Behavioral neuroendocrinology and treatment of anorexia nervosa.

Outcome in anorexia nervosa remains poor and a new way of looking at this condition is therefore needed. To this aim, we review the effects of food restriction and starvation in humans. It is suggested that body weight remains stable and relatively low when the access to food requires a considerable amount of physical activity. In this condition, the human homeostatic phenotype, body fat content is also low and as a consequence, the synthesis and release of brain neurotransmitters are modified. As an example, the role of neuropeptide Y is analyzed in rat models of this state. It is suggested that the normal behavioral role of neuropeptide Y is to facilitate the search for food and switch attention from sexual stimuli to food. Descriptive neuroendocrine studies on patients with anorexia nervosa have not contributed to the management of the patients and the few studies in which hormones have been administered have, at best, reversed an endocrine consequence secondary to starvation. In a modified framework for understanding the etiology and treatment of anorexia nervosa it is suggested that the condition emerges because neural mechanisms of reward and attention are engaged. The neural neuropeptide Y receptor system may be involved in the maintenance of the behavior of eating disorder patients because the localization of these receptors overlaps with the neural systems engaged in cue-conditioned eating in limbic and cortical areas. The eating behavior of patients with anorexia nervosa, and other eating disorders as well, is viewed as a cause of the psychological changes of the patients. Patients are trained to re-learn normal eating habits using external support and as they do, their symptoms, including the psychological symptoms, dissolve.

Eating Behavior and the Evolutionary Perspective on Anorexia Nervosa.

On the standard perspective, anorexia nervosa and other eating disorders are caused by genetically determined, neurochemically mediated mental illnesses. Standard treatment, cognitive behavioral therapy (CBT), targets cognitive processes thought to maintain the disorders. Effective neurochemically based treatments are not available and the rate of remission is ≤25% 1 year after CBT, with unknown outcomes in the long-term. With starvation as the major threat in biological history, the evolutionary perspective focuses on foraging for food and eating behavior. A neural network, including hypothalamic arcuate peptide-neurons, brainstem serotonin- and dopamine-neurons and their prefrontal cortical projections, mediates (rather than controls) the behavioral adaptations to variations in food availability; activation of the network is associated with opposing behavioral outcomes depending upon external variations. In the clinic, the control of eating behavior is therefore outsourced to a machine that provides feedback on how to eat. Hundreds of eating disorders patients have recovered by practicing eating; the rate of remission is 75% in on average 1 year of treatment, the rate of relapse is 10% over 5 years of follow-up and no patient has died. A two-parameter asymptotic exponential growth curve modeled the eating behavior of 17 healthy women but not that of 17 women with anorexia nervosa. When in remission, the eating behavior of the anorexic women approached that of the healthy women. It is suggested that the treatment of eating disorders should focus on eating behavior.

Neuropeptide Y facilitates activity-based-anorexia.

The hypothesis that treatment with neuropeptide Y (NPY) can increase running activity and decrease food intake and body weight was tested. Female rats with a running wheel lost more weight than sedentary rats and ran progressively more as the availability of food was gradually reduced. When food was available for only 1h/day, the rats lost control over body weight. Correlatively, the level of NPY mRNA was increased in the hypothalamic arcuate nucleus. This phenomenon, activity-based-anorexia, was enhanced by intracerebroventricular infusion of NPY in rats which had food available during 2h/day. By contrast, NPY stimulated food intake but not wheel running in rats which had food available continuously. These findings are inconsistent with the prevailing theory of the role of the hypothalamus in the regulation of body weight according to which food intake is a homeostatic process controlled by "orexigenic" and "anorexigenic" neural networks. However, the finding that treatment with NPY, generally considered an "orexigen", can increase physical activity and decrease food intake and cause a loss of body weight is in line with the clinical observation that patients with anorexia nervosa are physically hyperactive and eat only little food despite having depleted body fat and up-regulated hypothalamic "orexigenic" peptides.

Cognitive behavior therapy for eating disorders versus normalization of eating behavior.

We examine the science and evidence supporting cognitive behavior therapy (CBT) for the treatment of bulimia nervosa and other eating disorders. Recent trials focusing on the abnormal cognitive and emotional aspects of bulimia have reported a remission rate of about 45%, and a relapse rate of about 30% within one year. However, an early CBT trial that emphasized the normalization of eating behavior had a better outcome than treatment that focused on cognitive intervention. In support of this finding, another treatment, that restores a normal eating behavior using mealtime feedback, has an estimated remission rate of about 75% and a relapse rate of about 10% over five years. Moreover, when eating behavior was normalized, cognitive and emotional abnormalities were resolved at remission without cognitive therapy. The critical aspect of the CBT treatment of bulimia nervosa therefore may actually have been the normalization of eating behavior.

Psychoneuroendocrinology of anorexia nervosa.

It is suggested that the symptoms of anorexia nervosa are physiological responses to starvation. There is no evidence of a neural or non-neural dysfunction that predisposes women for anorexia nervosa and the endocrine and psychological consequences of starvation are reversed once patients have re-learnt how to eat and regained a normal body weight. Because variability in the supply of food may be a common evolutionary condition, it is more likely that body weight is variable than constant in normal circumstances. The role of the neuroendocrine system in times of feast and famine is to allow the individual to adopt behavioral strategies as needed rather than maintaining body weight homeostasis. Treatment of anorexic patients should aim at reducing their high level of physical activity in order to facilitate eating.

Dopamine and anorexia nervosa.

We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes.

Intake inhibition by NPY and CCK-8: A challenge of the notion of NPY as an "Orexigen".

We tested the hypothesis that neuropeptide Y (NPY) interacts with cholecystokinin octapeptide (CCK-8) in inhibition of intake of an intraorally infused solution of sucrose, a test of consummatory ingestive behavior. Both intracerebroventricular infusion of NPY (10 microg) and intraperitoneal injection of CCK-8 (0.5 micro/kg) reduced the intake of a 1M solution of sucrose infused intraorally at a rate of 0.5 ml/min in ovariectomized female rats, but the two peptides did not interact in inhibiting intraoral intake. By contrast, NPY increased intake if the sucrose solution was ingested from a bottle, a test demanding both appetitive and consummatory ingestive responses. CCK-8 inhibited intake in this test and its inhibitory effect was increased by simultaneous treatment with NPY. The activity in the nucleus of the solitary tract (NTS), a brainstem relay mediating inhibition of intake, judged by the expression of c-fos-like immunoreactivity, was significantly increased after treatment with CCK-8 or NPY to approximately the same extent. Combined treatment with NPY and CCK-8 did not increase the c-fos-like immunoreactivity in the NTS above treatment with NPY or CCK-8 alone. These results strengthen the hypothesis that NPY, like CCK-8, is an inhibitor of consummatory ingestive behavior and suggest that this inhibition is mediated via the NTS.

Pulse administration of estradiol-17 beta cancels sex difference in behavioral estrogen sensitivity.

No sex differences were found in the capability of estradiol-17 beta (E2) to induce female sexual behaviors in adult gonadectomized rats when it was administered by a pulsatile schedule and followed by progesterone. Administration of E2 in constant-release implants resulted in a clear behavioral sex difference, with females showing higher levels than males. The ovaries of proestrous females were shown to secrete E2 in a pulsatile manner and the schedule of E2 administration which cancelled the behavioral sex difference produced pulses of serum E2 of an amplitude which was within the physiological range. Thus, the sex difference in behavioral E2 sensitivity is dependent upon the manner of E2 administration and if a physiological schedule of E2 administration is employed the sex difference is cancelled.

Effects of a non-steroidal antiandrogen on sexual behavior and pituitary-gonadal function in the male rat.

An investigation was conducted on the effects of the non-steroidal antiandrogen flutamide (F; alpha-alpha-alpha-tri-fluoro-2-methyl-4-nitro-m-propionotoluidide) on two neuroendocrine mechanisms in the male rat, androgen-dependent sexual behavior, and LH regulation. F was administered in the dose of 50 mg/kg/day SC. In intact, sexually experienced adult males, no quantitative or qualitative behavioral effects were noted. In long-term castrates, F completely suppressed the effects of 100 mug testosterone propionate (TP) per day on accessory sexual glands and penes, but only partially inhibited the marked stimulatory effects of this moderate TP dose on mating. Although the incidence of testosterone (T)-activated ejaculatory behavior was markedly diminished, there was no statistically significant effect on occurrence of mount and intromission behavior. The rapid and profound elevations of circulating LH and T in intact males indicate an effective antagonism of the negative feedback effect of endogenous androgen, and suggest the usefulness of F as a provocative test of pituitary-testicular function. Pituitary LH response to exogenous LHRH was markedly enhanced, as previously found in castrated rats. The administration of F did not affect circulating T levels in T-treated or untreated castrates, indicating lack of interference of circulating F in the T assay. It was concluded that, like the steroidal antiandrogen cyproterone, non-steroidal F shows a divergence between its effects on peripheral androgen-dependent and central feedback mechanisms on the one hand, and sexual behavior on the other. It was not determined whether the inhibition of ejaculatory behavior following F treatment is centrally mediated or results from failure of the peripheral, androgen-dependent structural or functional elements.

GABA inhibits sexual behaviour in female rats.

Ejaculation by male rats caused an abrupt and marked increase in the concentration of GABA in the cerebrospinal fluid and an equally abrupt and marked inhibition of sexual behaviour in female rats. The increase in the concentration of GABA in the cerebrospinal fluid and the inhibition of the behaviour was specifically mediated by the ejaculation of the male; sexual stimulation unaccompanied by ejaculation had no effect. The post-ejaculatory suppression of sexual receptivity in female rats was partially reversed by intracerebroventricular injection of the GABA antagonist bicuculline and the behaviour of receptive rats was inhibited by intracerebroventricular injection of the GABA agonist muscimol. Increasing the concentration of GABA in the cerebrospinal fluid by i.p. injection of the GABA transminase inhibitor gamma-vinyl GABA caused an increase of the concentration of GABA in the cerebrospinal fluid and inhibited the display of sexual receptivity. It is suggested that GABA mediates physiologically relevant inhibition of sexual behaviour in female rats.

Cholecystokinin, dopamine D2 and N-methyl-D-aspartate binding sites in the nucleus of the solitary tract of the rat: possible relationship to ingestive behavior.

Receptor autoradiography was used to investigate the distribution of brainstem binding sites for cholecystokinin, dopamine and N-methyl-D-aspartate with particular reference to the nucleus of the solitary tract of the rat, an area involved in the control of ingestive behavior. Binding sites for the A and B subtypes of the cholecystokinin receptor, labeled with [(125)I]cholecystokinin octapeptide sulfate in the presence or absence of antagonists for the devazepide (A) or L-365,260 (B) receptor, were present throughout the caudal rostral extent of the nucleus of the solitary tract, the A type predominating in the commissural, medial and gelatinous part and the B type in the lateral part. In the most rostral part of the medial nucleus of the solitary tract, both A and B receptors were present. Dopamine D2 receptors, labeled with [(125)I]NCQ-298, were found in all parts of the nucleus of the solitary tract. No binding to the dopamine D1 receptor, labeled with [(125)I]SCH-23982, was found in the brainstem. N-Methyl-D-aspartate receptors, labeled with [(3)H]dizocilpine maleate, were also present in the entire caudorostral extent of the nucleus of the solitary tract. Binding to cholecystokinin A receptors was co-distributed with [(125)I]NCQ-298 and [(3)H]dizocilpine maleate binding in the caudal and rostral parts of the nucleus of the solitary tract, and binding to cholecystokinin B receptors overlapped with [(125)I]NCQ-298 and [(3)H]dizocilpine maleate binding in the rostral nucleus of the solitary tract. These results are consistent with the hypothesis that cholecystokinin, dopamine and glutamate interact in the nucleus of the solitary tract in the control of ingestive behavior.

Lordosis behaviour in male, female and androgenized female rats.

Sex differences in the lordodis response of adult rats to ovarian hormones were studied in a series of experiments. Male rats were less sensitive to oestradiol benzoate (OB, a single injection of 10, 100 or 1000 mug/kg or seven daily injections of 2, 10, or 50mglkg)then were female rats. Oestradiol benzoate-primed (10 mglkg)female, but not male, rats showed dose-dependent responses to progesterone (0-4, 2-0 or 10-0 mg/kg/. male rats responded clearly to progesterone (2 mg/rat) only when primed with a high dose of OB (100 mug/rat). Display of the whole pattern of female sexual behaviour was induced in male rats by treatment with 100 mug OB and 2 mg progesterone. Female rats treated with 1 mg testosterone propionate (TP) on day 4 of life, ovariectomized as adults and tested under the same endocrine conditions as the rats described above, retained behavioural OB sensitivity but responded poorly to progesterone. Evidence is presented that ovarian secretions during development significantly modify the response of neonatally TP-treated and normal female rats to OB in adulthood.

Effects of anti-oestrogen treatment of neonatal male rats on lordosis behaviour and mounting behaviour in the adult.

Male rats were treated daily with 100 microgram of the anti-oestrogen ethamoxytriphetol (MER-25) or oil during the first 10 days of life and tested for lordosis behaviour and mounting behaviour as intact adults, after castration and after castration and oestradiol benzoate or testosterone propionate treatment. The MER-25-treated rats showed higher levels of lordosis behaviour than oil-treated rats in all four treatment groups. Under each of these endocrine conditions, except after castration alone, the MER-25-treated rats showed a reduced capacity to ejaculate. Treatment of the neonatal rat with MER-25 reduced body weight in adulthood but did not change the weight of the accessory sexual glands, the testes, the number of cornified papillae on the glans penis or plasma testosterone concentrations during development. The response of the accessory sexual glands and cornified papillae on the glans penis to treatment with oestradiol benzoate or testosterone propionate after castration in adulthood was unaffected by treatment with MER-25. It is suggested that formation of oestrogen in the neonatal male rat brain from testosterone in the circulation inhibits the capacity to show lordosis behaviour and facilitates the capacity to ejaculate in response to ejaculate in response to gonadal hormone treatment in adulthood.

Dissociation between the ovarian factors controlling sexual receptivity and preovulatory secretion of LH in cyclic female rats.

Ovariectomy and treatment with oestradiol benzoate (10 micrograms OB) on the day before behavioural oestrus eliminated the preovulatory surge of LH and reduced the level of sexual receptivity on the following day. Sexual behaviour, but not the LH surge, was restored by progesterone (0.5 mg) given 18 h later. Injection of OB on the day after behavioural oestrus induced a small release of LH and normal sexual behaviour on the following day. Ovariectomy on the day after behavioural oestrus reduced the stimulatory effect of OB on sexual behaviour and eliminated its weakly stimulatory effect on LH release. Sexual behaviour, but not the small LH surge, was restored in these animals by progesterone (0.5 mg) given 18 h later. Treatment of rats ovariectomized 2 days before the day of the LH surge with implants containing oestradiol or injections of oestradiol (1 microgram) induced LH surges but the amplitudes of these LH surges were much smaller than those of the normal LH surge. Treatment of intact rats with OB increased serum progesterone levels 24 h later, an effect which was eliminated by ovariectomy. Injections of LH (20 micrograms) into intact rats on the day after behavioural oestrus also increased serum progesterone concentrations but failed to stimulate sexual behaviour. It is suggested that OB treatment of intact rats on the day after behavioural oestrus stimulates sexual behaviour by inducing a surge of LH secretion which activates ovarian secretion of progesterone. Thus, oestrogen and progesterone but not the LH surge are essential for sexual behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that progesterone does not inhibit the induction of sexual receptivity by oestradiol-17 beta in the rat.

Progesterone-filled constant-release implants facilitated the induction of sexual receptivity in ovariectomized rats given implants of oestradiol-17 beta precisely 32 h before testing, irrespective of the time of implantation. Inhibition by progesterone implants of the behavioural response to an injection of progesterone occurred after the facilitation 32 h after oestradiol implantation. Sexual receptivity could be induced in pseudopregnant rats in the absence of progesterone treatment by injection of 1 microgram oestradiol 32 and 16 h before testing at a time when endogenous serum levels of oestradiol were low and progesterone levels were high. The behavioural response of ovariectomized rats implanted with oestradiol and tested daily was unaffected by implantation of progesterone at the time of oestradiol implantation, although serum levels of progesterone varied with the number of progesterone implants inserted. Inhibition by progesterone implants of the behavioural response to an injection of progesterone 6 h before behavioural testing occurred only if the progesterone implants were present for at least 32 h of a 48 h period. Serum levels of progesterone were raised within 1 h of progesterone implantation and declined within a 6 h period after implant removal. It is concluded that progesterone does not inhibit the behavioral effect of oestradiol and that progesterone does not play an inhibitory role in the regulation of the behavioural oestrous cycle in our strain of rats.

Neonatal treatment with antioestrogen increases the diurnal rhythmicity in the sexual behaviour of adult male rats.

Male rats were given daily injections of the antioestrogen ethamoxytriphetol (MER-25, 100 microgram/day) or oil during the first 10 days of life. Rats treated with MER-25 showed a more pronounced diurnal rhythm in both mounting behaviour and lordosis behaviour than did oil-treated rats when tested as intact adults and after castration together with treatment with testosterone- or oestradiol-filled constant release implants. Serum levels of androgen varied markedly in samples obtained at four different times of the light : darkness (LD) cycle in both neonatal treatment groups and no significant LD-dependent pattern was obvious. Castration and treatment with testosterone implants produced stable androgen levels which showed little individual variation and did not vary with the LD cycle. The results supported the hypothesis that perinatal androgen stimulation affects the development of sexual behaviour in rats primarily by decreasing the diurnal rhythmicity of the behaviour of the adult.

Induction of sexual receptivity by oestradiol benzoate in cyclic female rats: influence of ovarian secretions before injection of oestradiol benzoate.

The ability of cyclic female rats to show sexual receptivity 24 h after an injection of 2 microgram oestradiol benzoate (OB) was lost 24 h after ovariectomy. Exposure of cyclic rats to antioestrogen (nitromophene monocitrate) implants 24 h before ovariectomy and OB treatment prevented the latter from inducing sexual receptivity within 24 h of administration. Treatment of ovariectomized rats with constant release implants filled with an oil solution of 15 microgram oestradiol/ml had no behavioural effect in itself, but prepared the rats to show lordosis 24 h after administration of OB. Progesterone treatment (4 mg) induced sexual behaviour in cyclic rats on days other than that of the oestrous cycle when the rats are normally receptive. Evidence is presented that a lower level of oestradiol stimulation than that present duing pro-oestrus was needed for the induction of sexual receptivity in ovariectomized rats. It is suggested that the low basal level of oestradiol which was present throughout the oestrous cycle was necessary for the induction of sexual receptivity and that an increase in oestradial stimulation served to increase the behavioural sensitivity to progesterone.