Effectiveness of Transcranial Direct Current Stimulation (tDCS) on Methamphetamine Craving

Introduction: Transcranial Direct-Current Stimulation is one of the most challenging version of non-invasive brain stimulation. Although it has promised effects on drug-cravings, it has not been approved by FDA as an intervention.The purpose of this study was to investigate the effectiveness of tDCS on reducingmethamphetamine craving.Method: This study was a quasi-experimental design with the pre-test, post-test and control group. The statistical population included all the methamphetamine users who were referred to the HematPayrovan Institute for treatment in 2019. The sample population were 60 males assigned randomly into two groups of experimental and control group. We applied 20 minutestDCS (2 Ma, Anode F4/Cathode FP1) for experimental group. Data were collected using the Individual Student Assessment Plan (ISAP), The Leeds Dependence Questionnaire (LDQ), and Desires for drug questionnaire (DDQ). The data were analyzed through multivariate analysis of covariance (MANCOVA).Results: The result showed that t DCS significantly decreases methamphetamine craving in the experimental group (P<0.03).Discussion: This finding has important implications pertaining the education and mental health of methamphetamine users. Based on the results, repeated DLPFC stimulation could be a promising approach for therapeutic intervention in decreasing methamphetamine craving

Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial [ISRCTN32121581]

BACKGROUND: Results of preclinical studies suggest that the GABA(B )receptor agonist baclofen may be useful in treatment of opioid dependence. This study was aimed at assessing the possible efficacy of baclofen for maintenance treatment of opioid dependence. METHODS: A total of 40 opioid-dependent patients were detoxified and randomly assigned to receive baclofen (60 mg/day) or placebo in a 12-week, double blind, parallel-group trial. Primary outcome measure was retention in treatment. Secondary outcome measures included opioids and alcohol use according to urinalysis and self-report ratings, intensity of opioid craving assessed with a visual analogue scale, opioid withdrawal symptoms as measured by the Short Opiate Withdrawal Scale and depression scores on the Hamilton inventory. RESULTS: Treatment retention was significantly higher in the baclofen group. Baclofen also showed a significant superiority over placebo in terms of opiate withdrawal syndrome and depressive symptoms. Non-significant, but generally favorable responses were seen in the baclofen group with other outcome measures including intensity of opioid craving and self-reported opioid and alcohol use. However, no significant difference was seen in the rates of opioid-positive urine tests. Additionally, the drug side effects of the two groups were not significantly different. CONCLUSION: The results support further study of baclofen in the maintenance treatment of opioid dependence

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments

Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats

Abstract: Rationale $\gamma$-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA$_B$ receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA$_B$ receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA$_B$ receptor agonists, GABA$_B$ receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. Objectives and methods: We examined whether the acute effects of the GABA$_B$ receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self- administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Results: Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. Conclusions: These results showed that BHF177 selectively blocked nicotine self-administration and prevented cueinduced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA$_B$ receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans

The Effect of L-arginine in the Ventral Tegmenta Area on the Improving Effect of Nicotine on Memory

Background and Objectives: Nitric oxide synthesis has been detected in ventral tegmental area, which is a key brain region that seems to mediate behavioral effect of morphine and nicotine. In the present study, the effects of L-arginine, a nitric oxide precursor, in the ventral tegmental area in nicotine’s effect on morphine-induced amnesia has been investigated.   Methods: This study was done experimentally on 250 male rats. Rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride, plus xylazine and then placed in a stereotaxic apparatus. Two stainless-steel cannuale were placed in the ventral tegmental area. The behavioral testing was started in inhibitory avoidance task, and the step-through latency for entering into the dark compartment was measured for the assessment of memory retention. One-side analysis of variance (ANOVA) and Tukey test were used to evaluate the statistical significance between experimental groups. A difference of p<0.05 was considered statistically significant.   Results: Post-training injection of morphine (5 and 7.5mg/kg) decreased the memory retrieval. Injection of nicotine or L-arginine before test by itself has no effect on memory retrieval. On the other hand, pre-test administration of morphine (7.5mg/kg), nicotine (0.5 and 1mg/kg), L-arginine or ineffective doses of L-arginine plus non-effective dose of nicotine restored memory impairment induced by post-training injection of morphine.   Conclusion: The finding of the study indicate that nitric oxide system of the ventral tegmental area may play an important role in the improving effect of nicotine on the morphine-induced amnesia