What Is the Role of Brain Stimulation Therapies in the Treatment of Depression?

What Is the Role of Brain Stimulation Therapies in the Treatment of Depression?

Curr Psychiatry Rep. 2013 Jul; 15(7): 368
Blumberger DM, Mulsant BH, Daskalakis ZJ

Brain stimulation therapies have demonstrated efficacy in the treatment of depression and treatment-resistant depression (TRD). Non-invasive brain stimulation in the treatment of depression has grown substantially due to their favorable adverse effect profiles. The role of transcranial direct current stimulation in TRD is unclear, but emerging data suggests that it may be an effective add-on treatment. Repetitive transcranial magnetic stimulation has demonstrated efficacy in TRD that is supported by several multicenter randomized controlled trials. Though, vagus nerve stimulation has been found to be effective in some studies, sham controlled studies were equivocal. Electroconvulsive therapy (ECT) is a well-established brain stimulation treatment for severe depression and TRD, yet stigma and cognitive adverse effects limit its wider use. Magnetic seizure therapy has a more favorable cognitive adverse effect profile; however, equivalent efficacy to ECT needs to be established. Deep brain stimulation may play a role in severe TRD and controlled trials are now underway. HubMed – addiction


Positive allosteric modulation of ?4?2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration.

Psychopharmacology (Berl). 2013 May 28;
Liu X

RATIONALE: The ?4?2 subtype of nicotinic acetylcholine receptors (nAChRs) plays a central role in the mediation of nicotine reinforcement. Positive allosteric modulators (PAMs) at ?4?2 nAChRs facilitate the intrinsic efficiency of these receptors, although they do not directly activate the receptors. ?4?2 PAMs are hypothesized to reduce nicotine self-administration in subjects engaged in routine nicotine consumption. The present study tested this hypothesis using a rat model of nicotine self-administration. METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine (0.03 mg/kg per infusion, free base) on a fixed-ratio 5 schedule. The effects of the ?4?2 PAM desformylflustrabromine (dFBr), ?4?2 agonist 5-iodo-A-85380, and acetylcholinesterase inhibitor galantamine on nicotine intake were examined. The ability of dFBr and 5-iodo-A-85380 to substitute for nicotine was also assessed. RESULTS: dFBr and 5-iodo-A-85380 dose-dependently reduced nicotine self-administration without changing lever responses for food. Galantamine decreased the self-administration of nicotine and food at high doses. Unlike 5-iodo-A-85380, dFBr failed to substitute for nicotine in supporting self-administration behavior. CONCLUSIONS: These results demonstrated the effectiveness of dFBr in reducing nicotine intake and the inability of dFBr to support self-administration behavior. These findings suggest that positive allosteric modulation of ?4?2 nAChRs may be a promising target for the treatment of nicotine addiction. Moreover, ?4?2 PAMs, in contrast to agonist medications, may have clinical advantages because they may have little liability for abuse because of their lack of reinforcing actions on their own. HubMed – addiction


Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase.

Bioorg Med Chem. 2013 May 7;
Sadovski O, Hicks JW, Parkes J, Raymond R, Nobrega J, Houle S, Cipriano M, Fowler CJ, Vasdev N, Wilson AA

Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an (18)F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [(18)F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [(18)F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [(18)F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [(18)F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [(18)F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding. HubMed – addiction


Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

Mol Psychiatry. 2013 May 28;
Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD, Taylor KM, Martinez D, Moore H, Balsam PD, Simpson EH, Javitch JA

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum-including the nucleus accumbens (NAc)-impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal’s willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.Molecular Psychiatry advance online publication, 28 May 2013; doi:10.1038/mp.2013.57. HubMed – addiction


Roles of levo-tetrahydropalmatine in modulating methamphetamine reward behavior.

Physiol Behav. 2013 May 24;
Su HL, Zhu J, Chen YJ, Zhao N, Han W, Dang YH, Xu M, Chen T

Levo-tetrahydropalmatine (l-THP), as an alkaloid purified from the traditional Chinese herbal medicine Corydalis and Stephania, has been widely used to produce many traditional Chinese herbal preparations. The effect of l-THP on methamphetamine-induced reward learning still remains unclear although it has been proved to be effective on treating allodynia and drug addiction. This experiment has been designed to examine the effect of l-THP on the acquisition, expression, extinction, and reinstatement of methamphetamine-induced conditioned place preference (CPP) in mice. The results show that methamphetamine (METH) could induce CPP in mice at doses of 0.5mg/kg, 1.0mg/kg and 2.0mg/kg respectively, but l-THP alone could not do so. Meanwhile, l-THP could not induce conditioned place aversion at doses of 1.25mg/kg to 20.0mg/kg in mice, but it could attenuate the acquisition and expression of METH-induced CPP and facilitate the extinction of METH-induced CPP in mice. Besides, l-THP could inhibit the reinstatement of METH-induced CPP at the dose of 10.0mg/kg whether it was given in the extinction training phase or 30minutes before the reinstatement. These results suggest that l-THP can globally suppresses the rewarding properties of METH on all phases of the CPP task and it may have potential effects on the treatment of METH abuse. HubMed – addiction



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