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Background Progesterone-derived neuroactive steroids have shown promise clinically (e.g., anti-seizure medications) but, as with other GABAA receptor modulators (e.g., benzodiazepines), may have the potential for abuse. Methods We evaluated the reinforcing effects of progesterone, a steroid precursor of endogenous neuroactive steroids, with and without pretreatments with the neuroactive steroid synthesis inhibitor, finasteride, in rhesus monkeys trained under a progressive-ratio (PR) schedule of i.v. midazolam injection. We also assessed reinforcing effects of the short-acting neuroactive steroid alphaxolone and the long-acting neuroactive steroid ganaxolone in comparison with the short-acting benzodiazepine triazolam and the long-acting benzodiazepine clonazepam. Results At least one dose of progesterone, alphaxolone, and ganaxolone was self-administered significantly above vehicle levels in all monkeys tested (n = 4 for progesterone, n = 3 for alphaxolone and ganaxolone). The 5α-reductase inhibitor finasteride attenuated progesterone self-administration, consistent with the reinforcing effects of progesterone being mediated by the in vivo synthesis of neuroactive steroids. The comparison drugs, triazolam and clonazepam, were self-administered significantly above vehicle by all monkeys. Although the maximum number of injections/session maintained by the neuroactive steroids was below that maintained by the midazolam training dose, analysis of break points (i.e., highest response requirement achieved) suggested modest differences in relative reinforcing effectiveness for neuroactive steroids compared with benzodiazepines. Conclusions Our results are consistent with endogenous and synthetic neuroactive steroids having reinforcing effects similar to that of benzodiazepines, with reinforcing effectiveness possibly lower for the neuroactive steroids compared with benzodiazepines based on some measures.

Background Opioid-use disorder is associated with a high degree of co-abuse with benzodiazepines. While the mechanisms underlying the co-abuse of opioids and benzodiazepines remain unknown, α1 subunit-containing GABAA receptors may play a critical role in the reinforcing effects of benzodiazepine-type compounds, depending on whether the monkeys have a history of benzodiazepine or stimulant self-administration. The present study extended our prior research by comparing the reinforcing effects of a compound lacking activity at α1 subunit-containing GABAA receptors with the reinforcing effects of non-selective GABAA receptor positive allosteric modulators in monkeys with a history of opioid self-administration. Methods The reinforcing effects of L-838,417 (partial intrinsic efficacy at α2, α3, and α5 subunit-containing GABAA receptors, but no efficacy at α1 subunit-containing GABAA receptors, i.e., “α1-sparing compound”) were compared with those of the non-selective GABAA receptor partial modulator MRK-696, and non-selective GABAA receptor full modulators, triazolam and lorazepam, in rhesus monkeys (n = 3) experienced in remifentanil self-administration under a progressive-ratio schedule of intravenous drug injection. Results Neither the partial modulator nor the α1-sparing compound were self-administered above vehicle levels. The full modulators triazolam and lorazepam were self-administered significantly above vehicle levels, albeit at lower levels than remifentanil. Conclusions Our findings suggest that relatively high efficacy at one or more GABAA receptor subtypes is required for a compound to have reinforcing effects in monkeys with a history of remifentanil self-administration, in contrast to monkeys with benzodiazepine or stimulant self-administration histories.

Background Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. Methods Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 h. Results Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100–300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10–30 times the therapeutic dose of DXM. Conclusion The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100–300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse.

Background Conventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. Methods Rhesus monkeys (n = 4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose–response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABAA-preferring antagonists), and XLi-093 (α5GABAA-selective antagonist). Results Flumazenil, βCCT and 3-PBC shifted the dose–response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil = βCCT > 3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABAA and α3GABAA receptors, but not α1GABAA or α5GABAA receptor subtypes. Conclusions Our findings were not entirely consistent with blockade of α1GABAA receptors and are consistent with the possibility of α2GABAA and/or α3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABAA modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2–4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3–6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

The pentobarbital-like discriminative stimulus effects of the benzodiazepine receptor partial agonist panadiplon were assessed in rhesus monkeys trained to discriminate pentobarbital (10 mg/kg) from saline. In test sessions, pentobarbital and the benzodiazepine full agonist triazolam engendered near 100% drug-appropriate responding in all monkeys, whereas panadiplon engendered near 100% drug-appropriate responding in two of four monkeys. Panadiplon pretreatment resulted in leftward shifts in the pentobarbital dose-response function but predominantly rightward shifts of the triazolam dose-response function. These results are consistent with findings that benzodiazepine partial agonists have pentobarbital-like discriminative stimulus effects in some subjects only, and further suggest that partial agonists enhance the effects of pentobarbital but antagonize the effects of a benzodiazepine full agonist.

Zaleplon is a chemically novel hypnotic that preferentially binds alpha(1)-subunit containing subtypes of the alphabetagamma configuration of the gamma-aminobutyric acid (GABA)(A) receptor. Zaleplon and the non-subtype-selective hypnotic triazolam occasioned 100% drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital from vehicle. Flumazenil shifted the zaleplon generalization gradient at least five-fold to the right. A plasma elimination half-life of 6-8 h for oral 10 mg/kg zaleplon and 0.32 mg/kg triazolam was paralleled by discriminative control for 7 h. Zaleplon maintained self-injection greater than vehicle, as did comparison doses of the similarly selective hypnotic zolpidem and triazolam. Concurrent food-maintained responding increased during self-injection of all three drugs. Preferential binding at this alpha(1)-containing GABA(A) subtype did not diminish the benzodiazepine (Bzs)-like behavioral effects of zaleplon.

This report examines the validity of the Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI) for measuring subjective effects after the use of sedatives, stimulants, and opioids. Data from four clinical trials in which this questionnaire was used have been analyzed. The Spanish ARCI short form was found to be sensitive in measuring subjective effects after the administration of alcohol, triazolam, and flunitrazepam (sedatives), cocaine (stimulants), and morphine, pentazocine, and naloxone (opioids) and to distinguishing among them. The response patterns were similar to those previously reported for the same drugs with the English version of ARCI. It is concluded that Spanish version of the 49-item short form of ARCI is a valid instrument for assessing the subjective effects of psychoactive drugs in the Spanish-speaking population context.

The effects of placebo, triazolam (2.0, 4.0 and 8.0 μg/kg) and ethanol (0.25, 0.5, 1.0 g/kg) on perceptual-motor performance were examined using a visual pattern matching-to-sample procedure in which pattern size and comparison stimulus discriminability were systematically varied. Baseline response rates and accuracy increased as the discriminability of the comparison stimuli increased. At the highest dose, both drugs decreased response accuracy. This disruption of accuracy was attenuated by increasing the discriminability of non-matching stimuli. Triazolam produced dose-related decreases in response rate while ethanol produced only slight decreases at the highest baseline rates of responding. Thus, triazolam produced response rate slowing at relatively lower doses than ethanol.

Background Multiple substance use is a common problem among heroin users. This study aims to describe patterns of multiple substance use one year before and during attendance at methadone maintenance treatment (MMT) programs and associated variables of continued heroin use in MMT clinics in Yunnan, China. Methods The study was conducted among 168 heroin addicts who had received treatment for at least one year at two MMT clinics in Kunming city. A structured questionnaire, a medical record, and computer database were used to obtain history of substances use, significant clinical information, and treatment details, respectively. Results Heroin, tobacco, and alcohol were the most commonly used substances both before and during MMT. After one year in MMT, use of heroin, alcohol, tramadol, and triazolam significantly decreased whereas use of ephedrine increased. Simultaneous substance use was halved but the decrease was not statistically significant. The proportion of injecting users was reduced from 61% to 43%. History of heroin use in the preceding 6 months during MMT increased the odds of continued heroin use (OR=5.8, 95% CI=[2.9-11.3]). An average 10mg higher methadone dose increment was associated with a reduced odds of heroin use by 10%. Conclusion MMT did not reduce the number of substances used, but the number of injecting heroin users after the first year of treatment decreased. Heroin use in the preceding 6 months during MMT treatment and lower methadone dose were associated with continued heroin use in MMT.

Seven healthy normal male and female volunteers (19–42 years) were trained to discriminate between the benzodiazepine triazolam (0.32 mg/70 kg; e.g. drug A) and placebo (e.g. drug B). During the first four daily sessions, drug A and drug B were administered orally in capsules 60 min prior to the session on alternate days and subjects were informed of the drug label at the time of drug administration. Subsequently, drug A and drug B were administered in a randomized-block fashion and subjects identified the drug code they thought they received. Subjects were informed of the drug code post-session. Once the criterion for discrimination was met (i.e. correct drug code identification on four consecutive sessions), the dose-effect curve for triazolam (0.1-0.75 mg/70 kg) was determined. The discrimination was acquired in all subjects; triazolam (0.32 mg/70 kg) and placebo produced approximately 85–95% correct responding. During the dose-effect curve determination, triazolam produced dose-related increases in triazolam-appropriate responding and self-reported sedation and drug strength. These results indicate that a triazolam-placebo discrimination can be acquired and that the triazolam discriminative stimulus effect is related to dose and to self-reported sedation.

Pre-clinical studies indicate that changes in progesterone levels across menstrual cycle phases modulate the behavioral effects of sedative drugs acting at GABA(A) receptor sites. In this study, seven healthy women learned to discriminate triazolam (0.25 mg/70 kg) from placebo. After acquiring the discrimination, a range of triazolam doses (0.00, 0.06, 0.12 and 0.25 mg/70 kg) was tested during the early follicular and mid-luteal menstrual cycle phases. During the mid-luteal phase, when progesterone levels were elevated, 0.12 mg/70 kg triazolam was identified as the active triazolam training dose (0.25 mg/70 kg), whereas 0.12 mg/70 kg triazolam was identified as placebo during the early follicular phase, when progesterone levels were low. Triazolam engendered prototypical sedative effects on subjective effect, performance and cardiovascular measures that were generally independent of cycle phase. These results suggest that the discriminative stimulus effects of the positive GABA(A) modulator, triazolam, are sensitive to menstrual cycle phase in healthy adult women.

Modafinil is a novel stimulant that is effective in the treatment of narcolepsy and excessive daytime sleepiness. In vitro and in vivo neuropharmacological data suggest that the mechanism of action of modafinil is distinct from that of prototypical abused stimulants like cocaine and d -amphetamine. In the present experiment, six human volunteers with recent histories of cocaine use learned to discriminate 150 mg oral cocaine HCL. After acquiring the discrimination (i.e. ≥80% correct responding on 4 consecutive days), a range of doses of oral cocaine (50, 100, and 150 mg), modafinil (200, 400, and 600 mg), and placebo were tested to determine if they shared discriminative-stimulus and self-reported effects with 150 mg cocaine. Methylphenidate (60 mg) and triazolam (0.5 mg) were included as positive and negative controls, respectively. Cocaine and methylphenidate, but neither modafinil nor triazolam, produced cocaine-like discriminative-stimulus, subject-rated, and cardiovascular effects. The results of the present experiment suggest that cocaine discrimination in humans is pharmacologically specific within and across drug classes.

This study compared the discriminative stimulus effects of zolpidem, a nonbenzodiazepine hypnotic, to benzodiazepines. Eight participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. The discriminative stimulus effects, self-reported subjective effects, and performance effects of triazolam (0.05–0.35 mg/70 kg), alprazolam (0.25–1.75 mg/70 kg), zolpidem (2.5–35 mg/70 kg) and caffeine (75–525 mg/70 kg) were assessed under two-response and novel-response drug discrimination procedures. Under the two-response procedure, triazolam, alprazolam and zolpidem fully substitued for triazolam and caffeine did not. Under the novel-response procedure, triazolam and alprazolam substituted for triazolam and zolpidem partially substituted for triazolam. Zolpidem, but not triazolam or alprazolam, also produced some novel responding. Caffeine produced both placebo-appropriate and novel responding. The self-reported effects of triazolam, alprazolam and zolpidem were similar. Overall, zolpidem produced similar, but not identical, effects as the benzodiazepines.

University of Arkansas for Medical Sciences, Department of Pharmacology & Toxicology, 4301 W. Markham Street, Little Rock, AR 72205, USA Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224-6823, SA Department of Neuroscience, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224-6823, USA

The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate D-amphetamine (AMPH; n = 4), pentobarbital (PB; n = 3) or triazolam (n = 3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n = 2). GHB (0.01-10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0-178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT 1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0–32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1–3.2 mg/kg p.o.; 0.1–32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1–18 mg/kg, p.o.; 0.1–1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group, Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.

The present study examined the effects of repeated administration of diazepam (DZ) and triazolam (TZ) on psychomotor performance and subject-rated drug liking. Subjects were 11 males (30-41 years) who had documented histories of drug abuse and who resided on a behavioral pharmacology research ward. Six subjects received 80 mg DZ every third day (3 subjects) or every sixth day (3 subjects) for a total of 3-6 dosing occasions and six subjects received TZ (2.0 or 3.0 mg) every second day (4 subjects) or every third day (2 subjects) for a total of 3-5 dosing occasions. The results showed that on the first dose occasion, the two drugs produced generally similar degrees of psychomotor impairment and subject-rated drug liking. Following the first DZ dose, subsequent doses produced less of an effect (i.e. single-dose tolerance). Across at least the first three dose occasions, progressive tolerance development was observed with DZ but no tolerance was observed with TZ. It is hypothesized that pharmacokinetic differences between DZ and TZ may account for the difference in the development of tolerance.