Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study.

BACKGROUND: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. METHODS: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. RESULTS: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. CONCLUSION: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469).

Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson's Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

Chemistry of opium alkaloids. Part 44: synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans.

7- and 8-substituted 6alpha,14alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morphinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7alpha- and 7beta-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5Beta-alkyl substitution of 6alpha,14alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5beta-methyl series the affinity for the mu and delta receptors increased from 7alpha-dimethylmethanol to 7alpha-methylhexylmethanol. In the 5beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6beta,14beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments.

An electrophilic affinity ligand based on (+)-MK801 distinguishes PCP site 1 from PCP site 2.

The electrophilic affinity ligand, (+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycl ohepten-5,10 - imine hydrochloride [(+)-MK801-NCS] was characterized for its ability to acrylate phencyclidine (PCP) and sigma binding sites in vivo. Initial studies, conducted with mouse brain membranes, characterized the binding sites labeled by [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP). The Kd values of [3H]TCP for PCP site 1 (MK801-sensitive) and PCP site 2 (MK801-insensitive) were 12 nM and 68 nM, with Bmax values of 1442 and 734 fmol/mg protein, respectively. Mice were sacrificed 18-24 hours following intracerebroventricular administration of the acylator. The administration of (+)-MK801-NCS increased [3H]TCP binding to site 2, but not to site 1. Although (+)-MK801-NCS decreased [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d; ccyclohepten-5,10-imine maleate ([3H](+)-MK801) binding to site 1, it had no effect on [3H]TCP binding to site 1. Viewed collectively with other published data, these data support the hypothesis that PCP sites 1 and 2 are distinct binding sites, and that [3H]TCP and [3H](+)-MK801 label different domains of the PCP binding site associated with the NMDA receptor.

Synthesis and binding properties of MK-801 isothiocyanates; (+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine hydrochloride: a new, potent and selective electrophilic affinity ligand for the NMDA receptor-coupled phencyclidine binding site.

Three new site-directed irreversible (wash-resistant) ligands for the high-affinity phencyclidine (PCP) binding site associated with the N-methyl-D-aspartate (NMDA) receptor were synthesized and their binding characteristics were studied. (+)-3- And (+)-2-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycl ohepten-5,10 - imine hydrochloride ((+)-8a,b.HCl) were prepared in four steps from the corresponding nitro derivatives (+)-4a,b, which were obtained by nitration of (+)-3 (MK-801). In the same way the optical antipode (-)-8a.HCl was synthesized from (-)-3. At a concentration of 100 nM, the 3-isothiocyanate derivative (+)-8a irreversibly labeled approximately 50% of the (+)-[3H]-3 binding sites, compared to 20 microM needed for its optical antipode (-)-8a and the 2-isothiocyanate (+)-8b. The apparent Ki values for reversible inhibition of (+)-[3H]-3 binding by (+)- and (-)-8a and (+)-8b were 37,838, and 843 nM, respectively. In contrast, metaphit (1b) and etoxadrol m-isothiocyanate (2b), two previously reported irreversible ligands for the PCP binding site, label about 50% of the (+)-[3H]-3 binding sites at 100 microM and 250 nM, respectively, with apparent Ki values for reversible inhibition of 535 and 94 nM. Compound (+)-8a is also a selective affinity ligand, displaying little or no irreversible in vitro affinity at 100 microM for opioid, benzodiazepine, muscarinic, and dopamine receptors. At a 25 microM concentration, (+)-8a caused an irreversible 52% reduction of binding to sigma 1-receptors. Compound (+)-8a is the most potent known electrophilic affinity label for the PCP binding site. Its potency and selectivity should enable it to be a valuable tool for the elucidation of the structure and function of the NMDA receptor-associated PCP binding site in the mammalian central nervous system.

Synthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at sigma receptors. 2. Piperazines, bicyclic amines, bridged bicyclic amines, and miscellaneous compounds.

As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4343) we conformationally restricted the sigma-receptor ligand 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. sigma-Receptor binding affinities were obtained using [3H](+)-pentazocine in guinea pig brain membrane sigma 1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding interaction. Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 [ as in 4-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[3.2.2]nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substituted homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The synthesis of 6,7-dichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding interaction at sigma-receptors. sigma-Receptor Ki's ranged from 0.55 nM for 1-[2-(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine (7) to 654 nM for 16. Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the sigma receptor is not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.

Synthesis, configuration, and activity of isomeric 2-phenyl-2-(N-piperidinyl)bicyclo[3.1.0]hexanes at phencyclidine and sigma binding sites.

The novel semirigid derivatives (+)-cis-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+)-8], its enantiomer (-)-8, and (+-)-trans-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+/-)-9] were synthesized as probes to investigate the mode of interaction of phencyclidine (PCP) with its binding site on the N-methyl-D-aspartate receptor complex. Each target compound was obtained in five steps starting from cyclopent-2-enone. (+)- and (-)-8 were obtained in greater than 98% optical purity through three recrystallizations from ethanol of the (S)-(+)- and (R)-(-)-mandelate salts of intermediate (+-)-cis-2-phenyl-2-bicyclo[3.1.0]hexylamine ([(+/-)-16]. Crystallization of the (R)-(-)-mandelate salt afforded (1R,2R,5S)-(-)-16, whereas the (S)-(+)-mandelate salt afforded (1S,2S,5R)-(+)-16; the absolute configuration was determined by single-crystal X-ray analysis of (-)-16.(R)-(-)-mandelate. Single-crystal X-ray analysis of (+/-)-9-picrate confirmed its trans configuration and provided conformational data. (+)- and (-)-8 and (+/-)-9 were examined for their ability to interact with PCP and sigma binding sites in vitro using [3H]TCP and [3H]pentazocine as radioligands. The binding was compared with that of PCP and contrasted with the rigid symmetrical phencyclidine derivatives cis- and trans-1-[3-phenyl-3-bicyclo[3.1.0]hexyl]piperidines (6 and 7). The results of the study indicated that the conformations of PCP represented by 6-9 are not optimal for potent interaction at either of these sites. Affinities ranged from 582 nM [(+/-)-9] to 29,000 nM [(+)-8] at PCP binding sites and from 1130 nM [(-)-8] to 16,300 nM (7) at sigma sites. In this assay, PCP exhibited affinities of 64.5 nM at PCP and 1090 nM at sigma sites. Qualitative correlation between the sigma and PCP binding data suggests some similarities between these binding sites. An axial phenyl and equatorial piperidine ring with the nitrogen lone pair of electrons antiperiplanar to the phenyl ring has been postulated as the receptor-active conformation of PCP-like ligands at the PCP binding site. Comparison of the binding data of 7-9 with that of the previously described methylcyclohexyl-PCP derivatives allowed its rationalization in terms of this model. It is likely that the lowered affinity in this bicyclo[3.1.0]hexane series is a consequence of nonoptimal geometry (pseudoequatorial phenyl or pseudoboat) for binding as opposed to the presence of steric bulk which proved deleterious in the methylcyclohexyl-PCP derivatives.