Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal

Previous studies from our laboratory using methylnaloxonium, a hydrophilic antagonist, showed that opiate receptors in the region of the nucleus accumbens are important for the acute reinforcing effects of heroin in non-dependent rats. A similar increased sensitivity to the response disruptive effects of intracerebrally injected methylnaloxonium in opiate dependent rats was observed in a fixed-ratio (FR) baseline of operant behaviors. These results suggest that the same opiate receptors in the region of the nucleus accumbens important for the positive reinforcing stimulus properties of opiates may also be responsible for the response disruptive, aversive stimulus properties of opiate withdrawal. These results also suggest that the neural substrates of some aspects of dependence may be partly related to those of the reinforcing effects of opiates. In particular, it is hypothesized that euphoria and dysphoria induced by opiates may reflect opponent motivational processes operating at a cellular level within the nucleus accumbens.     

Opponent process theory of motivation: neurobiological evidence from studies of opiate dependence

One hypothetical model for a mechanism of drug dependence involves the development of an adaptive process that is initiated to counter the acute effects of the drug. This adaptive process persists after the drug has been cleared from the brain, leaving an opposing reaction unopposed (abstinence signs). From a motivational perspective a particularly attractive hypothesis has been that of opponent process theory (32). Here many reinforcers elicit positive affective and hedonic processes that are opposed by negative affective and hedonic processes. Thus the intense pleasure of the opiate drug "rush" or "high" would be opposed by aversive withdrawal symptoms. The present paper presents neurobiological evidence to support the opponent process concept and suggests neural circuitry that may be involved. The region of the nucleus accumbens in the forebrain of the rat has been shown to be a particularly sensitive substrate not only for the acute reinforcing properties of opiate drugs, but also for the response disruptive effects of opiate antagonists in opiate dependent rats. This region also appears to be particularly sensitive to the aversive stimulus effects of opiate antagonists using a place aversion measure in dependent rats. These results suggest that the region of the nucleus accumbens and its neural circuitry may be an important neural substrate for both the positive and negative motivational aspects of drug dependence.     

Effector cells in natural cytotoxicity against human bladder cancer cell lines

Summary Human peripheral blood mononuclear cells obtained by ficoll-hypaque sedimentation were depleted of Fc-receptor-bearing (FcR+) cells. Cytotoxicity (direct killing of target cells by effector cells), tested in a 40 h assay, was significantly decreased against a variety of target cells. Tests in which no FcR+ cells could be detected were also positive for natural killing (NK) against a spectrum of target cells from normal donors. NK in this system was mediated by more than one subpopulation of lymphocytes. Monocytes probably did not play a significant role.Decreasing the FcR+ cells in peripheral blood mononuclear cells in patients with bladder cancer and in controls did not reveal specific antitumour activity.This work was supported by NTH grant CA16880 through the National Bladder Cancer Project, and grant CA12800 from the National Cancer Institute     

An enteroglucagon tumour

A hormone-secreting renal tumour that affected small bowel structure, motility, and function has been described by Gleeson et al (1971). The present studies show that the large amount of glucagon-like immunoreactivity which could be extracted from this tumour had the molecular weight, action on plasma insulin and glucose in vivo, and immunological reactions of the gut hormone enteroglucagon. This is the first enteroglucagonoma to be reported.     

Toward a code of ethics for primary prevention

This paper explores the topic of a code of ethics for primary prevention, and offers some tentative guidelines for the purpose of stimulating discussion. Codes of ethics provide guidelines for both procedural issues — such as the relationship of the practitioner with consumers, colleagues, and the community at large — and substantive issues — what goals and objectives to pursue, and how to resolve conflicts between them. This paper discusses some philosophical issues and then presents nine rules derived from the Hippocratic tradition, but expanded to fit the context of contemporary primary prevention.     

Developmentally regulated rat brain mRNAs: molecular and anatomical characterization

In order to identify markers for developing neural cell populations and gain molecular insights into the processes of neural development and differentiation, we have selected cDNA clones of rat brain mRNAs that are expressed in brain at embryonic day 16 (E16) with at least 10-fold greater abundance than they are in adult brain. Eleven such clones were obtained from a cDNA library of E16 brain poly(A)+ RNA using a combination of differential and subtractive hybridization screens. The temporal and spatial patterns of expression of the mRNAs corresponding to these clones were characterized by Northern (RNA) blotting and by in situ hybridization. Although all the mRNAs were enriched in embryonic brain, different mRNAs demonstrated maximum abundance at different times in late embryogenesis. The mRNAs can be grouped into 3 classes on the basis of their patterns of spatial expression in the embryo: one cDNA clone from each class and its corresponding mRNAs have been characterized in more detail. Class C represents mRNAs that are highly enriched in the nervous system and may be expressed in newly differentiating neurons; the example chosen was shown by nucleotide sequence analysis to encode the brain alpha 1 isotype of tubulin. Class B mRNAs have a broader distribution in the developing embryo but are expressed predominantly in the ventricular germinal zones of the developing nervous system and may represent molecules involved with neurogenesis. A third class (Class A) includes mRNAs with a more homogeneous distribution within the embryo and developing nervous system, which may encode "housekeeping" molecules. These clones and their encoded products will provide markers for cell populations at particular stages of neural development.     

Mitogenic peptides in breast cyst fluid: relationship with intracystic electrolyte ratios

Women with palpable breast cysts which are lined with apocrine epithelium may be at higher risk of developing breast cancer than women with breast cysts which are lined with flattened epithelium, the former group being characterized by intracystic sodium to potassium ratios below 3, while the latter group has intracystic sodium to potassium ratios above 3. In this study the distribution of intracystic concentrations of the mitogenic peptides, epidermal growth factor, endothelin and gastrin-releasing peptide in the 2 groups of breast cysts were compared to see whether differences in concentrations between the 2 cyst groups might provide an explanation for the higher risk of breast cancer observed in women with "apocrine" breast cysts. The concentrations of epidermal growth factor and gastrin-releasing peptide were significantly higher in the low electrolyte ratio group (p less than 0.001). There was no difference in endothelin concentrations between the 2 groups. Negative correlations were found between epidermal growth factor concentrations and Na+/K+ and between gastrin-releasing peptide concentrations and Na+/K+ (p less than 0.001). A positive correlation was found between gastrin-releasing peptide and epidermal growth factor concentrations in breast cyst fluid (p less than 0.001). The significantly higher intracystic concentrations of both epidermal growth factor and gastrin-releasing peptide in the low-electrolyte-ratio group may provide an explanation for the higher risk of breast cancer which has been observed in women with "apocrine" breast cysts.