Compulsive behavior in Parkinson’s disease
Introduction
Recent studies have showed a relation between the treatment of Parkinson’s disease and the onset of compulsive behavior like punding, alcoholism or pathological gambling. E.g. the prevalence of problem gambling is 0.6% while in treated patients the prevalence is between 3.4 and 6 %.
This correlation can be explained only understanding the function performed by dopamine in both motor system and reward system.
The role Of dopamine in motor system
In motor system, in the midbrain, this neurotransmitter act from the substantia nigra to inhibits the GABA-mediated transmission of the striatum, then dopamine performs a negative control on the movement.
As a consequence a lesion in this nucleus, as in Parkinson’s disease, produces shaking, rigidity, slowness of movement and problem with walking. The commonest treatment for this disease is levodopa, a metabolic precursor of dopamine in order to elevate its concentration in the midbrain
The role of dopamine in reward system.
Nevertheless, in the same time, dopamine is involved in other neural system, as the reward system. As a matter of fact the neuronal transmission from ventral tegmental area to accumbens nucleus and prefrontal cortex is dopamine-mediated. This system perform an essential role in the survival of the organism because it Is active during the fulfillment of an evolutionarily significant stimulus, like hunger, thirst or libido. However this system can be activated doing something we consider enjoyable like play an instrument, go out with friends or watch a film. It is obvious that for a satisfying every-day life we need this neural system and the complete stop of this function is a disease called anhedonia. On the other hand an excessive or better a uncontrolled functionality of this mechanism can lead to a compulsive behavior. A condition in which the patient is restless because of it continuous looks for the source of its pleasure.
In this person there is a mechanism called positive reward. i.e. they feel a positive sensation, due to a precise action, and this feeling will be the driving pressure to repeat this action, in a auto-reinforcing loop. Even though this complex behavior it can be hardly explained only with one single way the molecular base of this loop can be explained by Long Term Potentiation(LTP).
The molecular role of dopamine in LTP.
LTP need two type of glutamate receptor: AMPA and NMDA. Both are ionic channel but the first is ready to be open and it is cross by Na+ and K+, the second in basal condition is blocked by Mg2+ and it is cross also by Ca2+. When we have a low frequency of activation of AMPA channel the cell can’t be depolarized very much but when frequency increases the electric potential move Mg2+ from NMDA channel that now can be open and Ca2+ can enter in the cell. We must underline the importance of Ca2+ enter, the triggering process of this mechanism. As a matter of fact calmodulines bind this ion and switch on the function of specific CAMK, the phosphorylation of AMPA channel( in this way more active) and of MAPKS a family of proteins leading to protein translation. Specifically MAPKS phosphoryles CREB 2 a down regulator of CREB 1 function, the activation in the nucleus of CRE the last regulator of DNA transcription of a pool of genes responsible of the pontentiation of the synapses. This complex mechanism allows the neuronal cell to answer more and in a stronger way to any stimulus. As a consequence we can remember better the good sensation of a specific behavior and positive reward helped.
But what is the role of dopamine? This neurotransmitter can potentiate this response. Indeed it binds on two receptor D1 and D2, that respectively have a positive or negative effect on the concentration of C-AMP acting on adenylate-cyclase the producer of this second messenger. which again it is bind by PKA, and this complex phosphorilates the same MAPKS acting in LTP.
Conclusions.
It is important to know this anatomical and neurophysiological linking because millions of people suffer for Parkinson’s disease, hardly ever elderly, often fragile and alone, and the onset of a compulsive pathology it can be a tragedy for them. This tragedy can be avoided changing the drug used for the treatment preferring that with a different specificity for receptor D1 and D2. As a matter of fact the Parkinson’s disease motor signs are almost D2 dependent and the onset of compulsive behavior is almost D1 dependent.
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Asunción Ávila a,!, Xavier Cardona b, Montse Martín-Baranera c, Juan Bello a, Francesc Sastre b
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Atbin Djamshidian, MD,1 Francisco Cardoso, MD, PhD,2 Donald Grosset, MD, FRCP,3 Henrietta Bowden-Jones, MD,4,5 and
Andrew J. Lees, MD, FRCP1*
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http://en.wikipedia.org/wiki/Compulsive_behavior
http://en.wikipedia.org/wiki/Problem_gambling
http://www.parkinson.it/varie/punding_complicanza_poco_nota_della_terapia_dopaminergica.html
Gianotti Claudio
