Prescription psychostimulants for cocaine use disorder: A review from molecular basis to clinical approach.

Cocaine use is a public health concern in many countries worldwide, particularly in the Americas and Oceania. Overdose deaths involving stimulants, such as cocaine, have been increasing markedly in North America, especially with concurrent opioid involvement. To date, no pharmacological treatment is available to treat stimulant (including cocaine) use disorders. Prescription psychostimulants (PPs) could be useful to treat cocaine use disorder (CUD) as they share the pharmacological effects with cocaine, as evidenced by a recent meta-analysis that assessed 38 randomized clinical trials (RCTs). PPs were found to promote sustained abstinence and reduce drug use in patients with CUD. The aim of this paper is to provide a narrative review of the clinical pharmacology of PPs and comment on the current stage of evidence supporting PPs to treat CUD. We also propose a model of care that integrates PPs with evidence-based psychosocial interventions (such as cognitive-behavioural therapy [CBT] and contingency management [CM]), a harm reduction approach and case management with social support.

Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule.

This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 µg/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1-10 µg/kg/injection) or alprazolam (1.0-100 µg/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as "alprazolam-taking" and "non-alprazolam-taking" monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs' reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT: Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.

GABAA Receptor Subtypes and the Abuse-Related Effects of Ethanol in Rhesus Monkeys: Experiments with Selective Positive Allosteric Modulators.

BACKGROUND: Previous studies have investigated α1GABAA and α5GABAA receptor mechanisms in the behavioral effects of ethanol (EtOH) in monkeys. However, genetic studies in humans and preclinical studies with mutant mice suggest a role for α2GABAA and/or α3GABAA receptors in the effects of EtOH. The development of novel positive allosteric modulators (PAMs) with functional selectivity (i.e., selective efficacy) at α2GABAA and α3GABAA receptors allows for probing of these subtypes in preclinical models of the discriminative stimulus and reinforcing effects of EtOH in rhesus macaques. METHODS: In discrimination studies, subjects were trained to discriminate EtOH (2 g/kg, intragastrically) from water under a fixed-ratio (FR) schedule of food delivery. In oral self-administration studies, subjects were trained to self-administer EtOH (2% w/v) or sucrose (0.3 to 1% w/v) under an FR schedule of solution availability. RESULTS: In discrimination studies, functionally selective PAMs at α2GABAA and α3GABAA (HZ-166) or α3GABAA (YT-III-31) receptors substituted fully (maximum percentage of EtOH-lever responding ≥80%) for the discriminative stimulus effects of EtOH without altering response rates. Full substitution for EtOH also was engendered by a nonselective PAM (triazolam), an α5GABAA -preferring PAM (QH-ii-066) and a PAM at α2GABAA , α3GABAA , and α5GABAA receptors (L-838417). A partial (MRK-696) or an α1GABAA -preferring (zolpidem) PAM only engendered partial substitution (i.e., ~50 to 60% EtOH-lever responding). In self-administration studies, pretreatments with the functionally selective PAMs at α2GABAA and α3GABAA (XHe-II-053 and HZ-166) or α3GABAA (YT-III-31 and YT-III-271) receptors increased EtOH, but not sucrose, drinking at doses that had few, or no, observable sedative-motor effects. CONCLUSIONS: Our results confirm prior findings regarding the respective roles of α1GABAA and α5GABAA receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for α3GABAA and potentially α2GABAA receptors in several abuse-related effects of EtOH in monkeys. Moreover, they reveal a potential role for these latter subtypes in EtOH's sedative effects.

Effects of hydroalcoholic extract of Solidago chilensis Meyen on nociception and hypernociception in rodents.

BACKGROUND: Solidago chilensis (syn. microglossa) is a plant from the Asteraceae family widely distributed in South America and used to treat inflammatory diseases. In 2009, it was listed as one of the native medicinal herbal plants used in the Brazilian public health system. In addition to its anti-inflammatory properties, a recent clinical study has shown antinociceptive effects of S. chilensis, introducing a new potential medical use for this plant. The aim of the present study was to investigate the antinociceptive activity of the hydroalcoholic extract of Solidago chilensis (HESc) in rodent models of pain. METHODS: The dried plant extract was obtained from its aerial parts, maintained in ethanol (100 g/l) and filtered. Rats or mice were treated with intraperitoneal injections of HESc (3, 10 or 30 mg/kg) 30 min before being submitted to writhing, 0.2%-formaline or hot-plate tests or prostaglandin E2 (PGE2) administration in the hind paw. Mechanical hypernociception and motor impairment were evaluated by electronic von Frey and rota-rod, respectively. RESULTS: HESc dose-dependently inhibited abdominal contortions in the writhing test and attenuated phases I and II formalin-induced nociceptive behavior. Treatment with HESc also increased thermal threshold and decreased PGE2-induced hypernociception without promoting motor impairment. CONCLUSIONS: Our data suggest that, when systemically administered, HESc decreases nociception without inducing a sedative effect. Importantly, this effect was observed in both inflammatory and non-inflammatory models of pain and nociception, suggesting a specific non-inflammatory mechanism of HESc on pain. Our findings indicate that S. chilensis might be an important adjuvant in pain management.

Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study.

An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.

Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients.

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Suvorexant enhances oxycodone-induced respiratory depression in male rats.

BACKGROUND: Recent studies have proposed the use of dual orexin receptor antagonists, such as suvorexant, for the treatment of opioid use disorder (OUD) and opioid-related sleep disturbances because of orexin's role in sleep-wake regulation and addiction. Accumulating evidence suggests that orexin is also an important modulator of respiratory function, raising the possibility of adverse respiratory events when combining orexin antagonists and opioids. The aim of the present study was to investigate the effects of suvorexant, alone or in combination with the opioid oxycodone, on pulmonary ventilation in male rats. METHODS: Adult, male Sprague Dawley rats received treatments with vehicle, oxycodone (3 and 10mg/kg, i.p.) or suvorexant (10 and 18mg/kg, i.p.), and respiratory measures were obtained using whole-body plethysmography. We then tested the effects of a combination of suvorexant (10 and 18mg/kg, i.p.) and the highest dose of oxycodone that did not suppress respiration alone (3mg/kg, i.p). RESULTS: Oxycodone induced respiratory depression at 10mg/kg, but not 3.0mg/kg; as evident by significant decreases in minute volume (mls/min) and tidal volume (mls). Suvorexant alone did not alter any respiratory measures at the doses tested. When combined, 18mg/kg (but not 10mg/kg) suvorexant plus an ineffective dose of oxycodone significantly decreased minute and tidal volume compared with vehicle and either drug alone, whereas respiratory frequency was significantly decreased compared with vehicle. CONCLUSIONS: Our findings show that suvorexant, at a dose associated with sleep promotion and blockade of oxycodone self-administration, robustly enhanced oxycodone-induced respiratory depression in male rats.

Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys.

BACKGROUND: Benzodiazepines bind to γ-aminobutyric acid type A (GABAA) receptor subtypes identified by different α subunits (i.e., α1GABAA, α2GABAA, α3GABAA, and α5GABAA). Sedative-motor effects of benzodiazepines are thought to involve α1GABAA and α3GABAA subtypes. AIMS: We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABAA receptors), with varying degrees of selective efficacy at different GABAA receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABAA and α3GABAA efficacy. METHODS: Adult female rhesus monkeys (N = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABAA subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABAA subtypes), and MP-III-22 (preferential potency and efficacy for α5GABAA subtypes). RESULTS: As with alprazolam, all GABAkines induced significant levels of mild sedation ("rest/sleep posture"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABAA subtypes. CONCLUSIONS: GABAkines with preferential efficacy at α2/α3GABAA and/or α5GABAA subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABAA activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABAA subtype in this milder form of sedation.

Ayahuasca drinking using a two-bottle choice procedure in male mice.

Ayahuasca has been proposed as a treatment for substance use disorders. However, because of its hallucinogenic properties, studies investigating its abuse potential are needed. The aim of the present study was to investigate voluntary ayahuasca drinking in male mice using a two-bottle choice procedure. Male mice were exposed to two bottles, one of water and one of ayahuasca (0.01, 0.03 or 0.1 mg/ml), for 15 h/day, under 3 protocols (acquisition): (1) every other day access; (2) access every 3 days; (3) access every 5 days. Animals were then submitted to a 14-day drug-free period, followed by 3 re-exposure phases (same conditions as during acquisition), with 7 drug-free days between each. Regardless of the ayahuasca concentration, animals showed a preference for ayahuasca over water when exposed to ayahuasca every other day during the acquisition and re-exposure phases. Extending the period between ayahuasca exposures changed the expression of ayahuasca preference, with the longest break (every 5 days) being associated with preference for water over ayahuasca (i.e., ayahuasca aversion), an effect that was more predominantly observed at higher ayahuasca concentrations. A significant interaction was observed between frequency of exposure to ayahuasca and ayahuasca concentration for total ayahuasca intake during the later re-exposure phase. Our findings show that both the frequency of exposure and the ayahuasca concentration are critical when determining ayahuasca preference in a two-bottle choice model in mice, which can help guide therapeutic/ritualistic ayahuasca use.

Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice?

BACKGROUND: Although mood-congruent memory (MCM), or the tendency to recall information consistent with one's mood, is a robust phenomenon in human depression, to our knowledge, it has never been demonstrated in animals. METHODS: Mice were subjected to social isolation (SI) or crowding for 12 hours and had their depressive-like behaviour (evaluated by the forced swim, tail suspension, sucrose preference and splash tests) or their serum corticosterone concentrations evaluated. In addition, we determined the temporal forgetting curve of the plus-maze discriminative avoidance task (PM-DAT) and examined the effects of SI or crowding on memory retrieval in the PM-DAT. Finally, we verified the effects of metyrapone pretreatment on reinstatement of memory retrieval or on the increase of corticosterone levels induced by SI. RESULTS: Twelve hours of SI produced depressive-like behaviour, enhanced corticosterone concentration and reinstated retrieval of a forgotten discriminative aversive (i.e., negatively valenced) task. Depressive-like behaviour was critical for this facilitative effect of SI because 12 hours of crowding neither induced depressive-like behaviour nor enhanced retrieval, although it increased corticosterone levels at the same magnitude as SI. However, corticosterone increase was a necessary condition for MCM in mice, in that the corticosterone synthesis inhibitor metyrapone abolished SI-induced retrieval reinstatement. LIMITATIONS: Our study did not investigate the effects of the social manipulations proposed here in a positively valenced task. CONCLUSION: To our knowledge, the present paper provides the first evidence of MCM in animal models.

Insomnia as a Risk Factor for Substance Use Disorders in Women.

Gender differences exist for both insomnia and substance use disorders. Women show a higher prevalence of insomnia and increased susceptibility to the effects of drugs than men. Importantly, a growing body of evidence suggests that insufficient sleep predicts and puts individuals at a higher risk for substance use and associated psychosocial problems. However, the role of insomnia in substance use disorders among women remains poorly understood. The present article discusses gender differences in insomnia and in substance use disorders and reviews evidence suggesting that an increased prevalence of insomnia may be a risk factor for substance use disorders in women.

Pharmaco-EEG analysis of ligands varying in selectivity for α1 subunit-containing GABAA receptors during the active phase in rats.

RATIONALE: Benzodiazepines are known to evoke changes in cortical electrophysiological activity that can be correlated with action at distinct γ-aminobutyric acid type A (GABAA) receptor subtypes. OBJECTIVES: We used electroencephalography (EEG) paired with electromyography (EMG) to evaluate the role of α1 subunit-containing GABAA receptors (α1GABAARs) in benzodiazepine-induced sedation and changes in EEG band frequencies during the active phase of the light/dark cycle. METHODS: Male Sprague-Dawley rats (N = 4/drug) were surgically instrumented with EEG/EMG electrodes. The rats were injected i.p. with zolpidem, an α1GABAAR-preferring compound, or L-838,417, which has selective efficacy for α2/3/5 subunit-containing GABAARs (i.e., α1GABAAR-sparing compound), in comparison with the non-selective benzodiazepine, triazolam. RESULTS: All ligands evaluated induced changes in sleep-wake states during the active phase consistent with an increase in slow-wave sleep (SWS). The degree of SWS increase appeared to be related to the magnitude of delta power band changes induced by the ligands, with the strongest effects engendered by the α1GABAAR-preferring drug zolpidem and the weakest effects by the α1GABAAR-sparing compound, L-838,417. Consistent with other research, a selective increase in beta band power was observed with L-838,417, which may be associated with α2GABAAR-mediated anxiolysis. CONCLUSIONS: Overall, these findings support the establishment of pharmaco-EEG "signatures" for identifying subtype-selective GABAA modulators in vivo.

Context-dependent effects of the CB1 receptor antagonist rimonabant on morphine-induced behavioral sensitization in female mice.

Introduction: The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Methods: Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20 mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10 mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Results: Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Discussion: Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge.

Individual differences in the effects of midazolam on anxiety-like behavior, learning, reward, and choice behavior in male mice.

Introduction: The aim of the present study was to investigate the behavioral effects of the benzodiazepine midazolam in male mice, in models of anxiolysis, learning, and abuse-related effects. Methods: In a first set of experiments, male Swiss mice were submitted to the training session of a discriminative avoidance (DA) task on the elevated plus maze to evaluate anxiety-like behavior and learning after vehicle or midazolam (1, 2 or 5 mg/kg, i.g.) administration. The same animals were submitted to a conditioned place preference (CPP) protocol with midazolam (1, 2 or 5 mg/kg, i.g.). In a second experiment, outbred (Swiss) and inbred (C57BL/6) male mice were submitted to a two-bottle choice (TBC) oral midazolam drinking procedure. Animals were exposed to one sucrose bottle and one midazolam (0.008, 0.016 or 0.032 mg/ml) plus sucrose bottle. Results: Midazolam (1 and 2 mg/kg) induced anxiolytic-like effects, and all doses of midazolam prevented animals from learning to avoid the aversive closed arm during the DA training session. Assessment of midazolam reward via the CPP procedure and choice via the TBC procedure showed notable variability. A 2-step cluster analysis for the CPP data showed that midazolam data were well-fitted to 2 separate clusters (preference vs. aversion), albeit with the majority of mice showing preference (75%). Correlational and regression analyses showed no relationship between midazolam reward and anxiolytic-like effects (time spent in the open arms in the DA test) or learning/memory. Two-step cluster analysis of the TBC data also demonstrated that, regardless of strain, mice overall fell into two clusters identified as midazolam-preferring or midazolam-avoiding groups. Both midazolam preference and avoidance were concentration-dependent in a subset of mice. Discussion: Our findings show that midazolam preference is a multifactorial behavior, and is not dependent solely on the emergence of therapeutic (anxiolytic-like) effects, learning impairments, or on genetic factors (inbred vs. outbred animals).

Acute and chronic ethanol differentially modify the emotional significance of a novel environment: implications for addiction.

Using open-field behaviour as an experimental paradigm, we demonstrated a complex interaction between the rewarding/stimulating effects and the anxiogenic/stressful effects of both novelty and acute or chronic amphetamine in mice. As a consequence of this interaction, acute amphetamine-induced hyperlocomotion was inhibited, whereas the expression of its sensitization was facilitated in a novel environment. In the present study, we aimed to investigate the interactions between exposure to a novel environment and the acute and chronic effects of ethanol (Eth), a drug of abuse known to produce anxiolytic-like behaviour in mice. Previously habituated and non-habituated male Swiss mice (3 months old) were tested in an open field after receiving an acute injection of Eth or following repeated treatment with Eth. Acute Eth administration increased locomotion with a greater magnitude in mice exposed to the apparatus for the first time, and this was thought to be related to the attenuation of the stressful effects of novelty produced by the anxiolytic-like effect of acute Eth, leading to a subsequent prevalence of its stimulant effects. However, locomotor sensitization produced by repeated Eth administration was expressed only in the previously explored environment. This result might be related to the well-known tolerance of Eth-induced anxiolytic-like behaviour following repeated treatment, which would restore the anxiogenic effect of novelty. Our data suggest that a complex and plastic interaction between the emotional and motivational properties of novelty and drugs of abuse can critically modify the behavioural expression of addiction-related mechanisms.

Catching up on sleep: Recent evidence on the role of sleep in substance use disorders.

The objective of this editorial is to summarize the findings published in the special issue on "Sleep and Drug Abuse". The manuscripts in this issue include review articles as well as original investigations, and cover topics ranging from pre-clinical investigation to epidemiological-based clinical studies. Together, these papers provide evidence that sleep and drug abuse share a bidirectional relationship, with sleep playing a prominent role in substance use disorders. The knowledge included here can inform treatment development and future research endeavors, clearly pointing to the need for attention that focuses on sleep quality in the treatment of substance use disorders.

Methamphetamine-Induced Sleep Impairments and Subsequent Slow-Wave and Rapid Eye Movement Sleep Rebound in Male Rhesus Monkeys.

Use of amphetamine-type stimulants is associated with numerous adverse health outcomes, with disturbed sleep being one of the most prominent consequences of methamphetamine use. However, the extent to which methamphetamine alters sleep architecture, and whether methamphetamine-induced sleep impairment is associated with next-day sleep rebound effects, has received relatively little investigation. In the present study, we investigated the effects of acute morning methamphetamine administration on sleep parameters in adult male rhesus monkeys (N = 4) using a fully-implantable telemetry system. Monkeys were prepared with telemetry devices that continuously monitored electroencephalography (EEG), electromyography (EMG) and electrooculography (EOG) throughout the night. We investigated the effects of morning (10h00) administration of methamphetamine (0.01-0.3 mg/kg, i.m.) on sleep during the night of the injection. In addition, we investigated sleep during the subsequent night in order to assess the possible emergence of sleep rebound effects. Methamphetamine administration dose-dependently increased sleep latency and wake time after sleep onset (WASO). Methamphetamine also decreased total sleep time, which was reflected by a decrease in total time spent in N2, slow-wave (N3) and REM sleep stages, while increasing the percentage of total sleep time spent in sleep stage N1. Importantly, methamphetamine decreased time spent in N3 and REM sleep even at doses that did not significantly decrease total sleep time. Sleep rebound effects were observed on the second night after methamphetamine administration, with increased total sleep time reflected by a selective increase in time spent in sleep stages N3 and REM, as well as a decrease in REM sleep latency. Our findings show that methamphetamine administered 8 h prior to the inactive (dark) phase induces marked changes in sleep architecture in rhesus monkeys, even at doses that do not change sleep duration, and that sleep rebound effects are observed the following day for both N3 and REM sleep stages.

Effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in male rhesus monkeys.

Opioid use disorder (OUD) has been associated with the emergence of sleep disturbances. Although effective treatments for OUD exist, evidence suggests that these treatments also may be associated with sleep impairment. The extent to which these effects are an effect of OUD treatment or a result of chronic opioid use remains unknown. We investigated the acute effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in non-opioid-dependent male rhesus monkeys (Macaca mulatta, n = 5). Subjects were fitted with actigraphy monitors attached to primate collars to measure sleep-like parameters. Actigraphy recordings were conducted under baseline conditions, or following acute injections of vehicle, methadone (0.03-1.0 mg/kg, i.m.), buprenorphine (0.01-1.0 mg/kg, i.m.), or naltrexone (0.03-1.0 mg/kg, i.m.) in the morning (4 h after "lights on") or in the evening (1.5 h before "lights off"). Morning and evening treatments with methadone or buprenorphine significantly increased sleep latency and decreased sleep efficiency. The effects of buprenorphine on sleep-like measures resulted in a biphasic dose-response function, with the highest doses not disrupting actigraphy-based sleep. Buprenorphine induced a much more robust increase in sleep latency and decrease in sleep efficiency compared to methadone, particularly with evening administration, and detrimental effects of buprenorphine on sleep-like measures were observed up to 25.5 h after drug injection. Treatment with naltrexone, on the other hand, significantly improved sleep-like measures, with evening treatments improving both sleep latency and sleep efficiency. The currently available pharmacotherapies for OUD significantly alter sleep-like parameters in non-opioid-dependent monkeys, and opioid-dependent mechanisms may play a significant role in sleep-wake regulation.

Influence of Pair-housing on Sleep Parameters Evaluated with Actigraphy in Female Rhesus Monkeys.

Rhesus monkeys are naturally social animals, and behavioral management strategies have focused on promoting pairhousing in laboratory settings as an alternative to individual or group housing. In humans, co-sleeping can have a major impact on bed partners' sleep, raising the possibility that pair-housing also may influence sleep parameters in monkeys. In the present study, we investigated if pair-housing would impact home-cage partner's sleep in female rhesus monkeys, and if nighttime separation using socialization panels would alter this pattern. Sleep parameters of 10 experimentally naïve adult female rhesus monkeys (5 pairs) were evaluated for 7 consecutive days using actigraphy monitors attached to primate collars. Paired animals then were separated by socialization panels during the night, and sleep-associated measures were evaluated for 7 consecutive days. The data showed that sleep efficiency was significantly lower when monkeys were pairhoused as compared with when they were separated. On the nights when subjects were pair-housed, a positive correlation was detected for sleep measures (both sleep latency and efficiency) of both members of a pair (R2's = 0.16-0.5), suggesting that pair-housing influences sleep quality. On nights when subjects were separated, no correlations were observed for sleep measures between members of the pairs (R2's = 0.004-0.01), suggesting that when separated, the home-cage partner's sleep no longer influenced the partner's sleep. Our results indicate that pair-housing has a strong impact on the home-cage partner's sleep, and that this pattern can be prevented by nighttime separation using socialization panels. Studies evaluating sleep in pair-housed monkeys should consider the effects that the partner's sleep may have on the subject's sleep. Sleep is a biologic phenomenon and experimental outcome that affects physical and behavioral health and altered sleep due to pair-housing may affect a range of research outcomes.