Oxytocin secretion in response to cholecystokinin and food: differentiation of nausea from satiety.

Administration of cholecystokinin (CCK) to rats caused a dose-dependent increase in plasma levels of the neurohypophyseal hormone oxytocin (OT). The OT secretion was comparable to that found in response to nausea-producing chemical agents that cause learned taste aversions. The effect of CCK on OT secretion was blunted after gastric vagotomy, as was the inhibition of food intake induced by CCK. Food ingestion also led to elevated plasma OT in rats, but CCK and aversive agents caused even greater OT stimulation. Thus, after administration of large doses of CCK, vagally mediated activation of central nausea pathways seems to be predominantly responsible for the subsequent decrease in food intake. Despite their dissimilar affective states, both nausea and satiety may activate a common hypothalamic oxytocinergic pathway that controls the inhibition of ingestion.

Anti-cancer properties of phenolics from apple waste on colon carcinogenesis in vitro.

Colorectal cancer is one of the most common cancers in Western countries. The World Health Organisation identifies diet as a critical risk factor in the development and progression of this disease and the protective role of high levels of fruit and vegetable consumption. Several studies have shown that apples contain several phenolic compounds that are potent anti-oxidants in humans. However, little is known about other beneficial properties of apple phenolics in cancer. We have used the HT29, HT115 and CaCo-2 cell lines as in vitro models to examine the effect of apple phenolics (0.01-0.1% apple extract) on key stages of colorectal carcinogenesis, namely; DNA damage (Comet assay), colonic barrier function (TER assay), cell cycle progression (DNA content assay) and invasion (Matrigel assay). Our results indicate that a crude extract of apple phenolics can protect against DNA damage, improve barrier function and inhibit invasion (p<0.05). The anti-invasive effects of the extract were enhanced with twenty-four hour pretreatment of cells (p<0.05). We have shown that a crude apple extract from waste, rich in phenolic compounds, beneficially influences key stages of carcinogenesis in colon cells in vitro.

Differential activation of microglia and astrocytes following trimethyl tin-induced neurodegeneration.

We have investigated the response of astrocytes and microglia to trimethyl tin intoxication in the septum, hippocampus, olfactory bulb, and pyriform cortex of the rat. Microglia were studied qualitatively using lectin histochemistry, and astrocytes were examined both qualitatively with immunohistochemistry, and quantitatively using an immunoassay for glial fibrillary acidic protein. Our results show that activated microglia first appeared 2 days after trimethyl tin intoxication in the lateral septum and hippocampus. Four days after trimethyl tin intoxication, the same regions revealed a most intense microglial reaction characterized by microglial hypertrophy and the formation of phagocytic clusters. By day 7, microglial activation in the septum and hippocampus had lessened, suggesting that the cells were reverting to the resting phenotype. The microglial response in the pyriform cortex and olfactory bulb, while being later in onset than in the septum and hippocampus, showed a similar progression of microglial changes reaching maximal intensity 7 days after trimethyl tin intoxication. Significant increases in the expression of glial fibrillary acidic protein were observed in all regions examined and typically occurred after microglial activation was already underway. We conclude that microglial and astroglial reactions which occur in response to trimethyl tin-induced neuronal necrosis are separated in time, with microglial activation preceding astrogliosis. In addition, our study stresses the importance of microglia as an endogenous source of CNS macrophages, and illustrates the merit of histochemical analysis with microglial markers for the early delineation of neurotoxicant-induced brain damage.

Species-specific effects of bombesin on gastric emptying and neurohypophyseal secretion.

Previous reports have demonstrated that systemic injection of cholecystokinin (CCK) in rats produces dose-related decreases in food intake, increases in neurohypophyseal secretion of oxytocin (OT), and decreases in gastric emptying. The present studies determined whether systemic injection of bombesin (BBS), another peptide that potently reduces food intake in rats, had similar effects on OT secretion and gastric emptying. Although BBS produces a dose-dependent inhibition of food intake, even very high doses did not significantly affect plasma OT levels and only slightly decreased rates of gastric emptying. Consequently, despite their similar inhibitory effects on food intake, BBS does not appear to activate the same network of central nervous system pathways as does CCK in rats. However, parallel studies in monkeys demonstrated that systemic injection of BBS was effective in stimulating neurohypophyseal secretion of vasopressin rather than OT, in a pattern both qualitatively and quantitatively analogous to the effects of CCK in this species. Together with previous findings that BBS more potently inhibits gastric emptying in primates than in rats, these results therefore also suggest the presence of significant species differences in the central mechanisms by which BBS acts to reduce food intake.

Dorsal medullary injection of atrial natriuretic factor (ANF) excites vagal efferents and inhibits gastric motility.

Atrial natriuretic factor (ANF)-immunoreactive fibers are found in the dorsal motor nucleus of the vagus (DMN) along with receptors for that peptide. Previous investigations showed that ANF injections into the DMN did not influence cardiovascular functions. Since the DMN is largely (but not exclusively) involved with the control of gastrointestinal functions, we hypothesized that ANF may act on gastric, rather than cardiovascular vagal efferents. Injections of ANF (20 pmol rat atriopeptin III in 20 nl) into the DMN evoked a vagally dependent reduction in gastric motility. In a separate electrophysiological study, 10 of 15 (66%) antidromically identified DMN neurons were excited by micropressure-applied ANF (25-500 fmol in 50-1000 pl). We propose that ANF-containing neurons in the DMN reduce gastric motility by activating vagal efferents that synapse with inhibitory neurons in the gastric enteric nervous system.

Nucleus raphe obscurus (nRO) influences vagal control of gastric motility in rats.

Because the nucleus raphe obscurus (nRO) maintains a direct connection with the dorsal vagal complex in the medulla, this nucleus has the potential to influence vagal control of gastric function. Both electrical- and glutamate-induced activation of the nRO were found to enhance gastric motility and tone in the rat. The gastric responses to nRO stimulation were abolished by peripheral muscarinic blockade.

Effects of TRH on the activity of gastric inflation-related neurons in the solitary nucleus in the rat.

Thyrotropin-releasing hormone (TRH) has been identified as a potent central regulator of gastrointestinal function. It has been hypothesized that TRH influences gastric function by modulating the effectiveness of gastric vago-vagal reflexes. To test this hypothesis, we studied the effects of TRH on neurons of the nucleus of the solitary tract (NTS) that respond to gastric inflation. Of the 23 inflation-sensitive neurons studied, 11 or 48% had reduced spontaneous activity after TRH injection; none were excited. These results provide evidence that a part of the TRH effect on the regulation of gastric function involves suppressing the NTS response to gastric afferent input from the vagus nerve.

A 3-year progress report on the implementation of LAAM in the United States.

AIMS: LAAM, a long-acting opioid agonist, was approved by the US Food and Drug Administration in 1993 for use in licensed narcotic treatment programs. These programs have the exclusive authority in the United States to dispense methadone and LAAM for the treatment of opiate dependence. The purpose of this report is to describe the course of LAAM's implementation and to document some of the factors that have influenced the time course and extent of this process. DESIGN: Narcotic treatment programs approved for LAAM use were contacted by telephone at three timepoints following the FDA approval of LAAM in 1993. FINDINGS: Regulatory hurdles have been the most significant factor in slowing the use of LAAM. Some clinics have enthusiastically moved LAAM into mainstream use with great success. At other clinics LAAM implementation has been impeded by staff resistance and management reluctance. Some specific clinical practices, such as provision of adequate dose levels and flexible dosing practices, appear to be associated with superior clinical response, but issues of staff and organizational attitude toward the new medication are probably the most important impediments to a more positive response. CONCLUSIONS: The tasks involved with introducing a new opiate agonist treatment into mainstream use in the United States are numerous and complex. Clinical policies, fiscal issues and regulatory factors must all be addressed. The introduction of LAAM into the treatment system provides some useful lessons as other new addiction pharmacotherapies are moved into mainstream use.

Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts.

In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described.

Visceral factors in the control of food intake.

Some years ago, we reported that the increased blood intake of hypoglycemic rats was inhibited by the intravenous infusion of fructose, a sugar that cannot cross the blood-brain barrier and nourish cerebral chemoreceptors. More recent experiments therefore have focused on visceral factors in the control of food intake. Three observations have been emphasized in this review. First, we found that gastric emptying was increased during insulin-induced hypoglycemia, and that this effect also was eliminated by administration of fructose. Hepatic vagotomy abolished both this effect of fructose on gastric emptying and its effect on food intake. Second, we found that in rats with severe diabetes, the rate of gastric emptying did decrease in proportion to increasing concentration of an administered glucose load, as it does in intact rats, but calories emptied more rapidly than normal regardless of the concentration of the load. Third, we found that rats with varying degrees of streptozotocin-induced damage to the pancreas ate more food than intact rats did after an overnight fast, and that individual intakes were proportional to the induced glucose intolerance. The increased eating took the form of shorter intermeal intervals, as if the initial postfast meal did not remain satiating for a normal amount of time. These and other findings suggest that food intake is controlled in part by satiety signals apparently related to the delivery of utilizable calories plus insulin to the liver. These signals also seem to affect gastric emptying and thereby might influence other satiety signals related to gastric distention.

An intensive outpatient approach for cocaine abuse treatment. The Matrix model.

The Matrix model of outpatient treatment was developed during the 1980s in response to an overwhelming demand for cocaine abuse treatment services. The model was constructed using components based upon empirically supported findings from the substance abuse research field. Over the course of development, data were collected on the treatment model and the model was modified based upon empirical evaluation. A pilot study comparing the Matrix outpatient model with an inpatient hospital treatment program produced preliminary support for the clinical utility of the model. An open trial comparing publicly and privately funded patients demonstrated that patients with fewer resources were more difficult to engage and retain in this model of outpatient treatment. In a controlled trial, a clear positive relationship was documented between duration and amount of treatment involvement in the Matrix model and positive outcome at 1 year. Due to a variety of methodological issues, the study was not able to answer definitively the question of clinical efficacy. In all of these studies, patients treated with the Matrix model demonstrated statistically significant reductions in drug and alcohol use and improvements in psychological indicators. This body of work, along with the public acceptance the model has received in the treatment community, support the usefulness of this intensive outpatient approach for cocaine abuse. Further research is underway to provide additional controlled information on the value of this treatment approach.

Psychological approaches for the treatment of cocaine dependence--a neurobehavioral approach.

A variety of psychological approaches have been utilized for the treatment of cocaine dependence. Most information has been presented in case report format. However, several investigations have established integrated outpatient approaches which are currently being systematically evaluated. One of these approaches, the neurobehavioral model of cocaine dependency treatment establishes a clear timetable for cocaine recovery and focusses attention on four discreet areas of functioning. Strategies for addressing these areas of functioning include relapse prevention methods as well as individual therapy procedures, family systems materials, educational information, 12 step involvement and urine testing. The model constructs a comprehensive framework for facilitating involvement in recovery activities which promote positive behavior change. Use of this standardized treatment format allows for the evaluation of the treatment model. In an open trial with 486 cocaine users, a majority of subjects were retained in treatment for a clinically significant period of time and while in treatment provided urine samples indicating substantial periods of cocaine abstinence. Current research is underway to evaluate: (1) subject factors which appear to be related to successful outcome with this treatment model; (2) a controlled clinical trial to evaluate the treatment model with cocaine users using random assignment; (3) a double-blind evaluation of desipramine versus placebo and versus no medication as an adjunct to the support provided by the model.

The Matrix model of outpatient stimulant abuse treatment: evidence of efficacy.

The current study examined the effectiveness of Matrix outpatient stimulant treatment. We associated 146 subjects' in-treatment abstinence data, treatment lengths, and weekly treatment activities to their 6-month abstinence outcomes as part of an interim analysis of a NIDA treatment demonstration project. Results indicated that the pretreatment subject characteristics of ethnicity and drug of choice significantly associated with treatment outcome using Matrix model treatment. Findings also demonstrated a treatment dose/abstinence response such that those who received longer Matrix treatment episodes demonstrated better abstinence outcomes. Further, in-treatment abstinence status and treatment length significantly associated with drug use status at follow-up. This set of findings provides evidence for the value of Matrix treatment and allows for these outcome data to be compared with reports on recent psychosocial treatments for stimulant dependence. This study also provides direction for evaluating longer term effectiveness for these types of drug treatments.

Isolation of Leptospira from desert rodents of west Texas.

Urine, blood and tissue samples from 369 rodents of 13 species were cultured for Leptospira. Four serogroups, including ballum, isterohaemorrhagiae, pomona, and grippotyphosa, were isolated from 70 rodents (19%) of 9 species.

Cocaine abuse among methadone maintenance patients: are there effective treatment strategies?

Cocaine abuse among patients in methadone maintenance treatment has substantially increased in the past decade. No standard treatment approaches exist to address this problem. Empirical evidence has been collected on the effectiveness of several categories of techniques for treating this problem, including pharmacotherapies, behavioral methods (contingency management and relapse prevention), and methadone dose adjustment. Data on the effectiveness of these techniques is summarized. In addition, other treatment interventions that may be efficacious for this population, including day treatment and sober-living facilities, are described. Finally, methadone clinic management procedures that may aid in the reduction of cocaine abuse by methadone patients are discussed. Although many of these efforts are in early stages of evaluation, there are some reasons for optimism in the development of treatment for these patients.

Addiction pharmacotherapy 2000: new options, new challenges.

There are many indicators that substance abuse research and treatment are going to become better integrated. Hopefully, this development will produce new treatment options and will improve access and effectiveness of care. Among the most significant factors in this period of change are the advances in addiction pharmacotherapy. For the treatment of alcoholism, disulfiram has been joined by naltrexone, and soon acamprosate will be added to the list of available pharmacotherapies. Individuals with opiate dependence who, for 25 years, were limited to a single medication (methadone) now have LAAM as an available treatment. Furthermore, there is eager anticipation that buprenorphine/naloxone will bring many more opiate users into treatment since it appears that this medication will be available to doctors outside the traditional narcotics treatment program settings. Other opiate addiction treatment options, including sustained-release naltrexone and lofexidine, are in active development. The greatest area of challenge for pharmacotherapy research is the search for stimulant addiction medications. NIDA has extensive efforts underway to discover/develop medicines that can help in the treatment of cocaine and methamphetamine users. During the next decade, those who embrace these new treatments and integrate them into standard care will offer their patients the best chance for recovery.

Neurobehavioral treatment for cocaine dependency.

Relapse prevention techniques have recently been incorporated into some nonpharmacologic models of chemical dependency treatment. The neurobehavioral model of cocaine dependency treatment establishes a clear timetable for recovery from cocaine dependency and focuses on four distinct areas of functioning. Strategies for addressing these areas of functioning include the use of relapse prevention methods and individual therapy procedures, family systems materials, 12-Step involvement, and urine testing. The model constructs a comprehensive framework for facilitating involvement in recovery activities that promote positive behavior change. The relapse prevention group component of the model is described, the use of a systematic relapse analysis procedure is presented, and an outline of plans for evaluating the model is discussed. The development of a comprehensive outpatient treatment model for treating cocaine dependency provides a standardized structure within which other treatment interventions (e.g., medication, acupuncture) could be evaluated.

Moving research into community settings in the CSAT methamphetamine treatment project: the coordinating center perspective.

The CSAT Methamphetamine Treatment Project (MTP) has been established to conduct a ground-breaking exercise in bringing research into a closer relationship with community-based treatment service organizations. In this article, some of the opportunities and challenges faced by the MTP coordinating center as it has attempted to bring research into community treatment organizations are described. Initially, there has been an active, energetic effort to design the study protocol, focus the activities of the project, and prioritize the tasks to be accomplished. The methods for training the research staff and monitoring the conduct of the research in the community sites are described. A number of observations have been made about the different "cultures and values" of the researchers and the seven clinical organizations where the project has been conducted. The myriad mistakes made and lessons learned about how to conduct a rigorous randomized clinical trial in community treatment organizations may be important for future research-treatment efforts. There has been a wealth of experience gained in the first year of this project that may be of use as efforts move forward to reduce the gap between research and practice.

The matrix model of outpatient stimulant abuse treatment: history and description.

The Matrix model was originally developed in response to the cocaine epidemic of the 1980s. The program consists of relapse prevention groups, education groups, social support groups, individual counseling, and urine and breath testing delivered in a structured manner over a 16-week period. The treatment is a directive, nonconfrontational approach which focuses on current issues and behavior change. Several evaluations of the model have supported its usefulness and efficacy with methamphetamine (MA) users. Methamphetamine users appear to respond to treatment similarly to cocaine users and many continue to show improvements at follow-up.