Anorexia nervosa versus hyperinsulinism: therapeutic effects of neuropharmacological manipulation.

BACKGROUND: We have demonstrated that anorexia nervosa is underpinned by overwhelming adrenal sympathetic activity which abolishes the neural sympathetic branch of the peripheral autonomic nervous system. This physiological disorder is responsible for gastrointestinal hypomotility, hyperglycemia, raised systolic blood pressure, raised heart rate, and other neuroendocrine disorders. Therefore, we prescribed neuropharmacological therapy to reverse this central and autonomic nervous system disorder, in order to normalize the clinical and neuroendocrine profile. METHODS: The study included 22 female patients with anorexia nervosa (10 restricted type, 12 binge-eating type) who received three months of treatment with amantadine 100 mg/day. We measured blood pressure, heart rate, and circulating neurotransmitters, (noradrenaline, adrenaline, dopamine, platelet serotonin, free plasma serotonin) during supine resting, one minute of orthostasis, and a five-minute exercise test before and after one, two, and three months of treatment with amantadine, a drug which abrogates adrenal sympathetic activity by acting at the C1(Ad) medullary nuclei responsible for this branch of the peripheral sympathetic activity. RESULTS: We found the amantadine abolished symptoms of anorexia nervosa from the first oral dose onwards. Normalization of autonomic and cardiovascular parameters was demonstrated within the early days of therapy. Abrupt and sustained increases in the plasma noradrenaline:adrenaline ratio and disappearance of abnormal plasma glucose elevation were registered throughout the three-month duration of the trial. Significant and sustained increases in body weight were documented in all cases. No relapses were observed. CONCLUSION: We have confirmed our previously published findings showing that the anorexia nervosa syndrome depends on the hypomotility of the gastrointestinal tract plus hyperglycemia, both of which are triggered by adrenal sympathetic hyperactivity. The above neuroendocrine plus neuroautonomic and clinical disorders which underpinned anorexia nervosa were abruptly suppressed since the first oral dose of amantadine, a drug able to revert the C1(Ad) over A5(NA) pontomedullary predominance responsible for adrenal and neural sympathetic activity, respectively.

Effects of amantadine on circulating neurotransmitters in healthy subjects.

Considering that glutamatergic axons innervate the C1(Ad) medullary nuclei, which are responsible for the excitation of the peripheral adrenal glands, we decided to investigate catecholamines (noradrenaline, adrenaline and dopamine) plus indolamines (plasma serotonin and platelet serotonin) at the blood level, before and after a small oral dose of amantadine, a selective NMDA antagonist. We found that the drug provoked a selective enhancement of noradrenaline plus a minimization of adrenaline, dopamine, plasma serotonin and platelet serotonin circulating levels. Significant enhancement of diastolic blood pressure plus reduction of systolic blood pressure and heart rate paralleled the circulating parameter changes. The above findings allow us to postulate that the drug was able to enhance the peripheral neural sympathetic activity. Minimization of both adrenal sympathetic and parasympathetic activities was also registered after the amantadine challenge. The above findings supported the postulation that this drug should be a powerful therapeutic tool for treating diseases affected by adrenal sympathetic hyperactivity.

Anorexia nervosa depends on adrenal sympathetic hyperactivity: opposite neuroautonomic profile of hyperinsulinism syndrome.

OBJECTIVE: The aim of our study was to determine the central and peripheral autonomic nervous system profiles underlying anorexia nervosa (AN) syndrome, given that affected patients present with the opposite clinical profile to that seen in the hyperinsulinism syndrome. DESIGN: We measured blood pressure and heart rate, as well as circulating neurotransmitters (noradrenaline, adrenaline, dopamine, plasma serotonin, and platelet serotonin), using high-performance liquid chromatography with electrochemical detection, during supine resting, one minute of orthostasis, and after five minutes of exercise. In total, 22 AN patients (12 binge-eating/purging type and 10 restricting type) and age-, gender-, and race-matched controls (70 ± 10.1% versus 98 ± 3.0% of ideal body weight) were recruited. RESULTS: We found that patients with AN had adrenal sympathetic overactivity and neural sympathetic underactivity, demonstrated by a predominance of circulating adrenaline over noradrenaline levels, not only during the supine resting state (52 ± 2 versus 29 ± 1 pg/mL) but also during orthostasis (67 ± 3 versus 32 ± 2 pg/mL, P < 0.05) and after exercise challenge (84 ± 4 versus 30 ± 3 pg/mL, P < 0.01). CONCLUSION: Considering that this peripheral autonomic nervous system disorder depends on the absolute predominance of adrenomedullary C1 adrenergic nuclei over A5 noradrenergic pontine nucleus, let us ratify the abovementioned findings. The AN syndrome depends on the predominance of overwhelming adrenal sympathetic activity over neural sympathetic activity. This combined central and autonomic nervous system profile contrasts with that registered in patients affected by hyperinsulinism, hypoglycemia, and bulimia syndrome which depends on the absolute predominance of neural sympathetic activity.

Effects of an oral dose of l-glutamic acid on circulating neurotransmitters: Possible roles of the C1(Ad) and the A5(NA) pontomedullary nuclei.

OBJECTIVE: Investigation of the effects of an oral administration of a small dose of l-glutamic acid on the two peripheral sympathetic branches (neural and adrenal) of the autonomic nervous system. RESEARCH DESIGN AND METHODS: Circulating neurotransmitters and cardiovascular parameters were assessed in 28 healthy volunteers before and after the administration of 500 mg of l-glutamic acid or placebo. RESULTS: The drug triggered a significant and sustained enhancement of the noradrenaline and dopamine circulating levels which were paralleled and positively correlated with the diastolic blood pressure increases. Conversely, both platelet and plasma serotonin showed significant falls throughout the test. Significant positive correlations were registered between noradrenaline, dopamine, and noradrenaline/dopamine ratio versus diastolic blood pressure but not versus systolic blood pressure or heart rate. CONCLUSION: The above results allowed us to postulate that the drug provoked a significant enhancement of peripheral neural sympathetic activity and the reduction of adrenal sympathetic and parasympathetic drives. Both sympathetic branches are positively correlated with the A5 noradrenergic and the C1 adrenergic pontomedullary nuclei, which interchange inhibitory axons that act at post-synaptic α2 inhibitory autoreceptors. In addition, we discussed the mechanisms able to explain why the drug acted preferentially at the A5 noradrenergic rather than the C1 adrenergic nuclei.

Central nervous system plus autonomic nervous system disorders responsible for gastrointestinal and pancreatobiliary diseases.

Clinical digestive disorders depend on the non-adequate coupling of functioning of the gastrointestinal tract with that of its affluent systems, namely, the pancreatic exocrine and the hepato-biliary secretions. The secretion of gastrointestinal hormones is monitored by the peripheral autonomic nervous system. However, the latter is regulated by the central nervous system (CNS) circuitry localized at the medullary pontine segment of the CNS. In turn, both parasympathetic and adrenergic medullary circuitries are regulated by the pontine A5 noradrenergic (NA) and the dorsal raphe serotonergic nuclei, respectively. DR-5HT is positively correlated with the C1-Ad medullary nuclei (responsible for adrenal gland secretion), whereas the MR-5HT nucleus is positively correlated with the A5-NA pontomedullary nucleus. The latter is responsible for neural sympathetic activity (sympathetic nerves). Both types of sympathetic activities maintain an alternation with the peripheral parasympathetic branch, which is positively correlated with the enterochromaffin cells that secrete serotonin. Serotonin displays hormonal antagonism to the circulating catecholamines.

Amantadine reduces glucagon and enhances insulin secretion throughout the oral glucose tolerance test: central plus peripheral nervous system mechanisms.

OBJECTIVE: The purpose of the trial was to examine the effects of amantadine, a N-methyl-D-aspartate (NMDA) antagonist, on the oral glucose tolerance test (OGTT) plus insulin, glucagon and neurotransmitters circulating levels. Previous findings showed that hyperinsulinism and type 2 diabetes are positively associated with neural sympathetic and adrenal sympathetic activities, respectively. These peripheral sympathetic branches depend on the pontine (A(5)-noradrenergic) and the rostral ventrolateral (C(1)-adrenergic) medullary nuclei. They are excited by glutamate axons which act at NMDA postsynaptic receptors. RESEARCH DESIGN AND METHODS: One OGTT plus placebo and one OGTT plus oral amantadine test were carried out two weeks apart in 15 caucasic normal voluntary humans. Noradrenaline, adrenaline, dopamine, plasma-free serotonin, platelet serotonin, glucose, glucagon, and insulin were measured throughout the 180-minute testing period. RESULTS: Maximal reductions of plasma glucose and glucagon plus exacerbated insulin rises were significantly greater throughout the oral glucose plus amantadine test than those registered throughout the oral glucose plus placebo challenge. The above findings were paralleled by greater than normal noradrenaline/adrenaline plasma ratio increases. In addition, maximal reductions of the platelet serotonin and plasma serotonin circulating values contrasted with the normal rises of these parameters, always registered during the glucose load plus placebo challenge. CONCLUSION: This study supports the theory that amantadine might be a powerful antidiabetic tool and could be added to the therapeutic arsenal against type 2 diabetes.

Central nervous system circuitry involved in the hyperinsulinism syndrome.

Raised plasma levels of insulin, glucose and glucagon are found in patients affected by 'hyperinsulinism'. Obesity, hypertension, mammary plus ovary cysts and rheumatic symptoms are frequently observed in these patients. Sleep disorders and depression are also present in most subjects affected by this polysymptomatic disorder. The simultaneous increases of glucose, insulin and glucagon plasma levels seen in these patients indicate that the normal crosstalk between A cells, B cells and D cells is disrupted. With respect to this, it is well known that glucose excites B cells (which secrete insulin) and inhibits A cells (which secrete glucagon), which in turn excites D cells (which secrete somatostatin). Gastrointestinal hormones (incretins) modulate this crosstalk both directly and indirectly throughout pancreatic and hepatobiliary mechanisms. The above factors depend on autonomic nervous system mediation. For instance, acetylcholine released from parasympathetic nerves excites both B and A cells. Noradrenaline released from sympathetic nerves and adrenaline secreted from the adrenal glands inhibit B cells and excite A cells, which are crowded with beta(2)- and alpha(2)-receptors, respectively. Noradrenaline released from sympathetic nerves also excites A cells by acting at alpha(1)-receptors located at this level. According to this, the excessive release of noradrenaline from these nerves should provoke an enhancement of glucagon secretion which will result in overexcitation of insulin secretion from B cells. That is the disorder seen in the so-called 'hyperinsulinism', in which raised plasma levels of glucose, insulin and glucagon coexist. Taking into account that neural sympathetic activity is positively correlated to the A5 noradrenergic nucleus and median raphe serotonergic neurons, and negatively correlated to the A6 noradrenergic, the dorsal raphe serotonergic and the C1 adrenergic neurons, we postulate that this unbalanced central nervous system circuitry is responsible for the hyperinsulinism syndrome.

Central nervous system circuitry and peripheral neural sympathetic activity responsible for essential hypertension.

Both clinical and experimental studies dealing with patients affected by idiopathic or essential hypertension (EH) are devoted to the great deal of physiological, pharmacological and pathological as well as therapeutical issues of EH. However, most articles devoted to EH do not refer to the central nervous system mechanisms underlying this disease and the channels which allow that these mechanisms are funneled to the peripheral autonomic nervous system and trigger this cardiovascular disorder. In the present review article we attempted to reach this target devoted to the central nervous system circuitry involved in the cardiovascular pathophysiology. We postulated that EH depends on the predominance of the binomial A5 noradrenergic (NA) nucleus + median raphe serotonergic (5-HT) nucleus over the (A6)-NA + dorsal raphe-5HT nuclei. This hypothesis receives additional support from our results obtained throughout the neuropharmacological therapy of this type of neurophysiological disorder. Our therapeutical strategy is addressed to enhance the activity of the (A6)-NA + dorsal raphe-5HT binomial circuitry.

Dorsal raphe vs. median raphe serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: relevance for neuropharmacological therapy.

Monoaminergic neurons located in the central nervous system (CNS) are organized into complex circuits which include noradrenergic (NA), adrenergic (Ad), dopaminergic (DA), serotonergic (5-HT), histaminergic (H), GABA-ergic and glutamatergic systems. Most of these circuits are composed of more than one and often several types of the above neurons. Such physiologically flexible circuits respond appropriately to both external and internal stimuli which, if not modulated adequately, can trigger pathophysiologic responses. A great deal of research has been devoted to mapping the multiple functions of the CNS circuitry, thereby forming the basis for effective neuropharmacological therapeutic approaches. Such lineal strategies that seek to normalize complex and mixed physiological disorders, however, meet only partial therapeutic success and are often followed by undesirable side effects and/or total failure. In light of these, we have worked to develop possible models of CNS circuitry that are less affected by physiological interaction using the models to design more effective therapeutic approaches. In the present review, we cite and present evidence supporting the dorsal raphe versus median raphe serotonergic circuitry as one model of a reliable paradigm, necessary to the clear understanding and therapy of many psychiatric and even non-psychiatric disturbances.

Neurochemical, neuroautonomic and neuropharmacological acute effects of sibutramine in healthy subjects.

Sibutramine is a neuropharmacological drug that exerts central (CNS) and peripheral effects including noradrenaline (NA), and serotonin (5-HT) uptake inhibition. In addition, the drug is able to induce release from DA axons. We measured levels of circulating neurotransmitters in 20 healthy subjects during supine-resting (fasting) state before and after 15 mg of oral sibutramine. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were also monitored. Sibutramine triggered sustained and progressive increase of NA, NA/Ad ratio and DBP. Slight increases of DA were also registered between the 60 and 240 min periods. The rise in DA tended to fade progressively, reaching basal level at 360 min period. Diastolic blood pressure, but neither SBP nor HR, showed significant increases that correlated positively with NA/Ad ratios. Slight but significant negative correlation was also found between DBP and DA. This correlation tended to fade throughout the trial to show no significance at the 360 min period. Although neither plasma serotonin (f-5HT) nor platelet serotonin (p-5HT) values showed significant variation throughout the trial, the f-5HT/p-5HT ratio showed significant decrease throughout. Significant negative correlation was found between f-5HT/p-5HT ratio and NA/Ad ratio. Our results indicate that sibutramine stimulates neural sympathetic activity but not adrenal sympathetic activity in healthy individuals. Further, sibutramine lowers parasympathetic activity. The moderate rise in diastolic blood pressure triggered by sibutramine would be associated with CNS-NA enhancement plus parasympathetic inhibition.

Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters.

Tianeptine is a serotonin-uptake enhancer drug whose antidepressant effectiveness is based on its ability to reduce rather than increase serotonin availability at the synaptic cleft. This paradoxical neuropharmacological mechanism has raised doubt among neuropharmacologists and psychiatrists as to the role of tianeptine as a trusty-reliable antidepressant drug. This controversial issue led us to investigate the acute effects of a single, oral dose (12.5 mg) of this drug on circulating neurotransmitters and cardiovascular parameters in 50 healthy subjects. The drug provoked a striking and significant reduction of plasma noradrenaline (NA) and plasma serotonin (f-5-HT) while it increased plasma dopamine (DA) and platelet serotonin (p-5-HT) concentrations within the 4-h study period. No adrenaline (Ad) changes were registered. The NA/Ad ratio and the f-5-HT/p-5-HT ratio showed significant reduction throughout the test. Finally, although diastolic blood pressure (DBP) showed significant decrease, neither systolic blood pressure (SBP) nor heart rate (HR) showed significant change. These findings are consistent with the postulation that tianeptine reduces both neural sympathetic activity and parasympathetic activity without affecting adrenal sympathetic activity, enabling us to discuss the possible mechanisms involved in the antidepressant effects of tianeptine. The well-known fact that major depressed patients always show raised NA plus lower than normal p-5-HT levels, both disorders which are normalized by tianeptine, gives neurochemical support to the clinical improvement triggered by the drug in these patients. Summarizing, the results presented in this study demonstrate that tianeptine triggers significant reduction of circulating noradrenaline and plasma serotonin while increasing circulating dopamine and platelet serotonin. Other possible neuropharmacological effects are also discussed.