Cocaine and other indirect-acting monoamine agonists differentially attenuate a naltrexone discriminative stimulus in morphine-treated rhesus monkeys

Monoaminergic drugs can modify opioid withdrawal in nonhumans, and cocaine is reported to attenuate opioid withdrawal in humans. Drug discrimination was used to examine whether s.c. cocaine or other indirect-acting monoamine agonists attenuate morphine (3.2 mg/kg/day) withdrawal induced by naltrexone and by 27 h of morphine deprivation. Naltrexone-precipitated withdrawal was attenuated not only by morphine but also by cocaine, amphetamine, and imipramine. However, reversal of naltrexone-precipitated withdrawal was greater for morphine than for any of the indirect-acting monoamine agonists. Attenuation of the naltrexone discriminative stimulus by indirect-acting monoamine agonists was pharmacologically selective insofar as drugs lacking affinity for monoamine transporters (ketamine and triazolam) were without effect. Twenty-seven hours of morphine deprivation occasioned naltrexone-lever responding and decreased response rate, and both effects were reversed by morphine, cocaine, and amphetamine and not by imipramine, desipramine, ketamine, and triazolam. Thus, indirect-acting monoamine agonists attenuate some (e.g., discriminative) aspects of naltrexone-precipitated withdrawal, whereas only indirect-acting agonists with high affinity for dopamine transporters attenuate deprivation-induced withdrawal. These results suggest that dopamine is differentially involved in naltrexone- and deprivation-induced withdrawal and support the notion that opioid-dependent individuals use stimulants, in part, to attenuate withdrawal.     

STUDIES ON RABBIT LYMPHOCYTES IN VITRO : III. PROTEIN, RNA, AND DNA SYNTHESIS BY LYMPHOCYTE CULTURES AFTER STIMULATION WITH PHYTOHAEMAGGLUTININ, WITH STAPHYLOCOCCAL FILTRATE, WITH ANTIALLOTYPE SERUM, AND WITH HETEROLOGOUS ANTISERUM TO RABBIT WHOLE SERUM

In vitro cultures of the peripheral blood lymphocytes of rabbits may be stimulated with phytohaemagglutinin, staphylococcal filtrate, antiallotype serum, or sheep anti-rabbit whole serum to synthesize protein, RNA and DNA as indicated by the incorporation of radiolabelled precursor substances into these products. A sequence of events found in all stimulated cultures characteristically shows protein synthesis followed by RNA synthesis, histologic blast transformation, DNA synthesis, and mitosis, with the complete sequence requiring 48 hours. All four stimulants induce essentially identical metabolic changes. Characterization of the proteins synthesized by lymphocytes in vitro has failed to demonstrate immunoglobulin synthesis by stimulated or non-stimulated cultures. It is concluded that the majority of proteins produced by peripheral lymphocytes stimulated in vitro are most likely cellular proteins related to the metabolic alterations necessary for mitosis. Absorption of sheep antisera to whole rabbit serum with rabbit IgG does not always remove the transforming capacity of the sheep antisera. Thus, it is likely that antibodies to proteins other than IgG present in the small lymphocyte may also be able to stimulate transformation. A possible common mechanism for the induction of lymphoblast transformation may be the ability of both specific and non-specific stimulants to react with protein constituents of the lymphocyte which may also be present in serum.     

Patients prescribed injectable heroin or methadone -their opinions and experiences of treatment

Aims To describe the opinions and experiences of treatment of a cohort of patients prescribed injectable opiate treatment (IOT). Design, setting, participants Cross‐sectional survey of all patients on injectable diamorphine or methadone at a tertiary referral clinic in the northwest of England in June 2000. Findings A total of 104 subjects were prescribed IOT, mostly male (87.5%) and with a mean age of 36.3 years (SEM 0.66, range 20–53). The majority (75.0%) were prescribed injectable methadone with the remainder (25.0%) on injectable diamorphine. Most subjects (93.3%) used intravenously, many (58.7%) into the femoral vein. Treatment was sought most frequently in order to procure a drug supply of known dose and purity, to improve family relationships and to avoid trouble with the police. Half were satisfied with their treatment but many wanted to change to injectable diamorphine or to increase their doses. Subjects cited many advantages of injectable diamorphine over injectable methadone, although benefits of injectable methadone were acknowledged. Conclusions Subjects articulated a consistent desire for IOT in order to ‘stabilize’ their lives in a number of ways. This sample was recruited from one of the country's largest specialist IOT clinics. The generalizability of this study's findings to all patients in the United Kingdom currently prescribed IOT, however, was not examined. Nevertheless, these findings suggest that clinicians and policy makers should be aware of many heroin users’ perception of IOT as long‐term treatment and their clear preference for injectable diamorphine. Further investigation of differential outcomes between oral and injectable OT and between different injectable opiates is warranted.     

High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/- SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/- 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.     

Requirements for simian immunodeficiency virus antigen-specific in vitro proliferation of T cells from infected rhesus macaques and sooty mangabeys

The measurement of cell-mediated immunity against the etiologic agent of human AIDS (HIV) in the non-human primate model of AIDS (simian immunodeficiency virus, SIV) has been difficult. In general, culture of peripheral blood mononuclear cells from HIV-1- and SIV-infected humans and monkeys, respectively, with purified inactivated HIV and SIV virus preparations has given inconsistent or negative proliferative responses. However, we describe herein an assay which consists of coculturing monocytes that have been pulsed with inactivated SIVsmm with nylon-wool-purified autologous T cells, leading to antigen-specific T-cell proliferation. The proliferative response, which predominantly occurs in CD4+ T cells, is major histocompatibility complex (MHC) class II-restricted and requires antigen processing. This assay will greatly facilitate the identification of the immunodominant epitopes recognized by T cells in sooty mangabeys, which are naturally infected but remain clinically asymptomatic, and in rhesus macaques, in which experimental infection leads to clinical symptomatology similar to human AIDS, eventually resulting in death.     

Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor

Mice that are mutant at the op locus have a severe deficiency of mononuclear phagocytes due to an inactivating mutation in the CSF-1 (macrophage colony-stimulating factor, M-CSF) gene. op/op mice are toothless, possessing skeletal abnormalities, a low body weight, and compromised fertility; they are osteopetrotic due to a deficiency of osteoclasts. The congenital osteopetrosis, toothless phenotype, osteoclast deficit, and the defects in splenic and femoral macrophages were corrected by routes of administration of human recombinant CSF-1 that maintained normal circulating CSF-1 concentrations. Early restoration of circulating CSF-1 was required for rescue of the toothless phenotype, but only partially restored body weight. In contrast, the deficiencies of pleural and peritoneal cavity macrophages and the reduced female fertility were not corrected by restoration of circulating CSF-1. These results suggest that although circulating CSF-1 is required for osteoclast and macrophage production, local synthesis and action of the growth factor are important for certain target cell populations.