Understanding the role α7 nicotinic receptors play in dopamine efflux in nucleus accumbens

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction.Peer reviewe

Bridged Nicotine Compounds for Use in the Treatment of CNS Pathologies

Pharmaceutical compounds comprising bridged nicotine analogs of N-octylnicotinium iodide (NONI) having selective antagonist properties at α3β2-containing nicotinic receptor subtypes, and compositions containing these compounds. The compounds and compositions are used to treat central nervous system pathologies

\u3cem\u3eBis\u3c/em\u3e-Pyridino Containing Compounds for the Use in the Treatment of CNS Pathologies

N-n-Alkylation of nicotine converts nicotine from an agonist into an antagonist specifically for neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogs exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter

2,6-Disubstituted Piperidines as Modulators of Nicotinic Acetylcholine Receptor Mediated Neurotransmitter Release, Uptake and Storage

Compounds used for treating dependence on or withdrawal from a drug of abuse, for an eating disorder or for a CNS disease or pathology . . . To see the remainder of this abstract, please download this patent

Selective targeting of melanoma using N-(2-diethylaminoethyl) 4-[18F]fluoroethoxy benzamide (4-[18F]FEBZA): a novel PET imaging probe

Abstract Background The purpose of this study was to develop a positron emission tomography (PET) imaging probe that is easy to synthesize and selectively targets melanoma in vivo. Herein, we report the synthesis and preclinical evaluation of N-(2-diethylaminoethyl) 4-[18F]Fluoroethoxy benzamide (4-[18F]FEBZA). A one-step synthesis was developed to prepare 4-[18F]FEBZA in high radiochemical yields and specific activity. The binding affinity, the in vitro binding, and internalization studies were performed using B16F1 melanoma cell line. The biodistribution studies were performed in C57BL/6 normal mice, C57BL/6 mice bearing B16F1 melanoma tumor xenografts, and nu/nu athymic mice bearing HT-29 human adenocarcinoma tumor and C-32 amelanotic melanoma tumor xenografts. MicroPET studies were performed in mice bearing B16F1 and HT-29 tumor xenografts. Results 4-[18F]FEBZA was prepared in 53 ± 14% radiochemical yields and a specific activity of 8.7 ± 1.1 Ci/μmol. The overall synthesis time for 4-[18F]FEBZA was 54 ± 7 min. The in vitro binding to B16F1 cells was 60.03 ± 0.48% after 1 h incubation at 37 °C. The in vivo biodistribution studies show a rapid and high uptake of F-18 in B16F1 tumor with 8.66 ± 1.02%IA/g in this tumor at 1 h. In contrast, the uptake at 1 h in HT-29 colorectal adenocarcinoma and C-32 amelanotic melanoma tumors was significantly lower with 3.68 ± 0.47%IA/g and 3.91 ± 0.23%IA/g in HT-29 and C-32 tumors, respectively. On microPET images, the melanoma tumor was clearly visible by 10 min post-injection and the intensity in the tumor continued to increase with time. In contrast, the HT-29 tumor was not visible on the microPET scans. Conclusions A rapid and facile synthesis of 4-[18F]FEBZA is developed. This method offers a reliable production of 4-[18F]FEBZA in high radiochemical yields and specific activity. A high binding affinity to melanoma cells and high uptake in tumor was noted. The microPET scan clearly delineates the melanoma tumor by 10 min post-injection. The results from these preclinical studies support the potential of 4-[18F]FEBZA as an effective probe to image melanoma

Short-Term Consequences of Single Social Defeat on Accumbal Dopamine and Behaviors in Rats

The present study aimed to explore the consequences of a single exposure to a social defeat on dopamine release in the rat nucleus accumbens measured with a fast-scan cyclic voltammetry. We found that 24 h after a social defeat, accumbal dopamine responses, evoked by a high frequency electrical stimulation of the ventral tegmental area, were more profound in socially defeated rats in comparison with non-defeated control animals. The enhanced dopamine release was associated with the prolonged immobility time in the forced swim test. The use of the dopamine depletion protocol revealed no alteration in the reduction and recovery of the amplitude of dopamine release following social defeat stress. However, administration of dopamine D2 receptor antagonist, raclopride (2 mg/kg, i.p.), resulted in significant increase of the electrically evoked dopamine release in both groups of animals, nevertheless exhibiting less manifested effect in the defeated rats comparing to control animals. Taken together, our data demonstrated profound alterations in the dopamine transmission in the association with depressive-like behavior following a single exposure to stressful environment. These voltammetric findings pointed to a promising path for the identification of neurobiological mechanisms underlying stress-promoted behavioral abnormalities

Applying a Fast-Scan Cyclic Voltammetry to Explore Dopamine Dynamics in Animal Models of Neuropsychiatric Disorders

Progress in the development of technologies for the real-time monitoring of neurotransmitter dynamics has provided researchers with effective tools for the exploration of etiology and molecular mechanisms of neuropsychiatric disorders. One of these powerful tools is fast-scan cyclic voltammetry (FSCV), a technique which has progressively been used in animal models of diverse pathological conditions associated with alterations in dopamine transmission. Indeed, for several decades FSCV studies have provided substantial insights into our understanding of the role of abnormal dopaminergic transmission in pathogenetic mechanisms of drug and alcohol addiction, Parkinson’s disease, schizophrenia, etc. Here we review the applications of FSCV to research neuropsychiatric disorders with particular attention to recent technological advances