Reasons for drug use
Classification of drugs of abuse
Neurophysiology of drug abuse
Neurobiochemical changes induced by the different drugs
Animations on cocaine effects
Considerations about drug-abuse treatment
Ancient literary and religious texts show that, at all times and places, human beings deliberately used (and abused of) substances fitted to modify the nervous system functions, inducing altered bodily sensations and psychological states.
In his book "An intimate history of humanity", Theodore Zeldin states that "escaping to altered states of conciousness, towards sedation or exaltation, was a constant ambition everywhere, at all centuries. There wasn’t any civilization that didn’t try to evade normality with the help of alcohol, tobacco, tea, coffe, and all kinds of plants".
The search for agents able to modify the nervous functions is considered by some authors, like Ronald Siegel, an impulse as powerful as those impulses leading to the satisfaction of physiological needs, outdoing them sometimes. According to that author: "Our nervous system is arranged to respond to chemical intoxicants in much the same way it responds to rewards of food, drink, and sex. Throughout our entire history as a species, intoxication has functioned like the basic drives of hunger, thirst, or sex, sometimes overshadowing all other activities: Intoxication is the fourth drive".
Reasons for drug use
But why are the intoxicants (modifiers of nervous function) so sought after? What are the reasons that drive people to use them?
We think that we could assign these reasons to four basic groups:
1. In order to reduce unpleasant anxiety and depression feelings. These feelings are:
Some authors say that, considering the existential condition, it is no wonder that man feels anxious, but that he feels so little anxiety.
1.b. Specifical for certain individuals, originated by traumatic experiences or pathological conditions. Instances belonging to this kind are drug abuse by war veterans or persons affected by social phobias or depression.
3. In order to increase psychophysical performances, by reducing unpleasant bodily sensations like pain, insomnia, tiredness or by overcoming physiological needs like sleep and hunger. During the Inca empire, coca leaves were chewed by porters and messengers to increase their resistance and speed. Amphetamine is frequently used by truck drivers to shorten the time of their trips.
Chronic pains and persistent insomnia are well known causes of different analgetics and hypnotics abuse.
There are also reports on the use of drugs by shamans during their healing activities as well as on the alcohol-drinking by medium possessed by spiritual entities during trance states in rituals of Afro-American cults. Usually, in these cases, the use of drugs happens only in well-defined situations, culturally accepted and approved, without impairing the social performance of those persons. On the other side many drug users, like some hippies of the 60’s, use different drugs (mainly hallucinogens) in search of a substitute for religious experiences.
During mankind’s history several pharmacological agents have been used to induce intoxication, They comprise plant extracts, fermentation products and, more recently, different synthetic substances.
In his book "Phantastica: Narcotic and Stimulating Drugs"(1924), Louis Lewin classified the distinct psychological effects of the different agents. According to him, the agents then known, could be classified as:
a.Euphoriants – distinguished by their capabality of diminishing or suspending unpleasant perceptions or emotions, with little effect on conciousness. They induce a state of mental comfort. According to Restak:
Lewin included in this group opium and its derivatives as well as cocaine. The last mentioned agent, in Restak’s opinion, would today be taken out of this group by most psychopharmacologists, and included in the excitants group.
c. Inebriants – they produce behavioral excitement as well as perceptual, cognitive, and affective alterations. This group includes ether, chloroform, ethyl chloride, and the drug most used at all places and times, alcohol.
d. Hypnotics – substances used to induce sleep, like barbiturates and, modernly, some types of benzodiazepines.
e. Excitants – produce cerebral excitation and behavioral stimulation without altering consciousness. This group includes caffeine, amphetamines and, according to present standards, cocaine.
1 - Prevalence during lifetime
|Alcohol abuse without dependence||9,4%|
|Drug-abuse without dependence||4,4%|
Neurophysiology of drug abuse
Whenever a person uses a drug and the effect it produces is somehow pleasant, this effect gets a rewarding quality for that person. As experimental research by behaviorist psychologists have demonstrated, all behaviors that are reinforced by a reward have a tendency to be repeated and learned. Successive repetitions, besides fixing the reward-producing behaviors, also fix all previously indifferent stimuli, sensations, and situations, eventually associated with those behaviors. Seeing particular places or persons, hearing specific musics, etc, for instance, triggers in drug users the craving for their preferred drug.
Using Positron Emission
Tomography (PET) Dr. Edythe D.London and her colleagues at the Addiction
Research Center, in Baltimore, obtained images showing that in cocaine-users,
cues associated with the use of the drug sparked an increase in the metabolism
of glucose in brain areas that are associated with memory and learning
(lateral pre-frontal cortex, amygdala, and cerebellum).
Illustration: Jurema Sampaio
|Up to now is far from complete our knowledge about the cerebral, chemical and structural changes that underlie reward and act as reinforcers for different behaviors, including that of drug use. Nevertheless, recent researches point to a chain of reactions, involving several neurotransmitters, leading to the release of the neurotransmitter dopamine in a brain are a called nucleus accumbens. This nucleus receives projections from dopaminergic cells located in the ventral tegmental area and it is a convergence site for stimuli coming from the amygdala, hippocampus, entorrhinal area, anterior cingulate area, and part of the temporal lobe. From this nucleus efferent projections reach for the septus, hypothalamus, anterior cingulate area, and the frontal lobes. Due to its afferent and efferent connections the nucleus accumbens plays an important role in the regulation of emotion, motivation, and cognition.|
Ethiology of drug abuse
Investigations show that some alcoholics begin to drink due to social pressures or in response to stressing situations in their lives. Since the drinking behavior is initiated, its fixation is conditioned by the alcohol-induced psychophysiological reward. Contrariwise other alcoholics seem to be driven to use and abuse alcoholic beverages by an internal compulsion.
2 - Types of alcoholism
|Type I||Occurs both in men and women; requires both genetic and environmental influences; begins fairly late in life; greater possibility of recovery.|
|Type 2||Occurs primarily in men; overwhelmingly genetic in origin; begins during adolescence or early adulthood; usually associated with criminal behavior; lesser possibility of recovering.|
It seems that the same happens in relation to other psychoactive substances.
Genetic and inborn factors as well as learned and acquired factors for the drug abuse can thus be identified.
The influence of genetic factors on alcoholism was already anticipated in Ancient times. Plutarch stated that "drunkards beget drunkards". In his book "Alcohol and the addictive brain", Kenneth Blum summarizes the results of decades of studies about genetics x alcoholism stressing that:
a. Monozygotics twins of alcoholics are at significantly higher risk of developing alcoholism than dizygotic twins.
b. Children of alcoholics are approximately four times as likely to become alcoholics as children of non-alcoholics, even when the children of alcoholics are separeted from their biological parents at birth, and reared by non-alcoholic adoptive parents.
c. Children of non-alchoholic parents have a low rate of alcoholism, even when adopted by alcoholic parents.
d. There is a 25-50% lifetime risk of alcoholism among sons and brothers of severely alchoholic men.
Alcoholics and their offspring show several neurobiochemical abnormalities such as:
e. Increased resistance to the depressor effects of alcohol.
f. A smaller EEG alpha frequency response to alchool ingestion.
g. Lower mean cerebrospinal fluid levels of 5HIAA ( 5-hydroxy-indolacetic acid) the major metabolite of serotonin.
h. Enchanced sensitivity of the pituitary b -endorphin system to alcohol intake.
i. Behavior patterns similar to those observed in people with mild dysfunction of the frontal lobes (impulsiveness, attention deficits, hyperactivity, and poor emotional regulation).
In a paper that appared in a 1996 issue of American Scientist, Blum et al advance, as the physiological basis for drug abuse, what they call reward deficiency syndrome.
Box 3 - The brain’s drug
and amphetamine reward system includes neurons using dopamine found
in the ventral tegmental area, connected to the nucleus accumbens and other
areas such as the prefrontal cortex.
The opiate reward system besides the aforementioned structures, includes also areas that use endogenous opioids as neurotransmitters like the arcuate nucleus, amygdala, locus ceruleus, and the periaqueductal gray area.
The alcohol reward system, besides the dopaminergic neurons of the ventral tegmental area and the nucleus accumbens, includes also structures that use GABA (gamma-aminobutyric acid) as a neurotransmitter, like the cortex, cerebellum, hippocampus, superior and inferior colliculi, amygdala, and nucleus accumbens.
Neurobiochemical changes induced by the different drugs
Certain characteristics seem to be common to all abuse-inducing drugs:
In 1993 Robinson and Berridge showed that different kinds of psychostimulant drugs, and drug abuse, induced increase in the extracellular concentration of dopamine in the nucleus accumbens, an area of the mesolimbic dopaminergic system. This increase could be called forth by drugs like cocaine, amphetamine, opiates, alcohol, caffeine, barbiturate, and nicotine.
As described by Nastler (1994) dopamine acts on a G-protein, changing cyclic AMP (cAMP) levels in the nucleus accumbens. Cyclic AMP (cAMP) activates several protein- kinases that regulate transcription factors, like CREB (substances that bind to proteins in response to cAPM). These transcription factors bind to specific DNA areas, promoting increases or decreases in the speed of certain genic transcriptions.
Acute and, mainly, chronic stress play a significant part via the intense liberation of glucocorticoids, well-known for their capacity to increase the nucleus accumbens sensibility to drug-abuse, since they facilitate dopamine release in this nucleus.
The genetic bases of dependence involves multiple genes of the genoma. Activation transcription of the receptor in the dopaminergic system seems to lead to the activation of an specific gene (C-fos), responsible for the activation of the FOS-related protein. This protein may have a neuroadaptive role for the repetitive administration of drugs.
The identification of factors that might confer vulnerability to drug abuse and dependence is helped by new genetic analysis like the manipulation of the molecular genome.
Alcohol is a multiple-action depressor of the Central Nervous System, and the depression caused by it is dose-dependent. Although alcohol is mainly used because of its stimulating action, this action is only apparent and happens only with moderate doses. It results of the depression of inhibitory controlling mechanisms. Under the effect of alcohol the cortex is freed from its integrative role, thus resulting confuse and disorganized thinking, as well as disruption of adequate motor control.
Ethanol diffuses through lipids, modifying proteins fluidity and functions. High concentrations of ethanol can decrease the eletron-transporting functions of the Na+K+/ATPase pump, thus impairing electrical conduction.
Only recently was it possible to understand the neurobiological mechanisms responsible for many clinical manifestations of alcoholism. Ethanol affects different cerebral neurotransmitters. One of them is the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
The interaction between ethanol and the GABA receptor is evident in studies showing decrease in the symptoms of alcoholic-withdrawal syndrome by the use of substances that increase GABA activity, like GABA-reuptake blockers and benzodiazepines, thus demonstrating the possible influence of the GABAergic system on the physiopathology of human alcoholism.
Ethanol potentiates GABA-receptor actions via a mechanism independent of benzodiazepine-receptor.
GABAergic pathways play an important inhibitory action on the other neuronal pathways. GABA-receptor is associated with the chloride channel and the benzodiazepine receptor, making up a functional complex. When GABA binds to its receptor, it promotes an increase in the opening frequency of chloride channels, thus allowing a greater flow of this ion to the intracellular medium, making it more negative, and thus promoting neuronal hyperpolarization.
Low alcohol concentrations could promote facilitation of GABAergic inhibition on the cerebral cortex and spinal cord.
Some phenomena observed in alcoholism, such as tolerance and dependence, could be explained by the effects consequent to chronic ethanol exposure.
The quick tolerance to the increased chloride influx mediated by GABA begins already in the first hours and becomes established during chronic alcohol use.
Alcohol selectively modifies the cerebral synaptic action of glutamate. The glutamatergic system, whose neurons use glutamate as neurotransmitter, and is one of the main excitatory pathways in the central nervous system, also seems to play a relevant role in the nervous alterations induced by ethanol. Glutamate is the major neuroexcitatory neurotransmitter in the brain, accounting for 40% of all synapses.
Post-synaptic actions of glutamate in the central nervous system are mediated through two types of receptor: One of them is the inotropic receptor, related to ionic channels causing neuronal depolarization. The second type of receptor is the metabotropic (since its answers need cellular signalization metabolic steps); its intracellular actions are mediated by G-protein.
One of the inotropic glutamate receptors has two families diferentially identified by their pharmacological, biophysical, and molecular characteristics. In the first family we find the NMDA (n-metil-D-aspartate receptor), voltage-dependent, that sustains the currents, and is associated with ion channels permeable to calcium, sodium and potassium. In the second family of glutamate receptors we find the AMPA/Ka, whose preferental agonist is a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
Glutamate participates in synaptic plasticity and in long term potentiation (LTP), and it seems to play a critical role in memory and cognition.
The prevailing eletrophysiological effect of ethanol is the reduction of excitatory glutamatergic neurotransmission. It has been observed that low concentrations of ethanol can inhibit the stimulating actions mediated by NMDA upon hippocampal cells in culture.
In concentrations associated to "in vivo" intoxication, ethanol inhibits NMDA receptor current.
These findings could also explaim part of the genesis of physical dependence to alcohol, through a process that is the opposite to that of GABA. That means that when ethanol is interrupted, glutamatergic pathways induce overexcitement of the central nervous system, causing convulsions, anxiety, and delirium.
Calcium influx into the cells has an important function in the release of neurotransmitters in the synaptic cleft, as well as in the activity of cellular second messengers. Ethanol, in concentrations of 25mM, seems to inhibit calcium flow through ionic channels, thus decreasing neurotransmitters release. This could also be one of the mechanisms responsible for dependence and tolerance, because when alcohol-intake is stopped these ionic channels would increase calcium influx and, consequently, neurotransmission, giving rise to signs and symptoms of withdrawal syndrome.
Group of drugs with differing structures and common actions such as increased motor activity and lessening of sleep necessity. These drugs decrease fatigue, induce euphoria and have sympathomimetic effects (they increase sympathetic nervous system actions). The psychostimulants includes drugs of the amphetamine group and cocaine.
The most common group of psychostimulant drugs, it includes dextroamphetamine (or, symply, amphetamine) methamphetamine, and phenmetrazine. Methylenodioxyamphetamine (MDA) and methylenodioxymethamphetamine (MDMA – "ecstasy") have been introduced more recently. The effect of these last mentioned drugs are more amphetamine-like than hallucinogenic.
Amphetamine derivates can act in different ways, but they probably exert their actions by increasing neurotransmitters release.
Amphetamine-like drugs are classified as indirect action agonists of noradrenergic, dopaminergic, and serotonergic synapses. These actions result from the inhibition both of neurotransmitters reuptake and of the enzyme monoamine oxidase (MAO).
Amphetamine is an indirect action agonist of amines, specially of noradrenaline and dopamine:
Cocaine (Click here to see animations on cocaine effects)
Cocaine is an alkaloid extracted from a shrub belonging to the Erythroxylon genus, grown in Andean and Amazonian regions.
Cocaine dependence stem from its psychostimulating properties and its local anesthetic action. Dopamine is thought to be important in the brain reward system and its increase can answer for the great dependence potential of cocaine.
Cocaine chloride can be administered in many different ways. It can be inhaled and thus absorbed by nasal mucosa. Cocaine causes constriction of nasal arterioles leading to a vascular reduction that limits its absorption, Chronic use frequently brings about nasal septum necrosis and perforation, due to sustained vasoconstriction.
Intravenously injected cocaine induces an extremely quick, intense, and short-lived effect. More recently, its use via lungs became increasingly popular. The drug is then smoked in cigars or pipe-like devices. The drug form then used is crack, a free-base prepaired by alkalinizing cocaine chloride and employing non-polar solvents to extract it. Although part of the alkaloid is destroyed by heat, cocaine is quickly taken up by the lungs, reaching peak blood levels in just a few minutes, comparable to venous administration although for a reduced time. Intravenous injection is seldom used because of the possible intoxication caused by the excessive dose. Most of the cardiovascular alterations and arrhytmias are caused by intravenously injected cocaine.
Ample varations can be found on the potence and purity of illegally supplied cocaine.
Cocaine plasmatic half-life is short. Thus the effects of an isolated dose lasts only one hour or even a little less than that. Consequently the euphoria experiencing can be repeated several times during the course of one day or one night.
In normal doses cocaine increases dopamine and noradrenaline but only in higher doses does it increase serotonin. This increase happens because cocaine blocks the reuptake of these 3 neurotransmitters. Although this mechanism of action is generally agreed upon, discordances still exist about the competititive or non-competitive action.
Cocaine capability to induce mood alterations are dependent on the amount of dopamine and noradrenaline that are released in the brain.
The psychostimulant effect varies in intensity, from moderate to toxic, according to dose-increasing.
Tolerance sets for many of the described effects and the appetite suppressant effect comes up in a few weeks.
When cocaine is ingested together with alcohol, a conjugated cocetylene metabolite is formed. It has psychoactive properties and a half-life longer than that of both cocaine and alcohol, separately ingested. The accumulation of this metabolite quickly leads to intoxication.
Cardiovascular effects of cocaine are complex and dose-dependent. Noradrenaline increase makes total peripheral resistance greater, elevating arterial blood presure. This vasoconstriction decreases skin heat loss, thus contributing to hyperthermia. Local anesthetic effects interfere with myocardial conduction, leading to cardiac arrhytmias and convulsions.
Paranoid psychoses and bacterial endocarditis, due to contaminated syringes, are complications of the chronic use of cocaine.
Intoxications due to excessive doses of cocaine are commonly fatal, with arrhytmias, respiratory depression, and convulsions.
Hallucinogenic or "psychedelic" drugs have the capacity to induce hallucinations without delusion.
LSD (lysergic acid diethylamide) became the hallucinogenic drug prototype due to its widespread use, as well as, because it represents a similar family of drugs, and because it was amply studied.
The LSD group includes, besides LSD (a lysergic acid derivative), mescaline (phenyl-alkyl-amine), psilocybin (indol-alkyl-amine), as well as related compounds.
Although they are different from a chemical point of view, these drugs partake some chemical characteristics and several pharmacological characteristics.
LSD is a semi-synthetic chemical compound that does not exist in nature. This drug presents chemical similarities with neurotransmitters such as noradrenaline, dopamine, and serotonin. Because of its sympathomimetic effects it can cause midriases, tachycardia, piloerection, and hyperglicemia.
LSD interacts with several types of receptors for serotonin in the brain. It seems that it alters the metabolization of serotonine, as shown by the increase in the cerebral concentrations of its major metabolite, 5-hydroxy-indolacetic acid. It acts as an agonist in the serotonin receptor. The mechanism underlying the hallucinogenic action of LSD and analogues comprises 3 phases: (1) serotonin antagonism (2) reduction in the raphe system activity (3) agonist action on the post-synaptic serotonin receptor. It affects multiple regions of central nervous system, such as cortex and thalamus, where it acts in type 5HT2 serotoninergic receptors.
Sensory alterations, varying from simple aberrations in color and form of objects to personality degradation, are typical and their intensity depends on the used amount. Hallucination characteristics vary from one person to the other, probably in concordance with their personalities and their interests. The hallucinations can be visual, auditory, tactile, olfatory, gustatory or take the form of an anesthetic perception, in the absence of an external stimulus.
There is space distortion and the visualized objects grow bigger or smaller, the same happening with bodily parts. Depersonalization phenomena can occur, and the subject feels that his (her) body, or part of it, seems like turned off. Subjective time evaluation is also altered and minutes seem like hours. In the most intense hallucinatory states anxiety, disorientation, and panic can break out. Many subjects become severely depressed and attempt suicide.
There are reports about many cases of long lasting (days or months) or even permanent psychoses after the use of the drug, as well as about the spontaneous return of hallucinations, anxiety and reality distortion.
Marijuana’s active principle, D 9 cannabinol (THC) seems to be accountable for the drug’s central affects.
THC is lipophilic, quickly dissolving through plasmatic membranes and having a heterogenous distribution in the brain.
THC seems to stimulate phospholipase A2, increasing the production of arachdonic acid, diacylglycerol (DAG), and inositol triphosphate. Perhaphs this system is responsible for THC-induced inhibition of a Ca++ voltage-dependent channel that regulates neurotransmitter release.
In 1992 an endogenous ligand, with high binding affinity to THC, was described. This substance, named amandamide (N-arachnil-ethanolamide) is an ethanolamide of arachdonic acid. There are plenty of these binding places and they can be found in the pallidum, hippocampus, and brain stem. Clones of the protein G-bound receptor have already been obtained.
THC is described as a neuromodulator substance, acting via a receptor located in the cellular membrane that modifies the production of a second messenger regulated by another neurotransmitter.
THC causes a biphasic alteration, euphoria (stimulating phase) and sedation (depressive phase). During the stimulating phase, there are reports of an action similar to a dream, with the possibility of distortions in vision and time-experience. Concentration may be impaired. Memory decreases and appetite is suppressed, respectively reflecting THC effects upon acetylcholine and serotonine receptors. After the stimulating phase, lethargy and sleep are common.
Psychic effects are use-dependent. There are reports about anxiety phenomena that are almost panic-like. Amotivational syndrome is characteristic of the subject’s personality.
For the sake of brevity we shall not discuss in this paper the clinical manifestations induced by each drug or drug-group. We shall only present here the general classification used by the DSM-IV for the disturbances related to substances.
According to the present edition of DSM (Diagnostic and Statistic Manual), disturbances related to substances can be divided in two groups:
4 - Diagnostic Criteria for Substance Abuse
|A. A maladaptive pattern
of substance use leading to clinically significant impairment or distress,
as manifested by one (or more) of the following, occurring within a 12-month
(1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household)
(2) recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)
(3) recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct)
(4) continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights)
|B. The symptoms have never met the criteria for substance dependence for this class of substance.|
5 Diagnostic Criteria for Substance Dependence
|A maladaptive pattern
of substance use, leading to clinically significant impairment or distress,
as manifested by three (or more) of the following, occurring at any time
in the same 12-month period:
National Institute of Drug Abuse (NIDA) definition of drug addiction as "a chronic relapsing disease of the brain, which is expressed in behavioral ways and occur in a social context", expresses the difficulties one meets when trying to treat this condition. The treatment of addict patients comprises pharmacologic agents and psychotherapeutic procedures aimed at helping them to reshape their behaviors.
For sure, present knowledge about the neurobiochemical changes that happen as cause or consequence of drug abuse, have helped us to develop more efficient drugs and treatment strategies. The use of substances that modify opioid and GABAergic/glutamatergic neurotransmission, like naltrexone and acamprosate, respectively, helps alcoholic patients to remain abstinent. Naltrexone abolishes the alcohol-induced reward, and acamprosate reduces the drinking crave. Notwithstanding, we are still very far from a treatment that satisfies all our needs. Genetic therapy represents a future hope. If we arrive to identify the genes that answer for the neurobiochemical changes leading to drug-abuse, we may perhaps correct them.
Will it be possible for mankind, in a future time, to become completely drug-free? Or will it be more reasonable to imagine that we shall be able to develop perfect psychoative drugs, with few noxious side-effets, like the soma mentioned by Aldous Huxley in his book Brave New World, capable of inducing a remarkable sensation of well-being, quieting even existential anxieties? Only time will tell.
Interesting links on Drug Abuse
Alcoholism: Can your genes drive you to drink? – Crime Times Vol. 3, no. 1, 1997, pages 1 & 3 & 7 – http://www.crime.times.org/
Carvey P.M Drugs Action in the Central Nervous System. Oxford University Press -1998
Jaffe, J.H. – Substance related disorder – in Kaplan and Saddock’s Comprehensive Textbook of Psychiatry/VI CDROM, 1996, Williams & Wilkins – Baltimore
Kandel, E.R. – Disorders of thought: Schizophrenia in Kandel E.R. et al. Principles of Neural Science – Appleton & Lange – East Norwalk, 1991
Meuller, M.D. – NIDA – Supported Researchers Use Brain Imaging to Deepen Understanding of Addiction – NIDA Notes, Vol. 11, no.5, November/December, 1996. http://www.nida.nih.gov/NIDA_Notes
Nestler, E.J. Molecular neurobiology of drug addiction. Neuropsychopharmacology, 11,77-87, 1994
Piazza, P.V. & Le Moal,M The role of stress in drug self-administration Tips vol 19, 67-74, 1998
Randall M & Kendall,A D – Endocannabinoids: new class of vasoactive substances. Tips, vol 19: 55-58,1998
Restak, R.M. – Receptors – 1994 – Bantam Books, New York
Robinson, T.E & Berridge,K.C. The neural basis of drug craving: na incentive-sensitization theory of addiction. Brain Research, 18, 247-291, 1993
Robinson, T.E. and Kolb B. – J.Neurosci. 17 pp. 8491-8497, 1997
Swan, N. – NIDA-Brain Imaging Research Links Cue-Induced Craving to Structures Involved
In Memory – NIDA Notes, Vol. 11, no.5, November/December, 1996.
Tsai,G. &Coyle J. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu.Ver.Med. 49:173-84,1998
Uhi,G; Vandenbergh,D.J.; Rodrigues,A L; Miner,L and Takahashi,N. Dopaminergic Genes and Substance Abuse. Advances in Pharmacology, vol 42, 1024-33,1998
Zeldin T. – An intimate
history of humanity – Brazilian translation - Uma história Íntima
da Humanidade – 3rd edition, 1997, Editora Record, Brazil
Dr.Tereza Sollero Claudio-da-Silva, MD
Júlio Rocha do Amaral, MD - Júlio Rocha do Amaral, MD – Teacher of clinical pharmacology, anatomy and physiology. Medical Manager of Merck S/A Indústrias Químicas (pharmaceutical and chemical industries). Redactor of didactic manuals on anatomy, physiology and pharmacology used by Merck S/A. Editing supervisor of the following scientific publications: Senecta, Galenus and Sinapse. Redactor of clinical trials and protocols since 1978. Assistant coordinator of courses on Oxydology sponsored by the Human Being Institute and UNIGRANRIO (University of Great Rio). Head of Psychiatric Service. Neurosciences Department. The Human Being Institute. Co-author of the book "Principles of Neurosciences". Email: firstname.lastname@example.org