Music therapy, neural processing, and craving reduction: an RCT protocol for a mixed methods feasibility study in a Community Substance Misuse Treatment Service.

BACKGROUND: Music therapy has been shown to be effective for multiple clinical endpoints associated with substance use disorder such as craving reduction, emotion regulation, depression, and anxiety, but there are a lack of studies investigating those effects in UK Community Substance Misuse Treatment Services (CSMTSs). Furthermore, there is a demand for identifying music therapy mechanisms of change and related brain processes for substance use disorder treatment. The present study aims to evaluate the feasibility and acceptability of music therapy and a pre-test, post-test, and in-session measurement battery in a CSMTS. METHODS: Fifteen participants, from a community service based in London, will take part in a mixed-methods non-blind randomized-controlled trial. Ten participants will receive six-weekly sessions of music therapy in addition to the standard treatment offered by the CSMTS-five of them will receive individual music therapy and five of them will receive group music therapy-while a further five participants will act as a control group receiving standard treatment only. Satisfaction and acceptability will be evaluated in focus groups with service users and staff members following the final treatment session. Moreover, attendance and completion rates will be monitored throughout the intervention. Subjective and behavioral indexes will be assessed before and after the interventions to explore the effects of music therapy on craving, substance use, symptoms of depression and anxiety, inhibitory control, and will be correlated with associated neurophysiological signatures. In-session analysis of two individual music therapy sessions will serve to explore how music and emotion are processed in the brain within the therapy. The data collected at each step will be included in an intention-to-treat analysis basis. DISCUSSION: This study will provide a first report on the feasibility of music therapy as an intervention for participants with substance use disorder engaged within a community service. It will also provide valuable information regarding the implementation of a multifaceted methodology that includes neurophysiological, questionnaire-based, and behavioral assessments in this cohort. Notwithstanding the limitation of a small sample size, the present study will provide novel preliminary data regarding neurophysiological outcomes in participants with substance use disorder that received music therapy. TRIAL REGISTRATION: ClinicalTrails.gov, NCT0518061, Registered 6 January 2022, https://clinicaltrials.gov/ct2/show/NCT05180617.

Neuroplastic Changes in Addiction Memory-How Music Therapy and Music-Based Intervention May Reduce Craving: A Narrative Review.

Recent findings indicate that Music Therapy (MT) and Music-Based Interventions (MBIs) may reduce craving symptoms in people with Substance Use Disorders (SUD). However, MT/MBIs can lead SUD clients to recall memories associated with their drug history and the corresponding strong emotions (addiction memories). Craving is a central component of SUD, possibly linked to relapse and triggered by several factors such as the recall of memories associated with the drug experience. Therefore, to address the topic of what elements can account for an improvement in craving symptoms after MT/MBIs, we conducted a narrative review that (1) describes the brain correlates of emotionally salient autobiographical memories evoked by music, (2) outlines neuroimaging and neurophysiological studies suggesting how the experience of craving may encompass the recall of emotionally filled moments, and (3) points out the role of perineuronal nets (PNNs) in addiction memory neuroplasticity. We highlight how autobiographical memory retrieval, music-evoked autobiographical memories, and craving share similar neural activations with PNNs which represent a causal element in the processing of addiction memory. We finally conclude by considering how the neuroplastic characteristics of addiction memory might represent the ground to update and/or recalibrate, within the therapy, the emotional content related to the recall.

Interventions to improve inpatients' sleep quality in intensive care units and acute wards: a literature review.

BACKGROUND: Sleep is essential for the physical and psychological restoration of inpatients, and lack of sleep results in sleep deprivation and poor sleep quality, with potentially harmful consequences. AIM: To summarise sleep-promoting interventions in the Intensive care unit (ICU) and acute ward setting. METHOD AND RESULTS: Six databases were searched to obtain studies for review and eight studies were selected, appraised, analysed and produced two themes: sleep-disturbing factors and sleep-promoting strategies. Sleep-disturbing factors included environmental factors (such as light and noise), illness-related factors (such as pain, anxiety and discomfort), clinical care and diagnostics. Sleep-promoting strategies included using pharmacological aids (medication) and non-pharmacological aids (reducing noise and disturbances, eye masks, earplugs and educational and behavioural changes). CONCLUSION: The literature review showed that both ICU and acute ward settings affect patients' sleep and both use similar strategies to improve this. Nevertheless, noise and sleep disturbances remain the most critical sleep-inhibiting factors in both settings. The review recommended future research should focus on behavioural changes among health professionals to reduce noise and improve patients' sleep.

Sleep and the Pharmacotherapy of Alcohol Use Disorder: Unfortunate Bedfellows. A Systematic Review With Meta-Analysis.

Background: Sleep disorders are commonly associated with acute and chronic use of alcohol and with abstinence. To date, there are four approved drugs to treat alcohol use disorder (AUD): disulfiram, acamprosate, naltrexone, and nalmefene. These AUD therapies reduce the craving and risk of relapse into heavy drinking, but little is known about their effect on sleep. As recent evidences indicate a crucial role of sleep disorders in AUD, claiming that sleep problems may trigger alcohol abuse and relapses, it is fundamental to clarify the impact of those drugs on the sleep quality of AUD patients. This systematic review aims to answer the question: how does the pharmacotherapy for AUD affect sleep? Methods: We searched PubMed, Embase, CINAHL Plus, Cochrane, and Scopus using sleep- and AUD pharmacotherapy-related keywords. The articles included were appraised using the CASP checklists, and the risk of bias was assessed following the Cochrane risk-of-bias assessment tool. Finally, we pooled sleep outcomes in a meta-analysis to measure the overall effect. Results and Conclusion: We included 26 studies: only three studies focused on sleep as a main outcome, two with polysomnography (objective measurement), and one with subjective self-reported sleep, while all the other studies reported sleep problems among the adverse effects (subjective report). The only study available on disulfiram showed reduced REM sleep. Acamprosate showed no/little effect on self-reported sleep but improved sleep continuity and architecture measured by polysomnography. The two opioidergic drugs naltrexone and nalmefene had mainly detrimental effect on sleep, giving increased insomnia and/or somnolence compared with placebo, although not always significant. The meta-analysis confirmed significantly increased somnolence and insomnia in the naltrexone group, compared with the placebo. Overall, the currently available evidences show more sleep problems with the opioidergic drugs (especially naltrexone), while acamprosate seems to be well tolerated or even beneficial. Acamprosate might be a more suitable choice when patients with AUD report sleep problems. Due to the paucity of information available, and with the majority of results being subjective, more research on this topic is needed to further inform the clinical practice, ideally with more objective measurements such as polysomnography.

Novel Nut and Bolt Task Quantifies Motor Deficits in Premanifest and Manifest Huntington's Disease.

BACKGROUND: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease. METHODS: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn. RESULTS: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores. CONCLUSION: This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease.

OBJECTIVE: Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage. METHODS: We performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age- and sex-matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x-ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain. RESULTS: Compared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4-7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations. INTERPRETATION: The results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology.

Nicotine-induced increase of dopaminergic mesoaccumbal neuron activity is prevented by acute restraint stress. In vivo electrophysiology in rats.

Stress is well known to affect responsiveness to drugs of abuse and influencing approaching and drug-taking behaviour in both animals and humans. Consistently, in nicotine addicted subjects both negative events and perceived stress levels are reported to increase drug use and facilitate relapse to smoke even after long periods of abstinence. It has been suggested that stressful stimuli may influence the rewarding properties of abused drugs by acting on the dopaminergic mesolimbic system. In line with this hypothesis, a recent microdialysis study in rats has shown that acute restraint stress exposure prevents the nicotine-induced mesolimbic dopaminergic activation in the nucleus accumbens (NAC) shell via a corticosterone-mediated mechanism. In the present study we sought to evaluate the impact of acute restraint stress on nicotine-induced activation of the mesoaccumbal dopaminergic system by extracellular single unit recordings of antidromically-identified NAC shell projecting dopaminergic neurons within the ventral tegmental area (VTA). Nicotine intravenous administration dose-dependently (0.05-0.4mg/kg) stimulated the spontaneous firing and bursting of mesoaccumbal dopaminergic neurons in unstressed rats, as previously reported. By contrast, nicotine failed to increase mesoaccumbal dopaminergic neuron activity in rats previously exposed to 1-h immobilisation stress. Our observations show that acute restraint stress inhibits the response of the mesoaccumbal dopaminergic system to the stimulating properties of nicotine. These findings corroborate the notion that stress reduces the sensitivity to nicotine and suggest that the decreased dopaminergic release in the NAC shell is due to a reduced firing and bursting activity in the VTA.

Pregnenolone can protect the brain from cannabis intoxication.

Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

Coupled intracerebral microdialysis and electrophysiology for the assessment of dopamine neuron function in vivo.

INTRODUCTION: The central dopaminergic system is involved in the pathophysiology of several neuropsychiatric disorders. Intracerebral microdialysis and electrophysiology provide two powerful techniques to investigate dopamine (DA) function and the mechanism of action of psychotropic drugs in vivo. METHODS: Here, we developed a protocol allowing the combined measurement of neurochemical and electrical activities of the nigrostriatal and mesoaccumbens DA pathways, by coupling in vivo microdialysis and electrophysiology in the same isoflurane-anesthetized animal. DA neuron firing rate and burst firing were measured in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), whereas extracellular levels of DA and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were monitored in the striatum and the nucleus accumbens (NAc). The validity of the protocol was assessed using various drugs known to modify DA neuron activity in vivo. RESULTS: The peripheral administration of the DA-D2 agonist quinpirole decreased SNc DA neuron firing rate and burst firing, as well as DA and DOPAC outflow in the rat striatum. Opposite effects were observed after the peripheral administration of the DA-D2 antagonist haloperidol. In rats and mice, the peripheral administration of cocaine elicited a decrease in VTA DA neuron firing rate and burst firing, and an increase in accumbal DA outflow, paralleled by a reduction in DOPAC outflow. DISCUSSION: The obtained results, confirming previous electrophysiological and microdialysis studies, demonstrate that this protocol provides a suitable method for the study of DA neuron function and the mechanism of action of psychotropic drugs in the living brain of both rats and mice.

Chronic valproate fails to prevent imipramine-induced behavioural sensitization to the dopamine D2-like receptor agonist quinpirole.

Based on experimental evidence suggesting a relationship between dopamine and mania, we proposed the antidepressant-induced dopaminergic supersensitivity as a model of antidepressant-related mania. We have previously shown the ability of carbamazepine, but not lithium, to prevent this phenomenon. Here we show that sodium valproate (50 mg/kg/day for 3 weeks) fails to prevent imipramine (20 mg/kg/day for 3 weeks)-induced sensitization to the locomotor response to the dopamine D2-like receptor agonist quinpirole (0.15 mg/kg). Since lithium, carbamazepine and valproate are all considered poorly effective in the treatment of antidepressant-related mania, the validity of the proposed model should be disproved by the carbamazepine results, to which, however, a pharmacokinetic mechanism might have concurred.

Dopamine D3 receptor antisense oligodeoxynucleotide potentiates imipramine-induced dopaminergic behavioural supersensitivity.

Chronic antidepressant treatments result in the potentiation of dopaminergic transmission in the mesolimbic dopamine system revealed as an increased motor response to dopamine D2-like agonists. On the basis of the involvement of this system in the control of motivation and reward-related behaviour, which are impaired in depression, it has been suggested that such supersensitivity might play an important role in the mechanism of action of these drugs. Several studies have provided evidence suggesting a role of dopamine D3 receptors in mediating antidepressant-induced increased motor response to dopamine agonists. To test this hypothesis, we studied the effect of the intracerebroventricular infusion of a dopamine D3 receptor antisense oligodeoxynucleotide (10 microg/3 microl, 2-3 daily injections) on the expression of imipramine-induced supersensitivity (20 mg/kg daily intraperitoneal injections for 21 days) to the motor effect of the dopamine D2-like receptor agonist quinpirole (a single 0.3 mg/kg subcutaneous injection 24-48 h after imipramine withdrawal). The results show that a treatment previously shown to reduce the synthesis of dopamine D3 receptors, rather than resulting in an inhibitory effect, potentiated the ability of imipramine to induce dopaminergic motor supersensitivity. The present results suggest that increased dopamine D3 receptor expression following antidepressant treatments is not involved in the mechanism of dopaminergic supersensitivity, and are consistent with evidence supporting an inhibitory role for dopamine D3 receptors in motor activity, both in normal and in sensitized subjects.

Long-term imipramine withdrawal induces a depressive-like behaviour in the forced swimming test.

Chronic antidepressant treatments enhance dopaminergic neurotransmission in the mesolimbic dopamine system. We suggested that this potentiation might underlie both the antidepressant therapeutic effect and the antidepressant-induced switch from depression to mania. In a recent study we have shown a reversal of the imipramine-induced dopaminergic supersensitivity after 40 days of chronic imipramine withdrawal. We interpreted this result suggesting that the mood-switches observed in bipolar patients following antidepressant treatment and subsequent withdrawal, i.e. mania followed by rebound depression, might depend upon parallel changes in the mesolimbic dopamine system sensitivity. On this basis, one might predict a depressive-like behaviour after long-term interruption of a chronic treatment with imipramine. To test this hypothesis we examined the behaviour of rats treated with chronic imipramine 40 days after treatment interruption in an animal model of depression, the forced swimming test. The results show that animals treated with chronic imipramine, 40 days after treatment interruption, display a depressive-like behaviour in the forced swimming test, as indicated by their increased immobility with respect to the control group.

Dopamine D1 receptor agonists induce penile erections in rats.

The dopamine receptor agonist apomorphine has been recently introduced in the treatment of erectile dysfunction. While it is well established that dopamine D2-like receptors play a crucial role in this effect, conflicting result are reported in the literature as for the role of dopamine D1-like receptors. The aim of this study was to determine the effect of systemic administration of dopamine D1-like receptor agonists on penile erection in rats. Male Wistar rats were treated with three different, and not structurally related, dopamine D1-like receptor agonists: the partial agonists SKF38393 ((+) 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) and CY 208-243 ((-)-4,6,6a,7,8,12b-exahydro-7-methylindole [4,3-ab]fenantridine), and the full agonist A 77636 ((-)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride). All three compounds dose-dependently increased the number of penile erections, with the full agonist A77636 showing a more pronounced effect with respect to the other two. Moreover, the dopamine D1-like receptor antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) dose-dependently antagonised A77636 effect. These results show that systemic administration of dopamine D1-like receptor agonists induce penile erection in rats. This observation suggests that dopamine D1-like receptor agonists might be considered as a possible alternative to apomorphine in the treatment of erectile dysfunction, thus avoiding the typical side effects related to the stimulation of dopamine D2-like receptors such as nausea.

Reversal of antidepressant-induced dopaminergic behavioural supersensitivity after long-term chronic imipramine withdrawal.

Chronic antidepressant treatments enhance dopaminergic neurotransmission in the mesolimbic dopamine system. We suggested that this potentiation might underlie both the antidepressant therapeutic effect and the antidepressant-induced switch from depression to mania, which in turn, might be involved in the development of rapid cycling in bipolar patients. In this study, we investigated the changes occurring in the sensitivity of the mesolimbic dopamine system up to 40 days after antidepressant withdrawal. Male Sprague-Dawley rats were treated for 3 weeks with imipramine (20 mg/kg) and tested for motor activity 24 h, 12, 33 and 40 days after treatment withdrawal. Ambulatory activity and rearing counts were recorded after challenge with the dopamine D2-like receptor agonist quinpirole (0.15 mg/kg). Imipramine increased the motor response to quinpirole, 24 h after treatment discontinuation. No relevant differences between the groups were found after 12 and 33 days. After 40 days, a decreased level of rearing was observed in the group treated with imipramine. These results show a reversal of the imipramine-induced dopaminergic supersensitivity after 40 days of chronic imipramine withdrawal and suggest that the mood-switches observed in bipolar patients following antidepressant treatment and subsequent withdrawal, i.e. mania followed by rebound depression, might depend upon parallel changes in the mesolimbic dopamine system sensitivity.