[Obesity, metabolic syndrome and olfactory perception]. / Obesidad, síndrome metabólico y percepción olfativa.

Nowadays, it is well accepted that obesity and metabolic syndrome are diseases that constitute a global public health issue. In consequence, the interest in the study of the effects these pathologies produce in the central nervous system has greatly increased in the last decades. One of the most overlooked topics in the literature is the impact they exert in sensory systems, among which is olfaction. The olfactory system is related to a number of vital functions, like the activation of defense mechanisms, contribution to appetitive and digestive reflexes, recognition of conspecifics, and even has socio-sexual implications. It has been discovered that the olfactory system also plays a crucial role in food intake, the choice of foods, appetite and satiety mechanisms; therefore, it is involved in obesity development. Clinical studies have proven that obese patients exhibit hyposmia more frequently than aged-matched healthy controls. Olfactory alterations have also been found in obese rodents or in animals with similar features of human metabolic syndrome. The causes of this association are still being investigated. This work reviews the studies that have tried to understand this association from a preclinical and clinical approach as well as those biological mechanisms that could be involved. The evidences here presented suggest that obesity and metabolic syndrome affect the adequate function of olfactory sensory system.

TITLE: Obesidad, síndrome metabólico y percepción olfativa.En la actualidad, la obesidad y el síndrome metabólico son enfermedades que representan un grave problema global de salud pública. A consecuencia de ello, en las últimas décadas ha aumentado el interés por estudiar los efectos de estas patologías sobre el funcionamiento del sistema nervioso central. Uno de los aspectos más ignorados en la bibliografía ha sido el impacto que tienen sobre los sistemas sensoriales, entre los que se encuentra el olfato. El sistema olfativo se relaciona con distintas funciones vitales, como activar mecanismos de defensa, contribuir a la inducción de reflejos apetitivos y digestivos, y reconocer individuos de su misma especie, e incluso tiene implicaciones sociosexuales. Se sabe que, además, desempeña un papel importante en la ingesta de alimentos, en la decisión de lo que se va a consumir, en los mecanismos de apetito y saciedad y, por ende, está involucrado en el desarrollo de obesidad. Estudios clínicos han demostrado que pacientes con obesidad presentan hiposmia con mayor frecuencia en comparación con sujetos delgados de la misma edad. También se han encontrado alteraciones en el olfato de roedores que presentan obesidad o rasgos similares a los del síndrome metabólico del humano. Las causas por las cuales existe esta asociación apenas están comenzando a investigarse; en este trabajo se revisan los estudios que han intentado entenderla desde un enfoque clínico y preclínico, así como los mecanismos biológicos que hasta el momento se han explorado en la bibliografía.

Low Serum Tryptophan Levels as an Indicator of Global Cognitive Performance in Nondemented Women over 50 Years of Age.

Aging is a physiological decline process. The number of older adults is growing around the world; therefore, the incidence of cognitive impairment, dementia, and other diseases related to aging increases. The main cellular factors that converge in the aging process are mitochondrial dysfunction, antioxidant impairment, inflammation, and immune response decline, among others. In this context, these cellular changes have an influence on the kynurenine pathway (KP), the main route of tryptophan (Trp) catabolism. KP metabolites have been involved in the aging process and neurodegenerative diseases. Although there are changes in the metabolite levels with age, at this time, there is no study that has evaluated cognitive decline as a consequence of Trp catabolism fluctuation in aging. The aim of this study was to evaluate the relation between the changes in Trp catabolism and cognitive impairment associated with age through KP metabolites level alterations in women over 50 years of age. Seventy-seven nondemented women over 50 years old were examined with a standardized cognitive screening evaluation in Spanish language (Neuropsi), Beck anxiety inventory (BAI), and the geriatric depression scale (GDS). Also, serum levels of Trp, kynurenine (Kyn), kynurenic acid (KYNA), and 3-hydroykynurenine (3-HK) and the glutathione ratio (GSH/GSSG) were measured. Results showed a negative correlation between age and Trp levels and a positive correlation between age and KYNA/Trp and 3-HK/Trp ratios. The level of cognitive impairment showed a significant positive association with age and with kynurenine pathway activation and a significant negative correlation with Trp levels. The GSH/GSSG ratio correlated positively with Trp levels and negatively with Kyn/Trp and 3-HK/Trp ratios. The depression score correlated negatively with Trp and positively with the 3-HK/Trp ratio. We concluded that KP activation increases with age and it is strongly associated with the level of cognition performance in nondemented women over 50 years of age.

Relevance of Alternative Routes of Kynurenic Acid Production in the Brain.

The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D-amino acids or by means of other enzymes as D-amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed.

High level of footshock during inhibitory avoidance training prevents amnesia induced by intranigral injection of GABA antagonists.

Disruption of synaptic activity of a number of cerebral structures (e.g., neostriatum, amygdala, and thalamus) produces marked deficits in retention of instrumentally conditioned behaviors. When animals are given a relatively high number of training trials or high intensities of footshock during learning, however, such disruption is considerably less effective. Since there is a close anatomical and functional relationship between the neostriatum and the substantia nigra, it was of interest to determine whether enhanced training with a high level of footshock would prevent the reported amnesic state induced by injections of GABA antagonists into the latter structure. Rats were trained in a one-trial inhibitory task, using 0.2 or 0.4 mA, and then injected with microgram quantities of picrotoxin or bicuculline into the substantia nigra and posterior region of the zona incerta; retention was measured 24 h later. Only those groups that had been injected into the nigra and trained with 0.2 mA showed amnesia. These results support the hypotheses that (a) the normal activity of a set of structures is essential for the development of memory consolidation and (b) after an enhanced learning experience these structures may participate in memory consolidation, but are not necessary for the occurrence of this process.

Reversal of extinction by scopolamine.

The aim of this experiment was to determine the effects of muscarinic blockade on extinction of passive avoidance conditioning. Rats were trained with a foot shock of 2.5, 3.0, or 6.0 mA and were tested for retention for 8 weeks (once weekly). Five minutes before the seventh test they were injected with 8 mg/kg scopolamine. The groups that had been trained with 2.5 and 3.0 mA showed extinction, which was reversed by the scopolamine; the overreinforced group (6.0 mA) did not show extinction and the scopolamine did not alter the conditioned response. The data support the hypothesis that extinction represents the learning of a new response sustained by a set of cholinergic neurons, different from that which mediated original passive avoidance learning.

Effects of central muscarinic blockade on passive avoidance: anterograde amnesia, state dependency, or both?

It was recently reported that administration of relatively high intensities of footshock (overreinforcement) during training of passive avoidance protected animals against the amnesic effect of scopolamine, injected 5 min after training. This was interpreted in terms of a lesser involvement of acetylcholine in memory consolidation. An alternative explanation was that overreinforcement accelerated the consolidation process, which could have taken place before the injection of scopolamine. To test for this possibility, male Wistar rats were injected with 4, 8, or 12 mg/kg of scopolamine, 5 min before training with low or high levels of footshock and then tested for retention of the task. Scopolamine induced the expected memory deficit after the low-intensity footshock; after overreinforcement the higher doses of scopolamine induced state dependency, while no deficits were produced with the lower dose. It was concluded that: (a) acetylcholine is indeed involved in memory consolidation of passive avoidance; (b) scopolamine interacts with high footshock levels to produce state dependency; and (c) when relatively low doses of scopolamine are used in conditions of overreinforcement, protection against scopolamine-induced amnesia becomes evident.

Anxiolytics reverse the acceleration of ejaculation resulting from enforced intercopulatory intervals in rats.

The enforced interval of copulation (EIC) consists of the artificial prolongation of the interintromission interval, induces a reduction in the number of intromissions preceding ejaculation, and is accompanied by an anxiety like behavioral repertoire. The administration of the benzodiazepine anxiolytics diazepam, chlordiazepoxide, flurazepam, and flunitrazepam produced a dose-dependent inhibition of the EIC effect with a concomitant increase in mounting. These actions were blocked by the central benzodiazepine antagonist Ro 15-1788. The anxiogenic agent beta-carboline Zk 39106 had no effect. Treatment with pentobarbital also produced a blockade of the reduction in the number of intromissions during EIC, whereas muscimol and bicuculline lacked this effect. The serotonergic anxiolytic buspirone reversed the facilitatory action induced by EIC; however, two putative serotonergic antianxiety agents, 8-OH-DPAT and ipsapirone, did not modify or potentiate it, respectively. Finally, the nonanxiolytic serotonergic compounds 5-hydroxytryptophan and TFMPP drastically increased the number of mounts but did not antagonize the reduction of intromissions produced by EIC. These results suggest that an increase in the anxiety levels may be responsible for the excitatory action of EIC on sexual behavior.

Pharmacological manipulation of anxiety and male rat sexual behavior.

Several anxiolytic/anxiogenic treatments were evaluated on male rat sexual behavior. The anxiolytic drug diazepam (1.0 mg/kg) inhibited copulatory behavior as indicated by an increase in the number of mounts preceding ejaculation, prolongation of the ejaculation latency and the postejaculatory interval. These changes were not accompanied by alterations in motor coordination as tested on a treadmill apparatus. A lower dose of diazepam (0.5 mg/kg) did not affect the sexual behavior. The anxiogenic drug Zk 39106 (2 and 4 mg/kg) facilitated the copulatory behavior by reducing the number of intromissions preceding ejaculation. A higher dose of Zk 39106 (8 mg/kg) inhibited sexual behavior. The selective benzodiazepine antagonist, Ro 15-1788 (5 and 10 mg/kg), did not modify male sexual behavior, but effectively antagonized the effects of Zk 39106 and diazepam. The administration of Zk 39106 (2 mg/kg) reversed the inhibitory action of diazepam (1.0 mg/kg) on copulation; however, diazepam did not prevent the facilitory effect of Zk 39106. The data are discussed in terms of the possible relationship existing between anxiety and masculine sexual behavior.

Effects of physostigmine infusion on healthy volunteers deprived of rapid eye movement sleep.

Rapid eye movement sleep (REMS) deprivation is believed to alter the sensitivity of various neurotransmitter systems. In the present article, we studied 20 healthy volunteers divided into three groups. Group A attended the sleep laboratory for three nights: acclimatization, a baseline night, and one night of physostigmine infusion. Group B attended for eight nights; acclimatization, baseline, four nights of REMS deprivation, and two recovery nights. With the exception of the first recovery night, when group C volunteers were administered physostigmine, group C's schedule was identical to group B's. The infusions received by group A and C were composed of 1.0 mg of physostigmine, dissolved in 100 ml of saline solution. These were administered 5 min after sleep onset and thereafter every hour, except when the subjects were either awake or in REMS. All of the subjects receiving the cholinomimetic infusion were given a peripheral anticholinergic. Group A experienced a great number of awakenings with a decrease in REMS percentage. Group B recovery occurred over two nights, with an increase in the average length of REMS. Group C exhibited maximum REMS rebound on the first recovery night with an increased number of REMS episodes, as well as significant reductions in the first REMS latency. Our findings suggest that physostigmine alters REMS rebound following REMS deprivation.

Reduction in anxiety after ejaculation in the rat.

The anxiety levels, tested in the conditioned defensive burying behaviour paradigm, were analyzed after various phases of copulatory behaviour. No differences in anxiety were found between the group of animals without sexual activity and the group of animals tested after five intromissions of the first ejaculatory series. A decrease in anxiety, reflected as a reduction in the burying behaviour, was found in the group of animals tested during the first and the second postejaculatory intervals or after two intromissions from the second series of copulation. The possible involvement of the GABAergic system mediating the reduction in anxiety during these phases of copulation is discussed.

The effect of total sleep deprivation on plasma melatonin and cortisol in healthy human volunteers.

Twelve healthy volunteers were included in this study. Baseline curves for melatonin and cortisol were obtained after one night of adaptation to laboratory conditions. From 10:00 p.m. to 6:00 a.m., blood samples were drawn every hour. On the third night, the subjects were kept awake at the sleep unit. Curves for the two hormones were then obtained after 36 h of total sleep deprivation (SD). The levels of these hormones were evaluated by calculating the area under the curve at each hour in both situations (basal and after sleep deprivation). It was found that the melatonin levels were increased after sleep deprivation, whereas the cortisol levels remained the same. These results suggest a mechanism by which a reset of abnormal rhythms can occur in depression.