L-type Ca²âº channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory.

Drug addiction is driven, in part, by powerful and enduring memories of sensory cues associated with drug intake. As such, relapse to drug use during abstinence is frequently triggered by an encounter with drug-associated cues, including the drug itself. L-type Ca(2+) channels (LTCCs) are known to regulate different forms of synaptic plasticity, the major neural substrate for learning and memory, in various brain areas. Long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA) may contribute to the increased motivational valence of drug-associated cues triggering relapse. In this study, using rat brain slices, we found that isradipine, a general LTCC antagonist used as antihypertensive medication, not only blocks the induction of NMDAR LTP but also promotes the reversal of previously induced LTP in the VTA. In behaving rats, isradipine injected into the VTA suppressed the acquisition of cocaine-paired contextual cue memory assessed using a conditioned place preference (CPP) paradigm. Furthermore, administration of isradipine or a CaV1.3 subtype-selective LTCC antagonist (systemic or intra-VTA) before a single extinction or reinstatement session, while having no immediate effect at the time of administration, abolished previously acquired cocaine and alcohol (ethanol) CPP on subsequent days. Notably, CPP thus extinguished cannot be reinstated by drug re-exposure, even after 2 weeks of withdrawal. These results suggest that LTCC blockade during exposure to drug-associated cues may cause unlearning of the increased valence of those cues, presumably via reversal of glutamatergic synaptic plasticity in the VTA.

Electrochemistry-mass spectrometry unveils the formation of reactive triclocarban metabolites.

Triclocarban (3,4,4'-trichlorocarbanilide, TCC) is a widely used antibacterial agent in personal care products and is frequently detected as an environmental pollutant in waste waters and surface waters. In this study, we report novel reactive metabolites potentially formed during biotransformation of TCC. The oxidative metabolism of TCC has been predicted using an electrochemical cell coupled online to liquid chromatography and electrospray ionization mass spectrometry. The electrochemical oxidation unveils the fact that hydroxylated metabolites of TCC may form reactive quinone imines. Moreover, a so-far unknown dechlorinated and hydroxylated TCC metabolite has been identified. The results were confirmed by in vitro studies with human and rat liver microsomes. The reactivity of the newly discovered quinone imines was demonstrated by their covalent binding to glutathione and macromolecules, using ß-lactoglobulin A as a model protein. The results regarding the capability of the electrochemical cell to mimic the oxidative metabolism of TCC are discussed. Moreover, the occurrence of reactive metabolites is compared with findings from earlier in vivo studies and their relevance in vivo is argued.

Differential effects of intra-midbrain raphe and systemic 8-OH-DPAT on VTA self-stimulation thresholds in rats.

RATIONALE: Intra-median raphe nucleus (MRN) administration of the 5-HT(1A) receptor agonist 8-OH-DPAT decreases lateral hypothalamic self-stimulation thresholds and is reported to have biphasic effects following systemic administration. These experiments attempted to extend the previous findings to mesolimbic pathway self-stimulation at ventral tegmental area (VTA) electrodes. OBJECTIVES: This study was conducted to provide comparative data for systemic and intra-dorsal raphe nucleus (DRN) and intra-MRN effects of 8-OH-DPAT on VTA self-stimulation. METHODS: Male Sprague-Dawley rats with VTA electrodes were trained to respond for electrical stimulation. Systemic and intra-midbrain raphe 8-OH-DPAT effects on rate-frequency thresholds were measured. Systemic administration of WAY 100635 was used to confirm 5-HT(1A) receptor mediation of 8-OH-DPAT effects. RESULTS: 8-OH-DPAT (0.003-0.3 mg kg(-1) SC) increased rate-frequency thresholds and decreased maximal response rates. WAY 100635 alone (0.0125-0.1 mg kg(-1) SC) did not alter these measures. Intra-DRN and intra-MRN 8-OH-DPAT (5.0 microg) decreased rate-frequency thresholds without altering maximal response rates. Intra-DRN 8-OH-DPAT (0.1-5.0 microg) induced a slight decrease and intra-MRN 8-OH-DPAT a slight increase in locomotor activity. WAY 100635 (0.1 mg kg(-1)) blocked effects of 8-OH-DPAT on VTA self-stimulation. CONCLUSION: These results confirm threshold-decreasing effects of intra-MRN 8-OH-DPAT and extend this to the DRN and to VTA thresholds. Monophasic dose dependent increases in VTA thresholds following systemic 8-OH-DPAT are not equivalent to reports for hypothalamic self-stimulation. Differences between studies may be attributable to stimulation site and/or differences in threshold measurement procedures. Effects of WAY 100635 in this study indicate 5-HT(1A) receptor mediation of these 8-OH-DPAT effects.

In vitro validation of effects of BDNF-expressing mesenchymal stem cells on neurodegeneration in primary cultured neurons of APP/PS1 mice.

Alzheimer's disease (AD), the most common type of dementia, is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal loss in defined regions of the brain including the hippocampus and cortex. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) offers a safe and potentially effective tool for treating neurodegenerative disorders. However, the therapeutic effects of BM-MSCs on AD pathology remain unclear and their mechanisms at cellular and molecular levels still need to be addressed. In this study, we developed a unique neuronal culture made from 5xFAD mouse, an APP/PS1 transgenic mouse model (FAD neurons) to investigate progressive neurodegeneration associated with AD pathology and efficacy of brain-derived neurotrophic factor expressing-MSCs (BDNF-MSCs). Analyses of the expression of brain-derived neurotrophic factor (BDNF), synaptic markers and survival/apoptotic signals indicate that pathological features of cultured neurons made from these mice accurately mimic AD pathology, suggesting that our protocol provided a valid in vitro model of AD. We also demonstrated amelioration of AD pathology by MSCs in vitro when these FAD neurons were co-cultured with MSCs, a paradigm that mimics the in vivo environment of post-transplantation of MSCs into damaged regions of brains. To overcome failed delivery of BDNF to the brain and to enhance MSCs releasing BDNF effect, we created BDNF-MSCs and found that MSCs protection was enhanced by BDNF-MSCs. This protection was abolished by BDNF-blocking peptides, suggesting that BDNF supply from BDNF-MSCs was enough to prevent AD pathology.

Development of an ELISA for the detection of the residues of the insecticide imidacloprid in agricultural and environmental samples.

A competitive enzyme-linked immunosorbent assay (ELISA) for the chloronicotinyl insecticide imidacloprid was developed using a polyclonal antibody produced against a hapten conjugated through the imidazolidine to keyhole limpet hemocyanin. In the standard curve of imidacloprid, an IC(50) of 17.3 ng/mL was obtained using a competitive heterologous system at pH 10. Very low cross-reactivity was found for some structurally related compounds including the insecticide thiacloprid. The high cross-reactivity with a metabolite containing the carbonyl group in the imidazolidine moiety suggests the involvement of its polarity and stereochemical fitness in forming the antibody--antigen complex. The effects of various assay conditions, including organic solvents, detergent content, salt concentration, and pH on the sensitivity were evaluated. High-performance liquid chromatography was run for comparison to validate the ELISA with fortified water samples, the correlation being 0.997-0.998 (n = 15) with a slope of 1.10--1.38. The ELISA turned out to be a convenient tool for monitoring imidacloprid residues in agricultural and environmental samples.

A study on the acceptability of male fertility regulating methods in Korea.

PIP: In order to assess the acceptability of existing and potential male fertility regulating methods in Korea, a total of 353 male respondents were interviewed from 3 sampling areas: 99 cases from urban middle socioeconomic status, 104 cases from urban low socioeconomic status, and 150 cases from the rural area. Respondents from each area differed in terms of educational attainment and socioeconomic status. Respondents from each area have about the same level of knowledge of contraceptive methods, but their behaviors differ considerably. The rate of currently practicing contraception was highest among rural samples and lowest among urban low socioeconomic groups. The relative acceptability of 2 existing (condom and vasectomy) and 2 potential (daily pill and monthly injection) male fertility regulating methods was assessed using several measures of acceptability. Whatever measure used, the most consistent finding among sampling groups was that vasectomy is the least acceptable method. Vasectomy is least preferred among potential users, and this finding suggests that the current target system on vasectomy in the national family planning program should be reconsidered. For all measures of acceptability potential methods were more preferred than either condom or vasectomy for the rural and urban low socioeconomic status samples. With regard to the potential male methods, methods with longer duration of action are preferred to methods with a shorter duration. Urban-rural residence was found to be significantly related to the acceptability of condom and vasectomy; urban residents liked condom and vasectomy more than rural residents. Age of respondents was not significantly related to the attitudes toward using each male method but significantly related to the behavioral intention to use each male method. The education level is not significantly related to the acceptability of condom but related to the acceptability of other male fertility regulating methods. More than 1/2 of the respondents said that they would use male fertility regulating methods; less than 1/4 of the respondents said that only wives should practice birth control.^ieng

The 'unreached' in family planning: a case study of the Republic of Korea.

PIP: The family planning program of the Republic of Korea has been quite successful, yet it has not been able to extend its services to all couples of childbearing age. There still exists a group of couples who want no more children and yet are not currently using any contraceptive method. The word pong-eem which literally means being neglected, i.e. untouched by the family planning program, was coined to describe this group. National surveys have shown that the proportion of women of reproductive age in this group is significant. The study on which this article is based focuses on the psychosocial characteristics of the group to provide policy makers, family planning administrators and workers with the specific information they need in order to reduce its size. Among the factors affecting the family planning decisions of couples is demographic pressure. However, there was no statistically significant relationship between demographic pressure and family planning status. With regard to the couples' knowledge about contraception, the higher the respondents' level of knowledge was, the lower was their proportion in the pong-eem group. In both the urban and rural areas, the proportion of women in the pong-eem group was higher among those who disapproved of the Government's population policies. The proportion of women in the pong-eem group was much higher among those who were least motivated to limit family size. The lower the level of social support for family planning, the higher was the proportion of women in the pong-eem group in both the urban and rural areas. Among the psychosocial characteristics, social support for family planning was the most closely related to the family planning status of couples no matter what measure of social support was used.^ieng

Study on a method to improve simultaneously vital statistics and family planning among maternity cases.

PIP: In order to develop a public health program in Korea that would simultaneously improve the reporting of vital health statistics and spread the use of family planning, simple hygenic delivery kits with accompanying family planning information were distributed to expectant mothers in Kimchun city and the surrounding rural district of Kumnung Gun. There was a population of 70,000 people in the experimental and control areas during 1966-67. Vital statistic reports and family planning use were compared between areas with the delivery plan and control areas without the kit delivery. Since use of the delivery kits cut down the infant mortality rate, the mothers should be more receptive to family planning in this program. The delivery kit program was found to improve vital statistic reporting and reduce infant mortality. Though more urban mothers than rural mothers wanted to use the kits, more rural deliveries than urban deliveries actually employed the program's kit. The assigning of a vital events reporter in each area shortened the delay between the event and the report and even increased death reporting though it was not part of the program. Vital statistic reporting was more improved by this program in rural than in urban areas. Family planning acceptance in the experimental area was more than 2 times than in the control area. Though the length of the study is too short to accurately determine its effect on maternal health and fertility patterns in Korea, the combining of hygenic delivery kits with family planning information does improve maternal and infant health, increases vital statistic reporting, and aids family planning acceptacne.^ieng