|In 1954,the American psychologist, carrying on experiments on a rat, in order to study the "state of alertness", placed, by mistake, the electrodes in an area, deep inside the brain, which is responsible for the emotional reactions ( limbic structures) of the animal. The electrodes were wired to a lever that allowed the trained rodent to self stimulate the connected ares, whenever it so desired. Thus, Olds noticed that the rat triggered the lever continuously and frenetically, as if the stimulation gave rise to intense satisfaction. (Ref.1)|
FIG. 1 - RAT IN A SKINNER BOX. A typical laboratory scenery where self stimulation is carried out to produce a "reward sensation" (From Blum and col. - Ref.2)
the same experiment with other rodents, ídentical results were obtained.
Some of the rats used to acionate the lever 4 to 5 times per hour. The
pleasure they obtained was so strong that neither pain nor hunger would
stop the self stimulation. This only occurred when the animals became totally
Olds had discovered the brain areas responsible for the sensation of pleasure or reward !
FIG. 2 - THE REWARD CASCADE
demonstrated that the reward sensation is related to complex cascade reactions
involving several neurotransmitters and structures in the limbic system.
And that the ultimate result of the process is the activation of the mesolimbic
dopamine pathway, which starts in the tegmental ventral area and ends in
the dopamine D2 receptors on the cell membranes of neurons located in the
nucleus accumbens and the hippocampus. (Ref.3 e 4)
The process, as idealized by Blum at al. (Ref.2) starts in the hypothalamus, with the excitatory activity of serotonin-releasing neurons. This causes the release of the opioid peptide met-enkephalin in the ventral tegmental area, which inhibits the activity of neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
The disinhibition of dopamine-containing neuros in the tegmental ventral area allows them to release dopamine in the nucleus accumbens and (via amygdala) in certain parts of the hippocampus, permitting the completion of the cascade and the development of the reward sensation.
the cascade is working properly, the reward, as expressed in its commonest
and most significant way : the feeling of "well-being", is obtained, provided
certain basic conditions are fulfilled.
|In the less
developed species , these conditions are quite simple : in a healthy state,
the animal is rewarded if it feels safe inside its ecological niche, is
well feed, not thirsty and made warm (we rather say : "thermostable").
As the animal goes up in the zoological scale, new requirements are added
: sexual satisfaction and affective reciprocity, as well as acceptance
within the "family" or the community group. These last two are characteristic
of the mammalian, in general and, particularly, of the primates. Man requires
still more : social recognition and economic stability (Ref.5).
However, in humans (and also, perhaps, in other species), when the level of dopamine falls down in the post-synaptic neurons of the mesolimbic pathway, either due to a deficient production of dopamine in the tegmental ventral area or by a reduction in the number of D2 receptors in the nucleo accumbens and the hippocampus, those conditions, mentioned above, that acted as authentic "natural" stimuli , are now insufficient to generate pleasant sensations or feeling of "well being".
The individual then starts to search for alternatives that may, eventually, increase the liberation of dopamine to the limbic system. These alternative are represented either by changes in behavior, which, generally, display perverse characteristics or by the abusive consumption of certain chemical substances. But the results are, quite often, transitory. Therefore, the necessity for the chemicals or of the perverse attitudes tends to increase, more and more, so that he can obtain, through a feeling a pleasure, however fugacious and small, a relief to his anxiety and/or depression.
Such a situation, of a definite compensatory nature, configures the so-called REWARD DEFICIENCY SYNDROME (RDS).
D2 receptor is codified by a gene named A, located in the long (q) arm
of chromosome 11.
FIG.3 - Location of the gene A "locus"
gene A presents four variants or alleles : A1, A2, A3 and A4
A3 e A4 are extremely rare. The A1 allele is present in about 25% of the general population, whereas the A2 in nearly 75%.
The A1 allele becomes, sometime in life, generally during infancy or adolescence, responsible for the reduction of the number of D2 receptors and, consequently, it must be associated to the compulsive and impulsive disturbs of the RDS.
The different concentrations of D2 receptors between carriers of the A2 and A1 alleles is shown in Figs. 4 and 5.
FIG. 4 - A2 allele with a normal number of D2 receptors.
FIG. 5 - A1 allele with one third of the normal number of D2 receptors.
is a reduction in the number of D2 receptors, part of the dopamine accumulated
in the synaptic cleft, returns to the pre-synaptic axons, by means of a
reuptake process. As result, due to a negative feedback mechanism, the
dopamine-release neurons of the tegmental ventral area decreases or blocks
the liberation of this neurotransmitter.
For still unknown reasons, when the dopaminergic blockage occurs, the nor-adrenergic neurons located in the locus cerulus nuclei begin to liberate a greater amount of nor-epinephrine to the cerebral amygdala. The consequence is the development of anxiety, which, with time, brings about a concomitant depressive condition.
These are the primary symptoms of the RDS. The background for the other disturbances that shall, eventually, occur.
|The SDR complies
besides a permanent state of anxiety sometimes associated to depression,
a large range of compulsive and impulsive disorders.
1. Abuse of chemical drugs that seem to induce the increase of dopamine liberation to the limbic system : alcohol, cocaine, caffeine, nicotine (heavy smoking) and carbohydrate (tendency to obesity).
2. Compulsive gambling. Those who research on this subject point out that the risks and expectations associated with this vicious condition, give rise, in the obsessive gambler, to a stage of euphoria comparable to that produced by the inhalation of cocaine (Ref.6).
2. Attention –deficit disorder (mainly among young males).
3. Tourette syndrome. A condition characterized by uncontrollable multiple muscular tics, emission of not understandable noises and a strong tendency to utter obscene and insulting words.
Up to to now, there is no concrete evidence that the impulsive disorders are the result of a deficiency of dopamine in the limbic system. However, their entailment to the RSD is surmised by the high incidence of people carrying the A1 allele among those who display such disorders.
|So far, there
is little to say and a long way to go, concerning the treatment of the
reward deficiency syndrome.
Nevertheless, two different, if not opposite, approaches are being considered by those who investigate this subject.
The first consists in increasing the formation and subsequent liberation of dopamine towards the specific target areas of the limbic system : the nucleus accumbens and the hippocampus. This can be obtained by using a dopamine agonistic, such as bromocryptine or by the administration of enkephalins and the serotonin and dopamine precursors, L-Tryptophan and L-Tyrosine. It has been proved that patients treated with bromocryptine show na accentuated reduction of anxiety and compulsion for alcohol (Ref.7).
The second approach, on the contrary, aims that the patient failures to feel "rewarded" by the ingestion of alcohol or by the inhalation of cocaine. This is obtained by the blockage of the dopamine receptors (and also, perhaps, of other transmitters which may induce pleasure and satisfaction).
As far as alcohol is concerned, one uses the anti-opiate "Naltrexone"(Ref.8).
As for cocaine, the desired effect is reached by increasing the production of GABA, which is obtained by the administration of the anti-epileptic drug "Vigabatrin" (Ref.9).
If one considers the reward cascade, the explanation seems obvious, since GABA blocks the linkage of dopamine to its receptors, whereas the enkephalins, by inhibiting the inhibitory action of GABA, liberates dopamine.
Thus, theoretically, at least, the absence of dopamine in the post synaptic neurons of the nucleus accumbens and hippocampus, hinders alcohol and cocaine to promote the sensation of pleasure and reward. Therefore the addict "looses" the physical necessity for these drugs, since they cease to produce satisfaction.
However, once the the reward sensation is over, one expects the development of the abstinence syndrome. Consequently, the inevitable question occurs : what should be done about it ?
First of all, it is obvious that the dopaminergic blockage can not the sustained, but for a short period. Otherwise, the patient, in all probability, will develop a condition of total absence of pleasure (anedony), which will be certainly followed by depression. Therefore, not long after the dopamine block is installed, we must restart the lprocess of dopamine liberation to the limbic system. The best way todo it, is through the administration of certain enkephalins. We suggest "Tramadol", which also prevents the re-uptake of serotonin (an antidepressive effect) and the concomitant use of a dopamine precursors like L-Tyrosine. At the same time, psychotherapy may be applied, in order to try to convince the patient that reward and satisfaction can be obtained by other means, besides the dangerous use of alcohol, cocaine and similar deleterious drugs.
characteristics of the RDS is well established by the fact that the accentuated
hyperactivity and the attention-deficit disorder in children and pre-adolescents,
as well as the anti-social personality in adults are, often, associated
to alcohol and cocaine addiction.
On the other hand, the sociopath behavior in early ages predisposes the development od anti-social personality, alcoholism and drug abuses in adulthood.
The intensification of studies about the gene that codifies the D2 dopamine receptor is highly justified by its participation on the genesis of one of the most serious medical-social problems of our time.
Perhaps genetic engineering is the best weapon that our therapeutic arsenal has to eradicate or minimize the tragic compulsion for alcohol, cocaine and similar drugs.
Jorge Martins de Oliveira, MD, PhD
MD, PhD. Full Professor and Master of UFRJ (Rio de Janeiro). Associate Professor of UFF. Scientific Coordinator. Coordinador and Director of the Department of Neurosciences of the Institute of Human Being (RJ). Fellow in Research by Saint Vincent Charity Hospital, Cleveland, USA. Full Member of Brazilian Academy of Military Medicine. Member of the Brazilian Academy of Writers Physicians. Graduated by Superior School of War (ESG). Email: firstname.lastname@example.org