Ventral Tegmental Area

Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition and in pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine and dopamine were studied in numerous works, however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialys and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norepinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

The question: whether quantum coherent states can sustain decoherence, heating and dissipation over time scales comparable to the dynamical timescales of the brain neurons, is actively discussed in the last years. Positive answer on this question is crucial, in particular, for consideration of brain neurons as quantum computers. This discussion was mainly based on theoretical arguments. In present paper nonlinear statistical properties of the Ventral Tegmental Area (VTA) of genetically depressive limbic brain are studied {\it in vivo} on the Flinders Sensitive Line of rats (FSL). VTA plays a key role in generation of pleasure and in development of psychological drug addiction. We found that the FSL VTA (dopaminergic) neuron signals exhibit multifractal properties for interspike frequencies on the scales where healthy VTA dopaminergic neurons exhibit bursting activity. For high moments the observed multifractal (generalized dimensions) spectrum coincides with the generalized dimensions spectrum calculated for a spectral measure of a {\it quantum} system (so-called kicked Harper model, actively used as a model of quantum chaos). This observation can be considered as a first experimental ({\it in vivo}) indication in the favour of the quantum (at least partially) nature of the brain neurons activity.

Dopamine (DA)-containing neurons involved in the regulation of sleep and waking (W) arise in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). The VTA and SNc cells have efferent and afferent connections with the dorsal raphe nucleus (DRN), the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT), the locus coeruleus (LC), the lateral and posterior hypothalamus (LH), the basal forebrain (BFB), and the thalamus. Molecular cloning techniques have enabled the characterization of two distinct groups of DA receptors, D1-like and D2-like receptors. The D1 subfamily includes the D1 and D5 receptors, whereas the D2 subfamily comprises the D2, D3, and D4 receptors. Systemic administration of a selective D1 receptor agonist induces behavioral arousal, together with an increase of W and a reduction of slow wave sleep (SWS) and REM sleep (REMS). Systemic injection of a DA D2 receptor agonist induces biphasic effects, such that low doses reduce W and increase SWS and REMS (predominant activation of the D2 autoreceptor), whereas large doses induce the opposite effect (predominant facilitation of the D2 postsynaptic receptor). Compounds with DA D1 or D2 receptor blocking properties augment non-REMS and reduce W. Preliminary findings tend to indicate that the administration of a DA D3-preferring agonist induces somnolence and sleep in laboratory animals and man. DA neurons in the VTA and the SNc do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. The available evidence tends to indicate that during W there occurs an increase of burst firing activity of DA neurons, and an enhanced release of DA in the VTA, the nucleus accumbens (NAc), and a number of forebrain structures. A series of structures relevant for the regulation of the behavioral state, including the DRN, LDT/PPT, LC, and LH, could be partly responsible for the changes in the temporal pattern of activity of DA neurons.

Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D2/D3 autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway). Objectives We investigated the hypothesis that amisulpride, a D2/D3 receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions. Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA. Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels. Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D2/D3 receptors on VTA neurones and in the tuberoinfundibular system.

The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. Published by Elsevier B.V.