Chronic gut inflammation impairs contextual control of fear.

Chronic inflammatory diseases are highly comorbid with anxiety in humans. The extent to which chronic inflammation is responsible for this relationship remains to be determined. We therefore tested the hypothesis that prolonged, but not brief, gut inflammation is sufficient to evoke anxiety-related behaviours in mice. We used the discriminative fear to context conditioning paradigm to assess fear generalization, which is a prominent feature of anxiety disorders. Gut inflammation was induced by exposure to dextran sodium sulfate (DSS) in the drinking water, a well-established rodent model of ulcerative colitis evoking prolonged inflammation. Neither acute (1 × 5 day cycle) nor chronic (3 × 5 day cycles) exposure to DSS affected fear responses when tested shortly after conditioning. Mice in all groups generated more fear responses (freezing) in a chamber previously paired with mild shock, as compared to a chamber with no pairing. This suggests DSS exposure had no effect on acquisition or expression of conditioned fear. Acute and control animals showed this same contextual control of freezing when tested 9 days later. In contrast, at this remote time point, the chronically treated animals exhibited increased freezing in the unpaired chamber such that freezing was equivalent in both contexts. These animals, however, showed intact preference for the unpaired chamber when allowed to freely move between chambers. These data suggest that some mnemonic process engaged after training, such as memory consolidation, is affected by past chronic inflammation so as to generalize negative associations and engage fearful responding in inappropriate contexts, despite intact knowledge that the chambers have different affective associations sufficient for place preference.

Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders.

Most gastrointestinal diseases and disorders (GIDD) are associated with depression, anxiety, and cognitive dysfunction. This suggests that shared features of GIDD, particularly chronic pain and inflammation, affect specific neural targets. The critical review of clinical and animal research presented here reveals that anterior cingulate cortex (ACC) is a primary target. It is particularly sensitive to neuroinflammation, and its function accounts for altered mental function emergent in GIDD. We propose that peripherally-triggered neuroinflammation normally signals injury/illness to ACC, which increases threat assessment and pain sensitivity to cope with increased vulnerability. Chronic peripheral inflammation over-drives this process, leading to long-term ACC structural remodeling, and excessive threat signaling. This evokes anxiodepressive phenotypes even without direct evidence of threats because ACC utilizes schemas to infer affective outcomes (e.g. pain) based on complex contextual information. This activates the autonomic nervous system, exacerbates immune dysfunction, and promotes further gut pathology. This theory provides a mechanistic account of bidirectional interactions among gastrointestinal, immunological, and neural systems in GIDD, and is likely applicable to other chronic inflammatory conditions.

Chronic unpredictable stress shifts rat behavior from exploration to exploitation.

Chronic stress evokes wide-ranging behavioral alterations, including risk avoidance, increased motoric output, and reduced consummatory behaviors. These are often interpreted as dysfunctions, but they may subserve adaptations for coping with existential threats. We tested this in a cohort of rats previously exposed to mild unpredictable stress for 5 weeks. Previously stressed rats exhibited the typically increased avoidance of open field and altered responses to predator odor, suggesting enhanced sensitivity to threatening contexts and cues. Interestingly, these animals collected rewards at a higher rate than controls, because they locomoted faster, spent less time in off-task (exploratory) behavior, and committed fewer licks at feeders. Further, they were not impaired in flexibly shifting choice as reward probabilities changed among feeders, suggesting that behavioral adaptations are not simply of transference to behavioral control to neural systems insensitive to reward (e.g. habits). These data add to a small but growing body of evidence indicating that stress shifts responses away from exploration and toward exploitation of resources, possibly to reduce threat exposure.HighlightsRats with a history of stress collected reward at a higher rate than controls on an operant task, owing to increase locomotion speed, reduced off-task behavior, and reduced time licking at feeders.Previously stressed rats exhibited increased win-stay responses than controls, suggesting the involvement of neural circuits related to goal-directed responding.Previously stressed rats performed equally to controls on a task requiring a shift of preferences based on reward probability, suggesting that they are not simply relying more on habit-based neural systems.

The role of the medial prefrontal cortex in updating reward value and avoiding perseveration.

The medial prefrontal cortex (mPFC) plays a major role in goal-directed behaviours, but it is unclear whether it plays a role in breaking away from a high-value reward in order to explore for better options. To address this question, we designed a novel 3-arm Bandit Task in which rats were required to choose one of three potential reward arms, each of which was associated with a different amount of food reward and time-out punishment. After a variable number of choice trials the reward locations were shuffled and animals had to disengage from the now devalued arm and explore the other options in order to optimise payout. Lesion and control groups' behaviours on the task were then analysed by fitting data with a reinforcement learning model. As expected, lesioned animals obtained less reward overall due to an inability to flexibly adapt their behaviours after a change in reward location. However, modelling results showed that lesioned animals were no more likely to explore than control animals. We also discovered that all animals showed a strong preference for certain maze arms, at the expense of reward. This tendency was exacerbated in the lesioned animals, with the strongest effects seen in a subset of animals with damage to dorsal mPFC. The results confirm a role for mPFC in goal-directed behaviours but suggest that rats rely on other areas to resolve the explore-exploit dilemma.

Multigenerational prenatal stress increases the coherence of brain signaling among cortico-striatal-limbic circuits in adult rats.

Prenatal stress (PNS) is a significant risk factor for the development of psychopathology in adulthood such as anxiety, depression, schizophrenia and addiction. Animal models of PNS resemble many of the effects of PNS on humans and provide a means to study the accumulated effects of PNS over several generations on brain function. Here, we examined how mild PNS delivered during the third week in utero over four consecutive generations affects behavioral flexibility and functional signaling among cortical and limbic structures. These multi-generational prenatally stressed (MGPNS) rats were not impaired on an odor-cued reversal learning task as compared to control animals. Unilateral field potential (FP) recordings from the medial prefrontal cortex, basolateral amygdala, ventral hippocampus, and striatal territories revealed widespread differences in brain signaling between these groups during the odor sampling phase of the task. The FP power was significantly lower in most structures across most frequency bands in MGPNS animals, and the relative increase in power from baseline during the task was lower for the beta band (12-30Hz) in MGPNS animals as compared to controls. The coherence of FPs between brain regions, however, was much higher in MGPNS animals among all structures and for most frequency bands. We propose that this pattern of changes in brain signaling reflects a simplification of network processing, which is consistent with reports of reduced spine density and dendritic complexity in the brains of animals receiving PNS. Our data support the proposal that recurrent ancestral stress leads to adaptations in the brain, and that these may confer adaptive behavior in some circumstances as compared to single-generation PNS.

Attributes of long-term heavy cannabis users: a case-control study.

BACKGROUND: Although cannabis is the most widely used illicit drug in the United States, few recent American studies have examined the attributes of long-term heavy cannabis users. METHOD: Using a case-control design, we obtained psychological and demographic measures on 108 individuals, age 30-55, who had smoked cannabis a mean of 18000 times and a minimum of 5000 times in their lives. We compared these heavy users to 72 age-matched control subjects who had smoked at least once, but no more than 50 times in their lives. RESULTS: We found no significant differences between the two groups on reported levels of income and education in their families of origin. However, the heavy users themselves reported significantly lower educational attainment (P < 0.001) and income (P = 0.003) than the controls, even after adjustment for a large number of potentially confounding variables. When asked to rate the subjective effects of cannabis on their cognition, memory, career, social life, physical health and mental health, large majorities of heavy users (66-90%) reported a 'negative effect'. On several measures of quality of life, heavy users also reported significantly lower levels of satisfaction than controls. CONCLUSION: Both objective and self-report measures suggest numerous negative features associated with long-term heavy cannabis use. Thus, it seems important to understand why heavy users continue to smoke regularly for years, despite acknowledging these negative effects. Such an understanding may guide the development of strategies to treat cannabis dependence.

Neuropsychological performance in long-term cannabis users.

BACKGROUND: Although cannabis is the most widely used illicit drug in the United States, its long-term cognitive effects remain inadequately studied. METHODS: We recruited individuals aged 30 to 55 years in 3 groups: (1) 63 current heavy users who had smoked cannabis at least 5000 times in their lives and who were smoking daily at study entry; (2) 45 former heavy users who had also smoked at least 5000 times but fewer than 12 times in the last 3 months; and (3) 72 control subjects who had smoked no more than 50 times in their lives. Subjects underwent a 28-day washout from cannabis use, monitored by observed urine samples. On days 0, 1, 7, and 28, we administered a neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Test results were analyzed by repeated-measures regression analysis, adjusting for potentially confounding variables. RESULTS: At days 0, 1, and 7, current heavy users scored significantly below control subjects on recall of word lists, and this deficit was associated with users' urinary 11-nor-9-carboxy-Delta9-tetrahydrocannabinol concentrations at study entry. By day 28, however, there were virtually no significant differences among the groups on any of the test results, and no significant associations between cumulative lifetime cannabis use and test scores. CONCLUSION: Some cognitive deficits appear detectable at least 7 days after heavy cannabis use but appear reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use.

Residual neuropsychologic effects of cannabis.

Acute intoxication with cannabis clearly produces cognitive impairment, but it is less clear how long cognitive deficits persist after an individual stops regular cannabis use. Numerous methodologic difficulties confront investigators in the field attempting to assess the residual neuropsychologic effects of cannabis among heavy users, and these must be understood to properly evaluate available studies. At present, it appears safe to conclude that deficits in attention and memory persist for at least several days after discontinuing regular heavy cannabis use. Some of these deficits may be caused or exacerbated by withdrawal effects from the abrupt discontinuation of cannabis; these effects typically peak after 3 to 7 days of abstinence. It is less clear, however, whether heavy cannabis use can cause neurotoxicity that persists long after discontinuation of use. It seems likely that such long-term effects, if they exist, are subtle and not clinically disabling--at least in the majority of cases.

Why do young women diet? The roles of body fat, body perception, and body ideal.

BACKGROUND: To assess the relative roles of body fat, body perception, and body ideals as motivations for dieting in college women. METHOD: We compared 45 college women who reported having dieted with 32 who had not, using a novel computerized test of body image called the somatomorphic matrix. RESULTS: As expected, the difference in body fat between subjects' "perceived body" and "ideal body" was significantly greater in dieters than in nondieters (p < .001). Remarkably, however, this difference remained highly significant even after adjusting for the subjects' actual measured body fat (p = .002). Further analysis revealed that this difference persisted, not because dieters had unrealistic ideals of thinness, but because they had distorted perceptions of their fatness. CONCLUSION: Distorted body image perception, a potentially treatable condition, may play an unexpectedly large role in motivating young women to diet.

Over-the-counter drug use in gymnasiums: an underrecognized substance abuse problem?

OBJECTIVE: Many individuals, attempting to gain muscle or lose fat, use 'dietary supplements'. Though widely available over the counter or by mail order in America and Europe, some of these 'supplements' are actually potent drugs such as androstenedione and ephedrine. We sought to estimate the prevalence of these forms of drug use in American gymnasiums. METHODS: We distributed anonymous questionnaires to 511 clients entering five gymnasiums, asking about use of both supplements and anabolic steroids. RESULTS: Among men, 18% reported use of androstenedione and/or other adrenal hormones, 25% reported ephedrine use, and 5% reported anabolic steroid use within the last 3 years; among women these rates were 3, 13 and 0%. Extrapolating from these figures to the United States as a whole, we estimated that possibly 1.5 million American gymnasium clients have used adrenal hormones and 2.8 million have used ephedrine within the last 3 years. CONCLUSIONS: Millions of men and women are currently using potent drugs, widely sold over the counter as 'supplements', despite their known adverse effects, unknown long-term risks, and possible potential for causing abuse or dependence.

Body image perception among men in three countries.

OBJECTIVE: The authors tested the hypothesis that men in modern Western societies would desire to have a much leaner and more muscular body than the body they actually had or perceived themselves to have. METHOD: The height, weight, and body fat of college-aged men in Austria (N=54), France (N=65), and the United States (N=81) were measured. Using the somatomorphic matrix, a computerized test devised by the authors, the men chose the body image that they felt represented 1) their own body, 2) the body they ideally would like to have, 3) the body of an average man of their age, and 4) the male body they believed was preferred by women. The men's actual fat and muscularity was compared with that of the four images chosen. RESULTS: Only slight demographic and physical differences were found among the three groups of men. Modest differences were found between the men's measured fat and the fat of the images chosen. However, measures of muscularity produced large and highly significant differences. In all three countries, men chose a ideal body that was a mean of about 28 lb (13 kg) more muscular than themselves and estimated that women preferred a male body about 30 lb (14 kg) more muscular than themselves. In a pilot study, however, the authors found that actual women preferred an ordinary male body without added muscle. CONCLUSIONS: The wide discrepancy between men's actual muscularity and their body ideals may help explain the apparent rise in disorders such as muscle dysmorphia and anabolic steroid abuse.

Psychiatric and medical effects of anabolic-androgenic steroid use in women.

BACKGROUND: Although numerous studies have documented the psychiatric and physiological effects of anabolic-androgenic steroids (AAS) in males, virtually no studies have investigated the effects of illicit AAS use in women. METHODS: We performed psychiatric and medical evaluations of 75 dedicated women athletes, recruited by advertisement primarily from gymnasiums in the Boston, Mass., area. RESULTS: Twenty-five (33%) of the women reported current or past AAS use. Users were more muscular than nonusers and reported use of many other 'ergogenic' (performance-enhancing) drugs in addition to AAS. Some described a frank syndrome of ergogenic polysubstance dependence, often with significant morbidity. Fourteen (56%) of the users reported hypomanic symptoms during AAS use and 10 (40%) reported depressive symptoms during AAS withdrawal, but none met full DSM-IV criteria for a hypomanic or major depressive episode. Nineteen (76%) users reported at least one adverse medical effect associated with AAS use. Perhaps the most interesting findings were several unusual psychiatric syndromes reported by both the AAS users and nonusers. These included rigid dietary practices (which we have termed 'eating disorder, bodybuilder type'), nontraditional gender roles and chronic dissatisfaction and preoccupation with their physiques (a syndrome which we have termed 'muscle dysmorphia'). CONCLUSIONS: Dedicated women athletes exhibit not only AAS abuse, but use of many other ergogenic drugs, sometimes associated with significant morbidity. In addition, these athletes frequently display several psychiatric syndromes which have not previously been well described.

Compulsive weight lifting and anabolic drug abuse among women rape victims.

In the course of a study of 75 female weight lifters, we encountered 10 (13%) who reported that they were raped as teenagers or adults. Nine of these women began or greatly increased their weight lifting activities after the assault to be better able to defend themselves against men. Seven began abusing anabolic steroids and/or clenbuterol to gain muscle mass. Compulsive weight lifting and anabolic substance abuse may represent another form of response to the trauma of sexual assault.

Nalbuphine hydrochloride dependence in anabolic steroid users.

Nalbuphine hydrochloride, a nonscheduled opioid agonist/antagonist analgesic, is currently approved for the treatment of pain. Recently, nalbuphine dependence was reported in three anabolic steroid users in Britain. To further document this phenomenon, we conducted interviews on eleven subjects who reported nalbuphine use. Eight subjects were clinically dependent on nalbuphine, and seven of the subjects who were asked about tolerance and withdrawal with nalbuphine acknowledged these symptoms. Eight subjects, who had never used drugs intravenously before, reported using nalbuphine by this route. Nalbuphine-related morbidity was extensive and included medical complications and psychiatric symptoms. Nalbuphine users also exhibited a high rate of comorbid Axis I disorders, including other substance misuse. Virtually all subjects described widespread nalbuphine use in the gymnasiums they frequented. These observations, together with the recent increase in nalbuphine-related articles in the lay press, suggest that nalbuphine may represent a new drug of abuse among athletes, especially those using anabolic steroids, and that nalbuphine's scheduling status may need to be re-evaluated.

Attitudes toward DSM-IV dissociative disorders diagnoses among board-certified American psychiatrists.

OBJECTIVE: The authors assessed the opinions of American psychiatrists regarding the diagnostic status and scientific validity of the DSM-IV categories of dissociative amnesia and dissociative identity disorder. METHOD: A one-page questionnaire was mailed to a random national sample of 367 board-certified American psychiatrists. RESULTS: Three hundred one responses were received-a rate of 82%. Only about one-third of respondents replied that dissociative amnesia and dissociative identity disorder should be included without reservations in DSM-IV; a larger proportion replied that these categories should be included only as proposed diagnoses. Only about one-quarter of respondents felt that diagnoses of dissociative amnesia and dissociative identity disorder were supported by strong evidence of scientific validity. CONCLUSIONS: Among board-certified American psychiatrists, there currently appears to be little consensus regarding the diagnostic status or scientific validity of dissociative amnesia and dissociative identity disorder.

Ephedrine abuse among 36 female weightlifters.

Ephedrine, a central nervous system stimulant, is widely available over the counter in nutritional supplements for body-builders and other athletes. Recently, federal agencies in the United States have reported growing numbers of adverse events attributable to use of this drug. The authors describe preliminary observations of 36 dedicated female athletes who reported ephedrine use. Many of these women had used the drug for years, often in high doses. Most had experienced at least some adverse effects and seven (19%) displayed frank ephedrine dependence at the time of the interview. Eating disorders and disorders of body image appeared to be especially prevalent among ephedrine users.

Very long-term users of marijuana in the United States: a pilot study.

The authors recruited a sample of 37 Americans, aged 30-74, who had smoked marijuana on at least 5,000 separate occasions. These subjects were found to span a wide range of ethnic groups, educational backgrounds, occupations, and annual income; they did not display any obvious features which distinguished them from the population as a whole. They typically began smoking in the 1960s or early 1970s, and then continued to smoke heavily into middle adulthood because they felt that marijuana relieved unpleasant feeling states such as anxiety or depression. To our knowledge, individuals of this type have not previously been examined; further studies of older, long-term American marijuana users are needed.

Muscle dysmorphia. An underrecognized form of body dysmorphic disorder.

In the course of several ongoing studies, the authors have encountered men and women who display a form of body dysmorphic disorder in which they become pathologically preoccupied with their degree of muscularity. This condition, which the authors have tentatively termed "muscle dysmorphia," may cause severe subjective distress, impaired social and occupational functioning, and abuse of anabolic steroids and other substances. Epidemiologic data suggest that muscle dysmorphia, though rarely recognized, may afflict substantial numbers of Americans. The authors summarize the features of muscle dysmorphia, present several case examples, and offer proposed diagnostic criteria that may be useful for subsequent research.

The management of treatment-resistant depression in disorders on the interface of psychiatry and medicine. Fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, and premenstrual dysphoric disorder.

We have reviewed studies examining the efficacy of various psychotropic medications, primarily antidepressant agents, in the treatment of a group of disorders that appear to exhibit some phenomenologic and genetic relationship to major depression. These disorders all appear to benefit (albeit to varying degrees) from antidepressant medications of several different chemical families. This observation has important theoretical and clinical implications. From a theoretical perspective, these results invite the hypothesis that these various disorders may share some particular etiologic "step" in common with major depression-and that the various antidepressant classes benefit these various disorders and major depression via a common action at this hypothetical "step". Although there is an appealing parsimony to this hypothesis, several reservations must be considered. First, it must be recognized that the quality of the available studies varies widely. As noted in the text, these studies used numerous different designs, varying diagnostic criteria for the disorders under study, and diverse methods of rating outcome. Interpretation is further complicated by the fact that many studies included other concomitant medications or therapeutic interventions in addition to the psychotropic drugs administered. Also, the dose of antidepressant medications administered in many of these studies, especially those using TCAs, was often much less than that normally administered in the treatment of major depressive disorder itself. Finally, many of the studies did not systematically evaluate improvement in both the physical and psychological symptoms of a given disorder. For all of these reasons, any theoretic discussion of the results must be tentative. Nevertheless, the overall tally of results strongly favors the hypothesis that antidepressant agents, regardless of their chemical class, are generally useful in the treatment of these disorders. At a minimum, therefore, we can conclude that antidepressant treatment in these disorders deserves aggressive further investigation in studies with modern, rigorous designs. Second, even allowing that multiple antidepressant agents are effective in these various disorders, it still may be premature to conclude that these disorders are related to major depressive disorder. In particular, many of the studies found little correlation between improvement in psychological symptoms and physical symptoms of a given disorder. This observation would seem to argue against a relationship with major depressive disorder. The alternative hypothesis, however, namely, that these disorders do not share a common etiologic "step," seems even less attractive. It would be a remarkable coincidence if, say, fluoxetine possessed an antidepressant property, an independent antimigraine property, and a third, independent, antipremenstrual dysphoric disorder property. And it would be even more peculiar if various other antidepressant medications chemically unrelated to fluoxetine also, by chance alone, benefited all of these same disorders via still other independent mechanisms. Although we cannot, of course, rule out the possibility of multiple mechanisms and multiple causes, the experience of scientific research often has been that the simpler explanation of a phenomenon has proved to be correct. Therefore, the possibility of a link among these various antidepressant-responsive disorders deserves investigation. From a clinical perspective, too, these results are important. They suggest that trials of antidepressant medications should be strongly considered in patients with these disorders. Furthermore, other types of psychotropic medication appear to have a role in the treatment of individual disorders, as discussed in the corresponding sections.(ABSTRACT TRUNCATED)

Do patients use marijuana as an antidepressant?

Several lines of evidence suggest that cannabis may have antidepressant effects. However, methodologic limitations in available studies make the results difficult to interpret. We review this literature and present five cases in which the evidence seems particularly clear that marijuana produced a direct antidepressant effect. If true, these observations argue that many patients may use marijuana to "self-treat" depressive symptoms.