Psychopharmacology

Methadone as the most prevalent opioid substitution medication has been shown to influence the neurophysiological functions among heroin addicts. However, there is no firm conclusion on acute neuroelectrophysiological changes among methadone-treated subjects as well as the effectiveness of methadone in restoring brain electrical abnormalities among heroin addicts. This study aims to investigate the acute and short-term effects of methadone administration on the brain’s electrophysiological properties before and after daily methadone intake over 10 weeks of treatment among heroin addicts. EEG spectral analysis and single-trial event-related potential (ERP) measurements were used to investigate possible alterations in the brain’s electrical activities, as well as the cognitive attributes associated with MMN and P3. The results confirmed abnormal brain activities predominantly in the beta band and diminished information processing ability including lower amplitude and prolonged latency of cognitive responses among heroin addicts compared to healthy controls. In addition, the alteration of EEG activities in the frontal and central regions was found to be associated with the withdrawal symptoms of drug users. Certain brain regions were found to be influenced significantly by methadone intake; acute effects of methadone induction appeared to be associative to its dosage. The findings suggest that methadone administration affects cognitive performance and activates the cortical neuronal networks, resulting in cognitive responses enhancement which may be influential in reorganizing cognitive dysfunctions among heroin addicts. This study also supports the notion that the brain’s oscillation powers and ERPs can be utilized as neurophysiological indices for assessing the addiction treatment traits.

Amphetamine and related compounds have previously been shown to differentially release dopamine (DA) and serotonin (5HT) in vivo and in vitro. The purpose of this report is directly to compare five amphetamine analogs on differential reinforcement of low rate 36-s (DRL 36-s) schedule performance, and to determine whether the reported increases in dopamine and/or serotonin release induced by these drugs can be related to observed behavioral differences. Amphetamine (AMPH) and methamphetamine (METH) induced large increases in response rate, methylene-dioxymethamphetamine (MDMA) and para-chloroamphetamine (PCA) caused small increases in response rate, while fenfluramine (FEN) had no effect on response rate. AMPH, METH, PCA and MDMA caused a dose-dependent decrease in reinforcement rate, and FEN had no effect on reinforcement rate. AMPH, METH, and PCA but not FEN, shifted the peak of the inter-response time (IRT) distribution toward shorter intervals, MDMA decreased peak location only at the highest dose. All five drugs caused a dose-dependent decrease in peak area, indicating a loss of schedule control on the DRL 36-s schedule. Consistent with in vitro and in vivo release studies, the differential results of these five drugs on DRL 36-s schedule performance suggest a predominant dopamine role for AMPH and METH, a predominant serotonin role for FEN, and different degrees of combined dopaminergic and serotonergic roles for MDMA and PCA in the mediation of the task.

Associative learning during classical trace eyeblink conditioning has been shown to be regulated by serotonin 5-HT2A receptors and to be critically dependent on the integrity of frontal cortex. Chronic administration of 5-HT2A ligands has been shown to produce a selective up- or down-regulation of 5-HT2A receptors in frontal cortex. We examined whether alterations in 5-HT2A receptor density had a functional significance with respect to associative learning. Animals received chronic injections of LSD, BOL or MDL11,939 and 1 day later began classical trace conditioning of the eyeblink response. The density of 5-HT2A receptors in frontal cortex was significantly increased at 1–4 days after the cessation of chronic injections of the selective 5-HT2A receptor ligand MDL11,939. Rabbits demonstrated an enhancement of associative learning when training began at 1 day after cessation of chronic MDL11,939 injections, but acquired at the same rate as controls when training began at 8 days after cessation of injections, a time when receptor density had returned to control levels. Animals that began training 1 day after chronic injections of BOL or LSD, drugs that produce decreases in 5-HT2A receptor density, demonstrated normal rates of acquisition. These results indicate that increases in the density of 5-HT2A receptors in frontal cortex are associated with increases in the rate of associative learning, and further support an important role for this receptor in cortical circuitry that mediates learning. More generally, these results suggest an approach for functional remodeling of brain regions in the adult animal.

Chuột đực, dòng Holtzman đã được huấn luyện kỹ lưỡng trên một nhiệm vụ chú ý yêu cầu chúng phản ứng bằng cách nhấn cần điều khiển một lần duy nhất với một kích thích rất ngắn, được trình bày biến đổi để nhận phần thưởng thực phẩm, nhưng cũng yêu cầu chúng ức chế những phản ứng không phù hợp. Sau khi hiệu suất đã ổn định, hai nhóm đã được điều trị bằng bazo nicotine (100 Μg/kg, dưới da, ba lần mỗi ngày) hoặc dung dịch muối sinh lý trong 4 tuần. Hai nhóm được thay phiên nhau, trong đó nhóm đầu tiên nhận dung dịch muối sinh lý và nhóm thứ hai nhận nicotine trong 4 tuần tiếp theo. Sau đó là một giai đoạn phục hồi bằng dung dịch muối sinh lý kéo dài 3 tuần. Chuột được kiểm tra trên nhiệm vụ chú ý hàng ngày trong suốt tất cả các giai đoạn. Phân tích dữ liệu cho thấy rằng không phụ thuộc vào thứ tự điều trị, chuột hoạt động hiệu quả hơn dưới điều trị nicotine so với điều kiện dung dịch muối sinh lý. Cải thiện hiệu suất rõ rệt nhất trong việc giảm thiểu những phản ứng không phù hợp trong quá trình điều trị nicotine mạn tính. Tầm quan trọng của những thay đổi hành vi này được thảo luận liên quan đến những thay đổi sinh lý thần kinh do nicotine gây ra và giả thuyết hai loại kích thích.

We have previously shown that environmental novelty can potentiate the activating effects of morphine and the development of sensitization to this effect. Our main goal was to determine whether environmental novelty can also modulate the prophagic (time spent eating and food intake; experiment 1) and/or the analgesic (tail-flick test; experiments 2 and 3) effect of morphine, as well as the development of tolerance or sensitization to these effects. In experiment 1, two groups of rats were administered seven intraperitoneal (i.p.) injections of either saline or morphine (4.0 mg/kg) either in their home cages (home groups) or in a distinct environment (novelty groups). After 7 days of withdrawal, both groups underwent a morphine challenge (4.0 mg/kg, i.p.). In experiment 2, home and novelty rats were administered four doses of morphine (0.0, 2.0, 4.0, and 8.0 mg/kg, i.p.) following a counterbalanced order. In experiment 3, home and novelty rats were administered eight intraperitoneal (i.p.) injections of either saline or morphine (8.0 mg/kg) and then given a morphine challenge (4.0 mg/kg). Environmental novelty enhanced the locomotor activating effect of morphine and the expression of sensitization to this effect (even after a period of withdrawal). Environmental novelty had relatively little effect on morphine-induced eating, and no effect on morphine-induced analgesia. Environmental context can have very different consequences on distinct drug effects as well as on distinct neurobehavioral adaptations to the same drug treatment (e.g., psychomotor sensitization versus analgesic tolerance).

The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear. A systematic review and meta-analysis of randomised, placebo-controlled clinical trials (RPCCTs) investigating the efficacy of pharmacological treatment in children or adolescents with ADHD was carried out. Meta-analysis of treatment discontinuation, clinician-, parent- and teacher-rated efficacy and adverse events was performed. The effect of covariates was studied. Sixty-three studies were included. Ten drugs were investigated, with atomoxetine and methylphenidate the most frequently studied. RPCCTs had mostly a short duration (7.9 weeks). All-cause treatment discontinuation was lower with pharmacological treatment than placebo (OR = 0.68). Pharmacological treatment was more efficacious than placebo independently of the rater (clinician, standardised mean difference (SMD) 0.74; parent, SMD = 0.63; or teacher, SMD = 0.75). Evidence of publication bias was found for clinician-rated efficacy, especially in industry-sponsored RPCCT. Psychostimulants showed a higher efficacy and were associated with a better outcome on treatment discontinuation than non-stimulant drugs. Efficacy was smaller in RPCCTs for which a psychiatric comorbid disorder was an inclusion criterion, was larger in studies with a commercial sponsorship and showed a negative association with treatment length. In the short term, pharmacological treatment provides moderate–high symptom relief, is safe and shows lower treatment discontinuation than placebo, suggesting a suitable risk-benefit balance, particularly with psychostimulants. The efficacy is lower in patients with a comorbid psychiatric disorder and should be assessed periodically, as it appears to reduce over time. Publication bias of clinician-rated efficacy in studies with a commercial sponsor is suggested.