Salivary Chromogranin A (CgA) Response to the Noradrenaline Transporter Blocker Atomoxetine in Dogs

Since salivary chromogranin A (CgA) is one of the known sympathetic adrenomedullar system (SAM) stress markers in humans and pigs, this study aimed to investigate whether salivary CgA in dogs reflects SAM activation. Our hypothesis was that salivary CgA would increase when central noradrenaline was pharmacologically induced. A selective noradrenaline transporter blocker, atomoxetine, was orally administered without causing any aversive responses in nine laboratory dogs to see if it would increase salivary CgA. Three treatment groups (i.e., atomoxetine, placebo, and pre-administration of a selective alpha-2 adrenoreceptor agonist (dexmedetomidine) followed by atomoxetine) were prepared with a randomized crossover design. Saliva sample collection, heart rate measurement and behavior observation were performed at Time 0 (baseline) and at 30, 60, 90 and 150 min after each treatment administration. The results demonstrated that salivary CgA significantly increased at 90 and 150 min in the atomoxetine treatment (p < 0.05), whereas it was not observed in the other two treatments. The present study showed that salivary CgA was increased by atomoxetine-induced SAM activation. However, this increase was blocked if dexmedetomidine was pre-administered. Overall, the results indicate that salivary CgA is a potential candidate for SAM-mediated stress markers in dogs. Further study to determine the dynamics of salivary CgA will be helpful in its practical use.

Social Interactions of DAT-HET Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy

Social interaction is essential for life and is impaired in many psychiatric disorders like schizophrenia, au-tism, depression and major anxiety disorder. Monoamine transmission plays a key role in social behavior and both genetic and epigenetic modifications of dopamine and noradrenaline neurotransmission-related genes can affect the levels of social interaction. Since heterozygous individuals for a specific genetic trait possess only one mutant allele of that trait, in order to better evaluate the role of the interaction between genetics and epigenetics in unmasking latent genetically-determined predispositions, our interest has focused on studying the interplay between genetics and epigenetics influences on social behavior in male rats obtained by two different breeding schemes: a first group by breeding of knock-out (KO) male rats with wild-type (WT) female dams (homogeneous heterozygous offspring, termed MAT-HET), and a second group of heterozygous DAT male offspring by breeding of KO male and DAT-heterozygous female subjects (to obtain comparable control pups, termed MIX-HET). Their social behavior was then assessed by partner preference, social preference and elicited preference tests. In the first test MIX-HET and MAT-HET male mice had choice between two WT females one in estrous and the other not in estrous. In the second test they met either a MIX-HET or a WT male rodent. Also, the expression of the noradrenaline transporter (NET) was assessed in the prefrontal cortex, hippocampus and hypothalamus of MAT, MIX and WTs by immunofluorescence in order to estimate its involvement in the expression of social behavior. Our results show that MIX-HET focal rodents tend to have an asocial behavior when in contact with a female in estrous, and their behavior is similar to when the stimulus is a MIX-HET male. MAT-HET male rodents, instead, tend to be very attracted by the female in estrous, but they ignore the MIX-HET stimulus. MIX-HET progeny showed a lower expression of noradrenaline transporter in both hypothalamus and hippocampus with respect to MAT-HET rats, whereas MAT-HET rats displayed increased noradrenaline transporter immunofluorescence in the hypothalamus and in the hippocampus with respect to WT rats, while no difference was observed in the prefrontal cortex. Therefore we can hypothesize that the differences observed between the two heterozygous groups may be attributable to an epigenetic factor: the different maternal care received. These data can open new perspectives towards increased the preclinical knowledge about autism and bipolar disorder.

Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson’s disease

Study Objectives Parkinson’s disease (PD) commonly involves degeneration of sleep-wake regulating brainstem nuclei; likewise, sleep-wake disturbances are highly prevalent in PD patients. As polysomnography macroparameters typically show only minor changes in PD, we investigated sleep microstructure, particularly cyclic alternating pattern (CAP), and its relation to alterations of the noradrenergic system in these patients. Methods We analysed 27 PD patients and 13 healthy control (HC) subjects who underwent over-night polysomnography and 11C-MeNER positron emission tomography for evaluation of noradrenaline transporter density. Sleep macroparameters as well as CAP metrics were evaluated according to the consensus statement from 2001. Statistical analysis comprised group comparisons and correlation analysis of CAP metrics with clinical characteristics of PD patients as well as noradrenaline transporter density. Results PD patients and HC subjects were comparable in demographic characteristics (age, sex, body mass index) and polysomnography macroparameters. CAP rate as well as A index differed significantly between groups, with PD patients having a lower CAP rate (46.7 ± 6.6% versus 38.0 ± 11.6%, p = 0.015) and lower A index (49.0 ± 8.7/hour versus 40.1 ± 15.4/hour, p = 0.042). In PD patients, both CAP metrics correlated significantly with diminished noradrenaline transporter density in arousal prompting brainstem nuclei (locus coeruleus, raphe nuclei) as well as arousal propagating brain structures like thalamus and bitemporal cortex. Conclusions Sleep microstructure is more severely altered than sleep macrostructure in PD patients and is associated with widespread dysfunction of the noradrenergic arousal system.

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the “attention to detail” subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.