolites have activity at the GABAA receptor and may enhance the effect of GABAergic compounds (e.g., benzodiazepines). Because women are exposed to varying levels of progesterone from puberty until menopause, and appear more sensitive to the negative consequences of benzodiazepine use, it is important to understand the impact of progesterone on GABAergic drug effects. Objectives The purpose of this experiment was to characterize the behavioral effects of progesterone, alone and in combination with the short-acting benzodiazepine, triazolam, to determine if progesterone potentiates the behavioral effects of triazolam. Methods Oral micronized progesterone (0, 100, and 200 mg) and oral triazolam (0.00, 0.12, and 0.25 mg/70 kg) were administered to healthy, premenopausal women (n=11) under conditions of low circulating sex hormones. The subjective, performance and physiological effects of progesterone, alone and in combination with triazolam, were assessed. Results Triazolam alone produced prototypical sedative-like effects. Progesterone alone also engendered some sedative effects, although the time course of the effects was more limited than that of triazolam. Progesterone increased and extended the duration of triazolam effects and delayed the onset of triazolam peak effects, most notably at the 0.12 mg/70 kg dose. Conclusions Progesterone potentiates the behavioral effects of benzodiazepines and may contribute to benzodiazepine use and abuse among women.

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“…Both pre-clinical and clinical research indicates that neurosteroids modulate the rewarding, discriminative stimulus and performance effects of several drugs of abuse (McAuley et al, 1995; White et al, 2002; Justice et al, 1999; Lynch et al, 2002; Lile et al, 2007; Babalonis et al, 2008). Although genomic effects of sex steroids are well-established, progesterone and its metabolites, allopregnanolone and TH-DOC, also have non-genomic effects at binding sites on neuronal membrane-bound receptors and also modulate the activity of GABA, dopamine, opioid, glutamate and nicotinic acetylcholine receptors (Pluchino et al, 2006; Lena et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…The discriminative stimulus effects of ethanol in non-human primates are enhanced during the mid-luteal phase, when endogenous progesterone levels are elevated (Grant et al, 1997, Green et al, 1999). Clinical drug discrimination studies have also shown cycle modulation of benzodiazepine behavioral effects, with potentiation of the discriminative stimulus effects of triazolam occurring during the mid-luteal phase (relative to the early follicular phase), in healthy, premenopausal women (Babalonis et al, 2008). However, other studies have reported no cycle phase modulation of the subjective and performance-impairing effects of GABAergic drug effects (i.e., triazolam, ethanol) in premenopausal women (Holdstock & de Wit, 2000; Rukstalis & de Wit, 1999).…”

Section: Introductionmentioning

confidence: 99%

Progesterone effects on the discriminative stimulus, subjective and performance effects of triazolam in healthy, premenopausal women

Babalonis

Lile²,

Martin³

et al. 2011

Behavioural Pharmacology

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There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by progesterone metabolites. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABAA receptors. The purpose of this experiment was to determine the independent and combined discriminative stimulus, subjective and psychomotor effects of progesterone and triazolam in healthy adult premenopausal women. Oral micronized progesterone (100 mg), triazolam (0.06, 0.12 and 0.25 mg/70 kg) and placebo were administered to healthy, premenopausal women (n =9) under conditions of low circulating sex hormones. Triazolam alone functioned as a discriminative stimulus and produced prototypical sedative-like effects (e.g., performance impairment, enhanced reports of sedative effects). Progesterone alone produced sedative-like effects on several subjective and performance measures and the dose combination effects of progesterone and triazolam on several subjective measures of drug effect were similar to the summation of the two drug effects in isolation. Progesterone did not substitute for or modify the discriminative stimulus effects of triazolam. These results suggest that the parent hormone, progesterone, and triazolam have discordant neuropharmacological mechanisms of action. Additional research is necessary to determine the degree to which neurosteroids influence sex differences in benzodiazepine use and abuse.

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Modulation of the discriminative stimulus effects of triazolam across the menstrual cycle phase in healthy pre-menopausal women

Cited by 7 publications

References 33 publications

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women

Progesterone effects on the discriminative stimulus, subjective and performance effects of triazolam in healthy, premenopausal women

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