6) ARTICLE - dopamine [2012.I]


Dopamine, mental states, conditioning,

plasticity, autonomous nervous system,
Parkinson, psychosis, reward deficiency syndrome,
mirror neurons, default network, addiction

Dopamine is a neurotransmitter produced in: the sub cortex, the nucleus accumbens, the amygdala and the mesencephalic ventral tegmental area (VTA), where the reward pathway is situated.
It has an effect on the heart and vessels by tying the beta1, beta2 and alpha receptors.
Dopamine varies physiologically, determining all these natural alterations which are typical of every different mental state.
It is also involved in many pathologies: Parkinson, depression, psychosis, addiction and dysmetabolism.
Lastly, it is involved in therapeutic processes: many types of conditioning take place thanks to raised dopamine levels, and each cognitive therapeutic system recreates neural webs which have positive effects on dopaminergic circuitries.
Dopamine is a protein with a neurotransmettitorial function, a catecholamine. A precursor of adrenaline and noradrenaline, it is produced in different enkephalic locations; it is typical of the sub cortex, the nucleus accumbens, the amygdala, and the mesencephalic VTA, where the reward pathway is situated.
It also acts on systems other than the central nervous system. It is able to have an effect on the heart and on vessels. Other than being able to act on dopaminergic receptors it is able to tie other kinds of receptor: beta1 with chronotropic and positive inotropic effects, beta2 from which it produces vasodilatation, and finally alphas which mediate a vasoconstriction.
Dopamine varies physiologically, determining those natural alterations typical of every different mental state.
Moreover, it is involved in many pathologies: the par-excellence pathology with a dopaminergic alteration is Parkinson’s disease; dopamine is typically reduced in depressive states, altered with an hyperactivity tendency in psychosis and in dissociative states, in disequilibrium, in dependency and in the reward pathway syndrome. It is also altered in all dysmetabolism disorders.
However, it is also involved in therapeutic processes: many conditionings take place thanks to augmented levels of dopamine, and every therapeutic cognitive system tends to recreate neural webs with positive effects on dopaminergic circuitries.
The chemical formula for dopamine is C6H3(OH)2-CH2-CH2-NH2. Its chemical name is “4-(2-amminoethyl)benzene-1,2-diole”, and its acronym is DA. As all catecholamines, it is composed of a benzenic ring with two oxydrilic groups, to which it associates an ethyl-aminic group.
It is synthesized in the nervous tissue and in the adrenal medulla. Synthesis begins from tyrosine, in levo form: L-tyrosine. L-DOPA is then obtained; dopa-decarboxylase acts on it by removing the –COOH group, producing dopamine. From dopamine we obtain noradrenaline, another neurotransmitter, thanks to another enzyme (an hydroxylase).
Dopamine is stored in vesicles, which become synaptic vesicles, released in synapsis after an action potential. At this level it can be uptaken repeatedly and catabolized. Catecholaminic derivates are obtained through one of the actions of COMT and MAO enzymes; through another action, homovanillic acid, which is for example detectable in urine as a comparison of the catecholaminergic activity of metabolism, is obtained.
Many drugs act in synaptical locations: antagonists inhibit dopamine release at this level; conversely agonists raise the releasing of the neurotransmitter at nervous termination.
Dopamine acts on some receptors, whose expression depends on an over-regulation carried out by many neurotransmitters. Each receptor has a proper affinity for tying both with dopamine and with agonists and antagonists. The main receptors are:
- D1 – only postsynaptical; they are found in the striatum, in the thalamus, in the limbic system, in the hippocampus, in the hypothalamus. Their agonists are apomorphine (a drug used in Parkinson’s disease and in erectile dysfunction), and pergolide (indicated in Parkinson’s). The main agonist is haloperidol and its analogues (used as neuroleptics).
D1 receptors are responsible for the vasodilatation of vessels, mainly in the kidneys and in splanchnic (abdominal), coronary and cerebral vessels.
- D2 – pre and post synaptic; they are found in the striatum, in the substantia nigra and in the hypophysis. Its agonists are: apomorphine, pramipexole, ropirinole (drugs used in Parkinson’s disease therapy). Its antagonists: haloperidol, clozapine, clorpromaxine (used in psychotic conditions).
- D4 – frontal cortex, brain stem, mesencephalon. It has the same agonists and antagonist as D2.
The main system on which dopamine acts is that of the reward pathway, based on the reward concept, but it also includes some neural links which associate hypothalamic needs (neurovegetative) to emotions, among which, the main one is that of well-being, typical of the limbic system (cortical).
The place with major density of dopaminergic receptors is the mesencephalic area called the VTA. The links which make it possible to perceive vessels at a conscious level are linked bysinaptically (to and from):
o cortex: limbic (emotive) and frontal (finalized behavior)
o basal ganglia: striatum, amygdala, nucleus accumbens (emotion)
o hypothalamus and insula
o low brain stem
o periaqueductal grey system.
It is important to distinguish the medial system from the lateral system for all the consequences deriving from this, from a physio-pathological point of view. The medial system is mainly involved in the elaboration of stimuli and of neural webs that lead to the feelings of reward and gratification: those neural webs involve different kinds of cortex and basal ganglia, mainly ventro-medial striatum and the medial amygdala, and medial parts of the brain stem, which are then connected to parasympathetic branches.
The lateral system involves mechanisms which are linked to the attention concept and those which are transferred to stress metabolism, and all the pathologies which derive from it in different ways. The lateral system concerns: the cortex, the basal ganglia, in particular the ventro-lateral striatum and the lateral amygdala, the main part of hypothalamus (its axis CRH-ACTH, starting point for the stress system), the insula, and finally the RAA, the reticular ponto-bulbar activating substance of the brain stem.
This shows how dopamine is not only the molecule of pleasure and of gratification, but it is also able to act as a vehicle for stress messages. Stimuli which are not correctly oriented through well-being conditions after GABA-ergic circuitries, are shifted to lateral systems, where impulses are transmitted by dopamine. This system is involved in many degenerative pathologies in which, one or more alterations at mental level, associated with other factors lead to some dysmetabolism and create situations such as: atherosclerosis, Cushing’s syndrome and also diabetes mellitus. These pathologies have an hypertrophy of lateral system, a raise of the hypothalamic axis CRH-ACTH, with derived consequences in common: the hypertrophy of the adrenal glands, the raising of the cortisol levels, and stress molecules leading to many proteolysis. Vessels tend to degenerate and to become older, hunger is augmented and food which raises glycaemia is preferred (for a never-satisfied reward), there is some weight gain and the lipidic prophile worsens. Only a re-balance which is also mental, can take the encephalon towards a prevalence of the medial over the lateral axis.
Dopamine also acts as a molecule which is able to regulate the autonomous nervous system, that branch of the nervous system which is autonomous and as it can be said, does not have a superior control.
Delta dopaminergic receptors are present in the whole cardiovascular system, regulated at a central level by the insula, but controlled mainly at a peripheral level near those organs (which are innerved by a branch of the vagus nerve and by orthosympathetic system mainly cervico-thoracic). These are delta receptors, on which dopamine acts at the level of all major vascular systems: renal, splancnic-entherical, coronaric and cerebral. The prevalent effect is that of a vasodilatation.
Other receptors that dopamine can tie are the beta receptors, which are typical mainly of adrenaline. This has an inotrope and chronotrope positive effect on the heart: it raises the contraction force, and therefore the cardiac output, and it raises cardiac frequency. The consequence on the vessels is that of vasodilatation. On the other hand, there is a vasoconstriction when dopamine ties alpha receptors.
There are many variations of mental states (also called conscience states) that each person can perceive, but generally three of them can be identified: wake, sleep and hypnosis.
Each mental state in the brain corresponds to specific electrical activities which are recordable through EEG, electroencephalogram, to which there is also a correspondence of neurotransmettitorial variations mainly at a cortico-subcortical level.
During the wake state, a major consciousness oriented to external reality is present, during the sleep state, attention is oriented towards interiority, and during hypnosis there is a varying conscious interaction towards interiority.
This corresponds to a differently oriented activation throughout those encephalic structures (more or less deep), to which corresponds a reduced frequency of EEG rhythm waves and a higher prevalence of dopamine levels:
- beta rhythm (30-13,5 c/s) – the typical rhythm of cortical activity. The prevalent neurotransmitters in the cortex are serotonin, adrenaline, noradrenaline and many hormones that distinguish different cortical strati (oxytocin, androgens, estrogens).
- alpha rhythm (13-8 c/s) – a slower rhythm, at cortico-subcortical level. This is the level which presents the elaboration of the conscience level, it is here that people choose whether or not to access their unconscious or whether to activate some circuitries referring to the cortex, the place of many ego-defenses. This is the rhythm of the default network activity [1]: mental areas involved at rest, active areas when there is not a finalized action. It is in this place that cognitive therapies function. Hypnosis, on the other hand, acts mainly on the sub cortex, by reducing the conscience condition. Generally speaking we are in either a wake or rest condition. So there is a sub cortex prevalence with a rise in dopamine levels.
- theta rhythm (7,5-4 c/s) – mainly typical of babies’ minds.
- delta rhythm (4-0,5 c/s) – typical condition of different phases of sleep, in which differences in shape and typical complexes alternate.
The hypnosis state is deeper the longer we remain in the unconscious (sub cortex).
To different states of conscience correspond variations in the rhythm of breathing, variations in pupil diameters for the prevalence of an alarmed or relaxed state (orthosympathetic and parasympathetic, III cranial nerve, Edinger and Westphal nucleus) and modification in color.
There are some pathologies in the neuropsychiatry in which dopamine is involved with different roles:
1. Parkinson’s disease – the cause (for the production of free radicals and oxydative stress) is the degeneration of pigmentati neurons of the pars compacta of the mesencephalic substantia nigra, to which follows the lack of dopaminergic stimulation to the striatum; it begins in about the 7th decade of life with tremors at rest which worsen in stressful conditions, and to which rigidity, bradikinesy, amimia, hypophonia and micrography are associated. Therapy is carried out with: dopamine agonists, carbidopa/levodopa combinations, selegiline (inhibiting MAO-B), COMT inhibitors, entecapone, tolcapone, amantadine.
2. Psychosis and dissociative states – it has been found how in every psychotic condition, characterized by the absence in people’s thoughts of a reality principle, and often associated to positive symptoms, whether it is isolated or part of a more complex situation of schizophrenia, in which deliria and hallucinations prevail, a raise of dopamine levels (the so called ‘dopaminergic hypothesis’), probably more than simply augmented not regulated in the formulation of functional thoughts is present. There is a similar condition in dissociative states whether they are personality diseases such as schizoid and schizotypal or, the dissociations leading to a multiple personality disorder. For this kind of pathology the drugs used are neuroleptics: drugs of haloperidol family and chlorpromazine family. These are dopaminergic antagonists.
3. Depression – in depression there is a decrease of all cortical and sub cortical neurotransmitters, particularly of serotonin and dopamine, and also of noradrenaline. The patient has a depressed-irritable mood or lack of normal interest-pleasure for at least two weeks in combination with various symptoms: variations of hunger and of weight, insomnia or hypersomnia, weakness and loss of energy, psycho-motor slowdown or agitation, feelings of inadequacy or self-undermining or also a sense of guilt, reduced ability to concentrate and make a decision, recurring thoughts of death or suicide. Principal therapies are: ATC, tricyclic antidepressants that inhibit the neurotrasmettitorial recaptation mainly at an adrenergic level; SSRI, serotonin recaptation inhibitors; MAOI, which inhibit the MAO monoaminoxydase type A (noradrenaline) and type B (dopamine).
4. Addictions – in all addictions, such as gambling, alcohol addiction or chemical addiction, there is an alteration of the dopaminergic system mainly at reward level, for which the subject has a high demand. Recent studies [2] have shown that by administering cannabis or cocaine, the level of dopamine rises. The therapy of these pathologies is mainly at a conscious level: the subject must change his way of perceiving himself in wider contexts than just those of the intake of the substance, perhaps by substituting pathological addictions with others which are useful to well-being.
5. Reward deficiency syndrome [3] – a low reward syndrome, typical of individuals who have low basal dopamine levels in the reward pathway, characterized by hypo-dopaminemias, with the tendency to search every source leading to high dopamine, verging from addiction to dysmetabolisms.
6. Dysmetabolisms – the same mechanism that takes place in pathological addictions takes place even in food addictions, mainly when assumed in an unregulated way [4]. Furthermore, many molecules acting on the regulation of glucidic and lipidic metabolisms such as insulin, leptin and adiponectin, are actually involved in the superior and central regulation of this metabolism. It has been shown that insulin is able to raise the precursor of dopamine (mRNAs), at a mesencephalic level, which explains why diabetic people get to pathology phases in which more and more insulin is necessary for a peripheral and central re-balancing of the individual.
Relatively high dopamine is fundamental in each process of mental elaboration.
It has been shown how hyper-dopaminemia conditions are present concomitantly to the activation of mirror neurons.
Mirror neurons are those particular neurons of the prefrontal pre-motor cortex which are activated when we observe a finalized action taking place in front of us, or when we read or listen to the description in order to emulate it. The activation takes place with an automatic mechanism immediately and in an unavoidable way. The effect is not only that of predisposing to action, but also of rebounding on other mental areas so as to involve us in a synchronic and empathic way towards a situation, a consequence that explains the ‘power of the word’. Empathy, the capacity of living the mental state of others, therefore derives from those mechanisms typical of gratification and of Pavlovian conditioning.
Recent studies [5] have shown how the synchronization of dopaminergic neurons, particularly of mesencephalic ones, is activated by events which are able to activate rewards. It is true then, that relative hyper-dopaminemia states are those able to condition the formation of new neural webs that imprint themselves on certain neural frequencies and certain conformations of neural webs. Another step towards conditioning is that of the activation of a reward: if that condition activates reward, the well-being sensation will bring a gratification to the individual so as to have a strengthening of the situation that led to that ‘neural arrangement’, characterized by certain thoughts, certain emotions, and all the consequences of the case.
This is possible thanks to brain plasticity, formed by perpetual neurons but also furnished of neural stem cells so that we can continuously re-elaborate the content and the form of our mind after the interaction with the environment. The brain continuously reviews itself so as to strengthen those neural paths with more advantages and well-being and, on the contrary, to modify thoughts, that is, neural webs which are still not correctly formed.
Relatively high rates of dopamine are involved in all principal psychotherapies: cognitive-behavioral therapy or hypnotherapy, but mainly in the correction of ises.
Cognitive-behavioral psychotherapy in fact acts on those cortico-subcortical circuitries typical of subconscious mechanisms, where the unconscious led to certain behavioral choices variably controlled by the conscious, and has determined the preference of certain ways of approaching that subject, acts automatically despite the doubtful advantage of the situation. Such psychotherapy calls into question the ways of thinking of the subject, who by analyzing each thought and each behavior learns to evaluate the effects of his way of thinking and acting, particularly noticing which emotions derive from them, considering if such hypotheses lead to correct well-being or not. So it is a form of psychotherapy which modifies numerous encephalic structures, so that the subject is more conscious of his sub cortical system of approach, by making thicker neural webs from the cortex to sub cortex, a typical dopaminergic location.
Hypnosis exploits relatively high dopamine mental states to carry out its therapeutic effect [6]: it is based on a voluntary reduction of the cortical function in the subject, to which follows a parallel rise in sub cortical activity, in order to carry out a review of all that was lived and of what is part of the unconscious, which has been re-elaborated thanks to the help of the hypnotherapist. The subject will ‘cut his/her knots’ thanks to a trance status, the first point of a deep work of revision of the mental state of a person. The patient will reach suggested objectives when he/she becomes conscious of the procedures lying behind the pathologies or dysfunctions noticed, and he/she subconsciously becomes the owner of an optimized way of thinking and way of perceiving emotions.
Continuous thought conditionings take place, during hypnosis sessions, by making prevail those ideas which lead to greater usefulness and well-being for the subject, by emphasizing those neural webs that the subject will retrace spontaneously in a semi-automatic way.
Particularly high levels of dopamine will be found in those sessions in which the subject will find himself/herself solving situations that provoked abreaction, with a sort of living traumatic event, or to solve ises, the so called repeated scenes, those traumas that the subject has removed for years and has found himself/herself facing many times in an ineffective way because they were never really analyzed initially. Therapy will be more effective as the subject will live and solve his/her traumas during a trance, by making hypotrophic ise areas that lead to traumas, and by seeing everything in a different way, by associating the (cortical) deterrence of the case to something optimistic.
Other than therapies for pathologies directly connected to the mind, other therapeutic forms do exist, and are able to act on the reward system: typically, diterpenes, those of coffee or those of stevia, a plant which regulates metabolism (useful in diabetes) and nootropic, which are able to raise dopamine levels.
Dopamine has been recently identified as a success molecule [7]. It seems to be at basis of personal motivation. The most motivated people to pursuit and reach their objectives are those with more D2 receptors for dopamine in the striatum, the place which, more than others, regulates behaviors oriented to obtaining a reward, influencing frontal cortical areas involved in decisional processes, in adjusting behavior to contest and in reasoning.
Dopamine is a fundamental molecule in the whole central nervous system. Its balance, made possible by correct thoughts which direct emotions of well-being and gratification, is fundamental.
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2. Blum K, Chen TJ, Chen AL, Madigan M, Downs BW, Waite RL, Braverman ER, Kerner M, Bowirrat A, Giordano J, Henshaw H, Gold MS. (2010) Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS). Med Hypotheses. 2010 Mar;74(3):513-20. Epub 2009 Nov 14.
3. Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F. (2011) Quantification of Behavior Sackler Colloquium: Addiction: Beyond dopamine reward circuitry. Proc Natl Acad Sci U S A. 2011 Mar 14.
4. Figlewicz (2009) Insulin leptin & food reward; Am J Physiol Regul Integr Comp Physiol 296: R9-R19, 2009. First published October 22, 2008
5. Joshua, Synchronization of Midbrain Dopaminergic Neurons Is Enhanced by Rewarding Events; Neuron, Volume 62, Issue 5, 695-704, 11 June 2009
6. Dragoni D (2010) Ipnosi e reward pathway; SMIPI Rivista Medica Italiana di Psicoterapia e ipnosi; 2010, vol 1
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