Reward pathway & metabolism
Correlations between mesencephalic reward pathway
and typical metabolic dysfunctions of internal pathologies
KEY WORDS
Adiponectin, diabetes, dopamine,
insulin, mind, nafld,
reward pathway, metabolic syndrome.
ABSTRACT
With the intention of understanding the most important scientific findings typical of a strictly medical field and of the neuroscience world, the relationships that emerge by analyzing the functions of the midbrain reward system and the features of the currently most common metabolic pathologies (diabetes, obesity, nafld hepatopathy) assume fundamental importance in obtaining a more complete knowledge and outlining more global therapeutic plans that come closer to the needs of the patient.
ORIGINAL ARTICLE
Neuroscience can now understand and explain more and more the strictly medical physiopathology that takes place at a molecular and cellular level through a systemic and metabolic approach.
Generally speaking, the most recent scientific findings regard peptides and hormones with a peripheral role at a glance, and the ability of the same molecules to work as important regulators in the CNS central nervous system, explaining why therapeutic approach to care and healing used to treat many pathologies must give high consideration to neuroscientific logic.
The key points of this neuro-medical logic approach are:
1. The reward pathway system
2. The most frequent metabolic pathologies and their relationships
3. An integral vision of the whole, with the consequences to therapy.
1) THE REWARD PATHWAY SYSTEM
The functions of this system that regulate and create our strictly hypothalamic instincts must be related in neuroanathomic manner by linking them to the sensation of well-being generated by the reward system.
From a neuro-anathomical point of view, this regards mesencephalic level, in truncus encephali, particularly in the ventral tegmental area or VTA. This is the site most popuylated by dopaminergic-receptors, responsible for the wellness percepted at a conscious level (or cortical) due to many causes, but mostly by VTA.
Neural-webs have synaptic links to and from:
- telencephalic basal ganglia, lateral and medial (respectively arousal-attention-stress vs reward-wellness), and particularly: ventrolateral and ventromedial striatus, lateral and medial amygdala, nucleus accumbens, lymbic system (emotivity field)
- hypotalamus and insula, particularly linked with lateral systems (autonomic-vegetative system according to arousal-stress)
- several cortical areas: anterior cingulatus for the limbic-emotive component, frontal cortex able to develop finalistic behavior
- truncus encephali: on its lateral part (arousal derived from ponto-bulbar reticular activating system ) and its medial part, linked in direction of parasympathetic branches; moreover there are connections with the periaqueductal gray, responsible for the antinociceptive opioids mechanisms.
From a neuronal point of view, the system’s basal dopaminergic activity, is characterized by a phasic rather than tonic function, which means that it’s potential actions get started so to lead to a higher releasing flow of dopamine, on the basis of stimuli starting anywhere.
It seems that the first nucleus being activate is the nucleus accumbens, which with its cortical link determines the more or less conscious voluntary control of dopamine direction: medially (if there are excitatory cortical signals) or laterally (if not). In the first condition, which is more fortunate in terms of health (less stress) and evolution one, pallidus dishinibition occurs with consequent limbic-system disinhibition and all the effects derived.
The cognitive functions involved in this system are:
- instinctive, automatic, or inconscious mechanisms (regulated from the complex interactions between telecephalic basal ganglia and the cortex, with a particular role played by the cortical-subcortical circuits)
- emotive response (limbic system)
- superior hormonal system regulations (hypothalamus-hypophysis)
- vegetative reactions (typically at an hypothalamus-insula site)
- nervous authonomic system functions (hypothalamus-parasympathetic nuclei and medullary sites of orthosympathetic and parasympathetic branches)
- pain and antinociceptive system
2) GENERAL SURVEY
The reward pathway is one of the partition points for inputs leading to: conscious and unconscious behavior choices and their interaction.
This is one of the anatomical sites in which Pavlov-conditionings take place, and is the system on which many exogenous and endogenous molecules act.
The common mechanism of all these input stimuli is quite logical: dopamine easily determines facilitation in every activity of our organism.
A clear example in medical pathology is provided by Parkinson’s disease in which a lowering of dopamine that affects clinical features can be easily healed by the pharmacological supplementation of levo-dopa.
It is the same from a psychological point of view: instinctively preferred behaviors are those in which animals or human beings have raised dopamine levels; it is an auto-feeding reward.
In consequence, a low dopamine level determines the search for behaviors that in past lead to raised dopamine.
The interesting thing, is that many molecules with beneficial-therapeutic effect, all of which categorized as “drugs” (drugs, exogenous molecules, etc…regardless of situations) have VTA as target.
From this consideration, it is obvious that our mind is the real protagonist in the care and healing process, even if the first clinical action occurs on a peripheral organ with all the metabolic consequences.
Therefore all the therapeutic means capable of working on our mind (psychotherapy, hypnotherapy) can provide support or even be the first step in the healing process.
3) METABOLIC CORRELATIONS
Considering classical medicine system the neuropsychological logic point of view, it is clear that the mind’s role must be taken into consideration in both diagnostic observation, and in healthcare administration practices.
Every time we treat a metabolic pathology, we should associate those elements with every knowledge that is more and more integrated, from a molecular point of view, in holistic systems which are based at the same time on organicistic facts and a systemic metabolic vision.
The metabolic pathology par-excellence is “metabolic syndrome”, a clinical feature that includes diabetes and obesity, the most diffused diseases of all.
Their most frequent association is with nafld, non-alcoholic fatty liver disease, an asymptomatic common pathology.
From a molecular point of view, the interesting elements relating to VTA are: insulin, leptin, adiponectin.
The first is a molecule produced by the pancreas each time post-eating hyperglycaemia takes place; insulin acts at cellular level: glucose gets into the cell and is used for anabolism with the consequent systemic eu-glycaemia as a return to equilibrium state.
Insulin also acts on VTA: experimental data show that insulin is liked to raised dopamine mRNA [1- Figlewicz, 2009]. The effect is a positive dopamine-induced stimulation on nucleus accumbens, leading to a positive reward pathway [2- Galli, 2007]. In diabetic people (insulin-resistant), this mechanism is abnormal with a differently reduced stimulation on VTA to the point of requiring exogenous insulin supplementation or therapeutic systems able to raise insulinemy necessary to maintain optimal glucose levels (artificial insulin secretagogues, glitazones, or natural ones derived from plants like stevia: those molecules act at the same time on both peripheral cells and in CNS, in this way stimulating VTA).
In obese patients the molecules involved in peripheric and central metabolic regulations are leptin and adiponectin.
The first has an anorexogenic role; it is produced by adipocyte in normo-weight BMI subject and acts on VTA by inhibiting excessive food request: as a result there is a negative effect on nucleus accumbens with the reduction of hungriness. Obese subjects have a deregulation of leptin production (reduced) with paradoxical consequent raised hungriness: VTA is hardly stimulated, and food seems to be the only dopamine source (in this pattern, raised by insulin too) [1- Figlewicz, 2009; 4- Morton, 2009].
Adiponectin is similarly produced by peripherical cells (3p27); discovered in preadipocyte, the substance is found in the bloodstream as a potential product of every cell involved in the regulation of lipid metabolism, and probably even by normo-funcioning hepatocyte [3- Joo, 2008]. The molecular effect takes place at various levels: antiflogistic and antifibrotic on the liver and at systematic level (with the reduction of the hepatopaty and hypothetically of atherosclerosis typically associated with metabolic syndrome and with diabetes), and as a regulating factor on dopaminergic VTA system (where it is reduced in hepatopatic patients with a disequilibrium of hungriness); it seems that adiponectin determines a correct surfeit sense in a BMI normo-weight condition just as leptin does.
In conclusion, the action of adiponectin on mesencephalon determines a reduction of food introit and a raise of expenditure of energy.
4) CONCLUSIVE PERSPECTIVE
There is a growing need for:
- molecular logics based on human holistic vision
- anathomic approaches that consider metabolic dynamics
- pharmacological classical therapies related more and more with care systems that bear in mind the precepts derived from a global knowledge of medical science.
In particular, the relation between the mesencephalic reward pathway function and metabolic pathologies typical of the Western world help us more consciously understand standard therapies (insulinic, anti-obesity, etc) with new molecules (at present studied in experimental phases, as diagnosis targets and for therapeutic use), and with every therapeutic means (psychotherapy, hypnotherapy) that might be able to help our mind which is the only entity related to encephalic structures and functions while deriving from and transcending them at the same time.
BIBLIOGRAPHY
ARTICLES
1. Figlewicz D, Benoit S; (2009) Insulin leptin & food reward; Am J Physiol Regul Integr Comp Physiol 296: R9-R19.
2. Galli A (2007) Insulin brain impact links drugs and diabetes, PLoS Biology
3. Joo Young H & Hunjoo H (2008) Antifibrotic effect of globular adiponectin in human hepatocyte, FASEB J. 22: 978.11
4. Morton G, Blevins J, Kim F, Matsen M, Figlewicz D (2009) The action of leptin in the VTA to decrease food intake is dependent on Jak-2 signaling; Am J Physiol Endocrinol Metab 297: E202-E210.
BOOKS
5. Hilgard’s Introduzione alla psicologia (1999) Piccin
6. Kasper (2005) Harrison’s Principi di Medicina Interna, McGrawHill
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