Noradrenergic Modulation of Learned and Innate Behaviors in Dopamine Transporter Knockout Rats by Guanfacine.

Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate and learned forms of behavior of dopamine transporter knockout (DAT-KO) rats to evaluate the possible noradrenergic modulation of behavioral deficits. DAT-KO and wild type rats were trained in the Hebb-Williams maze to perform spatial working memory tasks. Innate behavior was evaluated via pre pulse inhibition (PPI). Brain activity of the prefrontal cortex and the striatum was assessed. Repeated administration of GF improved the spatial working memory task fulfillment and PPI in DAT-KO rats, and led to specific changes in the power spectra and coherence of brain activity. Our data indicate that both repeated and acute treatment with a non-stimulant noradrenergic drug lead to improvements in the behavior of DAT-KO rats. This study further supports the role of the intricate balance of norepinephrine and dopamine in the regulation of attention. The observed compensatory effect of guanfacine on the behavior of hyperdopaminergic rats may be used in the development of combined treatments to support the dopamine-norepinephrine balance.

Effects of Atomoxetine on Motor and Cognitive Behaviors and Brain Electrophysiological Activity of Dopamine Transporter Knockout Rats.

Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine (ATX) is a selective norepinephrine transporter (NET) inhibitor that is currently used for ADHD treatment. In this study, we aimed to evaluate the effect of atomoxetine on the behavior and brain activity of dopamine transporter knockout (DAT-KO) rats, which are characterized by an ADHD-like behavioral phenotype. Prepulse inhibition (PPI) was assessed in DAT-KO and wild type rats after saline and ATX injections, as well as behavioral parameters in the Hebb-Williams maze and power spectra and coherence of electrophysiological activity. DAT-KO rats demonstrated a pronounced behavioral and electrophysiological phenotype, characterized by hyperactivity, increased number of errors in the maze, repetitive behaviors and disrupted PPI, changes in cortical and striatal power spectra and interareal coherence. Atomoxetine significantly improved PPI and decreased repetitive behaviors in DAT-KO rats and influenced behavior of wild-type rats. ATX also led to significant changes in power spectra and coherence of DAT-KO and wild type rats. Assessment of noradrenergic modulation effects in DAT-KO provides insight into the intricate interplay of monoaminergic systems, although further research is still required to fully understand the complexity of this interaction.

Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice.

It is known that the trace amine-associated receptor 1 (TAAR1) receptor is involved in limbic brain functions by regulating dopamine transmission and putative reward circuitry. Moreover, other TAARs are expressed in the olfactory system of all studied vertebrate species, sensing innate socially-relevant odors, including pheromones. Therefore, one can assume that TAARs may play a role in rodent social and sexual behavior. A comparative behavioral and biochemical analysis of TAAR1 knockout (TAAR1-KO) and wild-type mice is also important for the preliminary evaluation of the potential side effects of future TAAR1-based therapies. In our studies, we adapted a sexual incentive motivation test for mice to evaluate the sexual behavior of TAAR1-KO and wild-type mice. Previously, similar methods were primarily applied to rats. Furthermore, we measured testosterone and other biochemical parameters in the blood. As a result, we found only minimal alterations in all of the studied parameters. Thus, the lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.

Trace Amine-Associated Receptor 2 Is Expressed in the Limbic Brain Areas and Is Involved in Dopamine Regulation and Adult Neurogenesis.

Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity-particularly, decreased spectral power of the cortex and striatum in the 0, 9-20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.

In Vitro and In Vivo Study of the Short-Term Vasomotor Response during Epileptic Seizures.

Epilepsy remains one of the most common brain disorders, and the different types of epilepsy encompass a wide variety of physiological manifestations. Clinical and preclinical findings indicate that cerebral blood flow is usually focally increased at seizure onset, shortly after the beginning of ictal events. Nevertheless, many questions remain about the relationship between vasomotor changes in the epileptic foci and the epileptic behavior of neurons and astrocytes. To study this relationship, we performed a series of in vitro and in vivo experiments using the 4-aminopyridine model of epileptic seizures. It was found that in vitro pathological synchronization of neurons and the depolarization of astrocytes is accompanied by rapid short-term vasoconstriction, while in vivo vasodilation during the seizure prevails. We suggest that vasomotor activity during epileptic seizures is a correlate of the complex, self-sustained response that includes neuronal and astrocytic oscillations, and that underlies the clinical presentation of epilepsy.

Effect of alpha-NETA on auditory event related potentials in sensory gating study paradigm in mice.

The potential contribution of trace amines (TA) to the pathophysiology of neuropsychiatric disorders makes it interesting to examine the effect of TA receptor ligands on schizophrenia biomarkers. We studied the effect of systemic administration of a putative Trace Amine-Associated Receptor 5 (TAAR5) agonist, alpha-NETA (2-(alpha-naphthoyl) ethyltrimethylammonium iodide), on the amplitude of the N40 event related potentials component and on the sensory gating (SG) index in C57BL/6 mice. It was found that low doses of alpha-NETA (2.5 mg/kg and 5 mg/kg) do not elicit a significant effect on the parameters of the N40 component and the SG index. However, the higher dose of alpha-NETA (10 mg/kg) induces a significant effect on the N40 component, but since a decrease in amplitude is observed on both the first and second stimuli in the pair, the SG index does not change. Thus, alpha-NETA administration causes a steady decrease in the N40 amplitude in response to both the first and second stimuli in the paired-click paradigm, and an increase in the N40 peak latency.