Engs, Ruth [Ed.], "Controversies in the Addition's Field". CHAPTER 4: R.D. Myers, Ph.D. Neurobiological Basis of Alcohol Reinforcement and Drinking
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CHAPTER 4 Neurobiological Basis of Alcohol Reinforcement and Drinking
R.D. Myers, Ph.D.
"Absence of proof is not proof of absence...of anything."
C. Pert (1989)
Controversy is in the mind of the beholder. Unlike the eye required for perceiving beauty, controversy feeds solely on thought, be it logical or illogical. In the domain of science, the processes of scientific thought and of experimental research should not, by definition, necessarily generate controversy. When the scientific method is precisely followed with all documented rules and internal controls in place, an observation is obtained which is factual. It is immutable; it does not lie. How then can a relatively specialized area of scientific inquiry evolve into an outright controversy? Several reasons are readily identified.
First, a moral, religious, or other belief system can hinder the acceptance of a new scientific or theoretical viewpoint. When such a belief system is instilled strongly enough in one's childhood, for example, a subsequent interpretation of a scientific finding can be unbending in an individual, depending largely on the intensity and circumstances of early indoctrination. To illustrate, an activity as commonplace as transportation has been a vehicle for controversy over the generations with people divided into two camps: those who will travel in a conveyance and those who will not. My great-grandfather would never ride on a trolly car—too dangerous; my grandmother would not drive an automobile—too dangerous; my own father would not fly in an airplane—too dangerous. Of course, I would never consider a trip in a space shuttle—obviously, too dangerous!
Second, because of private conviction held in a specific area of scientific study, the revelation of a new observation may be dismissed regardless of the evidence presented. Consequently, a preconceived viewpoint about the operation of a biological or other process simply blots out the data. As a consequence, new experimental results may be transformed to suit one's own subjective
view. This is not uncommon in individuals trained competently in a given scientific discipline. Installed over the entrance to a coffee lounge at a NortheastemUniversity was a placard which simply stated ... "Don't confuse me with facts: my mind is made up!"
Third, even though bench-top data acquired by different scientists under diverse circumstances may collectively verify a new experimental result and substantiate a new theory, the experimental procedures of one study may vary to such a degree that a "negative" result is obtained. A scientist then may choose to ignore the set of positive findings, perhaps unintentionally, cite only the negative, and reject the theory. Consequently, the interpretation of the data can be misconstrued and the conclusion drawn erroneous.
These circumstances apply to both physical and biological sciences. In atomic research, the stakes encompassing an issue such as cold-fusion are high and of world-wide impact. Disciplines which focus on fundamental clinical-social research, such as addiction to neuroactive drugs are equally affected. In the field of alcohol research, for example, virtually every facet of experimental endeavor has been plagued by persistent debate or disbelief.
Basis of Discrepancy. Typically, the basis of an experimental discrepancy and contradictory interpretation rests usually in the design and actual conduct of the experiment. When a laboratory scientist attempts conscientiously to repeat another's observation, subtle deviations from the path of replication ordinarily arise. Why? Often one seeks to do the experiment "better," with more subjects or more "precise" measurement. Alternatively, the specific question is attacked from a different perspective using, for example, a different drug or schedule of testing. Other variables such as strain or age of animal may be introduced with the intention of ascertaining whether the original finding is applicable to a related theory or hypothesis.
Moreover, because the natural phenomenon of biological variation is so pervasive, a replication experiment is unlikely to generate an identical result. Thus, the degree to which instrumentation, methods, test subjects, and procedures match the original study will determine the magnitude of concordance of the data obtained. Since the replicating scientist rarely duplicates in detail the study of the first experimenter, the findings of the original observation may be eschewed or rejected.
Controversy in a given discipline of science can be very healthy for the field. It can lead to a serious re-evaluation of a question, stimulate new thinking, instigate the collection of new data, and kindle fresh ideas. On the other hand, controversy may be harmful to an issue and potentially
destructive to a discipline; it can prevent any further experimental study. This happens particularly when a negative result either is misinterpreted and blown out of proportion, or if zealousness develops on either or both sides of the issue. Alternatively, a controversy may not really matter sufficiently to have any substantial impact on the thinking extent in the field.
Controversy in Alcohol Research
A plethora of controversy exists in many areas of basic research into the biological phenomena associated with alcohol drinking and the disease concept of alcoholism: the role of liver factors in tolerance; membrane fluidity and alcohol's action; role of membrane and cytosolic calcium; effects of aldehyde dehydrogenase, isoenzymes and aldehyde metabolites on alcohol drinking; the chloride channel and benzodiazepine receptors in intoxication; role of brain endorphins and enkephalins in alcoholism; and biological markers such as serum transferrin. This chapter win deal with one of these controversies: the role of aldehyde metabolites in the reinforcing properties of alcohol and abnormal drinking.
Nature of Reinforcement. One can conceive of at least three internal levels of perceived experiences which are reinforcing. First, many persons frequent the theater, art museums and concerts, or play cards with friends. Others may play a musical instrument or engage actively in golf or tennis. Still others experience great pleasure by eating gourmet food at a sophisticated restaurant and sampling a Premier Crux from Bordeaux. Each sequence of behavior becomes part of a reinforced pattern and is fulfilling to an individual in a unique way. One may become so habituated to a specific activity that life without it is unfulfilling.
A second level of behavioral response may be more intensely reinforcing for certain individuals but somewhat less acceptable by one's peers or society. Such activity typically involves physiological events which provide the signal for the pleasurable sensation. The involvement may extend to such a point that personal obligations to one's family and occupation are relinquished: persistent sexual promiscuity, compulsive overeating to the point of obesity, incessant jogging, or other exercise. Some individuals report a transient or prolonged "high" from repetition of the activity, which is extremely gratifying. although exogenous chemical substances are not involved, humoral factors in the brain may underlie the intensity of the reinforcement. Enhanced levels of trophic hormones released from the pituitary, or endorphins ard other opiate substances synthesized in the brain's limbic system (Gianoulakis, 1989) may promote further entrainment of the activity.
A third type of behavior is the self-administration of an addictive compound taken repeatdly
for its reinforcing quality. Upon entry into the brain, certain drugs can become incorporated in the cellular machinery responsible for the function of nerve cells in structures of the limbic system. They can act to release neurotransmitters which enable nerve impulses to traverse the synaptic cleft from one neuron to another; perturb receptor binding characteristics for these neurothransmitters; interfere pre- or postsynaptically with the transport of cellular constituents including Cl- or Ca2+ ions; and promote new synthesis of substances which are themselves addictive. Because limbicforebrain pathways ostensibly underlie rewarding sensations, the stage is set whereby one or more of these interneuronal events can trigger an all-consuming demand to continue self-administration of the compound at all costs.
The nature of this chemical reinforcement contrasts sharply against the first two types. This is not to imply that the intense pleasure derived from an activity involving art, music, eating, or sport is not represented in the brain by an intricate network of neuronal systems comprising the substrate for reward. Rather, the addictive compound introduced into this same neuronal system may simply engulf and override the activity which is nominally gratifying and pleasurable.
Brain Metabolites, Opiate Receptors, and Alcoholism
Since the 1960s, neurotransmitter systems in the brain have been implicated in the processes leading to the addictive drinking of alcohol. Serotonin (5-HT), which is involved in functional control mechanisms for body temperature and sleep (Myers, 1974) is one candidate possibly responsible for several aspects of the alcohol drinking mechanism. A pharmacologically induced disturbance to 5-HT in the brain can markedly alter alcohol drinking in the rat (Myers and Veale, 1968; Myers et al., 1972; Myers, 1978a). Studies in which dopamine pathways are ablated by a neurotoxin also implicated catecholamine neurotransmitters in alcohol drinking, in that alcohol intake post-lesion increases sharply and persists for several weeks (Kiianmaa et al., 1975). Thus, a basis for a direct link between neurochemical systems in the brain for reward and the magnitude of alcohol drinking is being established gradually (Myers, 1979a; 1989; Blum et al., 1989).
In 197O, a new theory emerged which traced the etiology of alcoholism to the formation of unique metabolites following alcohol's degradation (Davis and Walsh, 1970; Cohen and Collins, 1970). The theory is summarized as follows (See Myers, 1989). When alcohol is consumed, the enzyme, aldehyde dehydrogenase, degrades acetaldebyde, the toxic metabolite of alcohol. An insufficiency of this crucial enzyme or its preferential diversion to the breakdown of acetaldehyde can lead to an
accumulation of other biogenic aldehydes. These aldehydes can react instantaneously with a neurotransmitter or precursor to form a new compound either in brain or periphery or both. One product arising from a dopamine-dopaldehyde reaction is the biological precursor to morphine in the opium poppy, tetrabydropapaveroline (THP). Another class of derivatives, tetrahydro-B-carbolines (THBC), arise from an indoleaminealdehyde reaction and act to evoke intense anxiety.
Following alcohol drinking, two of the classes of compound detected peripherally and in brain (e.g., Sjoquist et al,1981; Rommelspacher et al., 1984) are found to exert a myriad of neurobiological actions: they bind to opiate and other receptors in the brain (Gianoulakis, 1989), act as false transmitters, and alter vital functions including blood pressure (Myers, 1980; Melchior and Collins, 1982; Myers, 1985a; b). Drinking to excess, therefore, is hypothesized to lead to even more drinking because of the addictive/anxiogenic nature of the metabolites.
THP-Induced Alcohol Drinking. To test a part of this theory, THP or salsolinol (SAL), adopamine-acetaldehyde metabolite, was infused directly into the brain of the rat. Water and ethanol were always available to the animal in increasing concentrations ranging from a palatable 3% to a highly aversive 30%. Almost immediately after the THP infusions began, alcohol intake increased sharply even in the aversive concentrations offered (Myers and Melchior, 1977a). THBC infused similarly evoked an identically intense shift in alcohol drinking (Myers and Melchior,1977b). Thus, the "Multiple Metabolite" theory of alcoholism was born which states that prolonged alcohol drinking promotes synthesis of aldehydecatechol- or indole-amine metabolites which sequester in specific structures in the brain. Their presence in critical anatomical sites mediate not only the rewarding or pleasurable property of alcohol but serve to sustain alcohol consumption. They even intensify drinking irreversibly to the point of clinical pennanency (Myers, 1989).
Evidence for the "Multiple Metabolite" theory is summarized as follows:
1) increasing amounts of alcohol are consumed by a test animal at higher concentrations of alcohol following chronic infusions of either THP or THBC into the cerebral ventricles (ICY) (Myers and Melchior, 1977a; b; Myers and Oblinger, 1977);
2) elevated pRference for alcohol is pharmacologically specific since alcohol is prefered over both palatable (Melcior and Myers, 1977)and other drugs (Rommelspacher et al., 1987);
3) re-tests of drinking 1-6 months after exposure to metabolites reveals a permanent shift in alcohol selection (Duncan and Deitrich, 1980; Huttunen and Myers, 1987; Myers and Melchior, 1977b; Myers and Oblinger, 1977; Myers and Privette, 1989) reminiscent of the alcoholic patient;
4) THP-induced drinking is attenuated transiently by opiate receptor antagonists
(Critcher et al., 1983; Myers and Critcher, 1982; Myers et al., 1986);
5) blood alcohol levels reach pharmacologically significant amounts during drinking induced by THP(Critcher et al., 1983; Melchior and Myers, 1977);
6) patterns of alcohol intake vary diurnally with bouts of drinking occurring during the active part of the daynight cycle (Melchior and Myers, 1977; Myers, 1978b);
7) withdrawal symptoms are comparable to those described after the rat is withdrawn from morphine (Myers and Oblinger, 1977; Sinclair and Myers, 1982);
8) THP-induced alcohol intake is dose-dependent, a high dose generally suppressing intake and a low dose enhancing it (Myers, 1989; Myers and Oblinger, 1977);
9) lesions of metabolite-sensitive sites in the brain do not augment alcohol preference (Myers et al.,1983; 1982b; Swartzwelder and Myers, 1983);
10) intake of calories derived from solid food remains unchanged by metabolite injections;
11) gustatory discrimination is not impaired by the metabolites (Myers and Oblinger, 1977);
12) anatomical sites mapped in the brain of the rat which are reactive to THP and mediate alcohol drinking correspond to dopamine-enkephalin pathways (Duncan and Fernando, 1990; Myers, 1990; Myers and Privette, 1989);
13) salsolinol is detected in CSF of the alcoholic patient (Sjoquist et al.,1981; 1982a) and increases in concentration postmortem in dopaminergic-rich regions of the brain of alcoholics (Sjoquist et al., 1982b);
14) alcoholdependent synthesis of B-carbolines arises endogenously (Collins, 1985) in volunteers who drink alcohol (Peura et al., 1981) as well as in alcoholic patients, whose urinary levels remain elevated after two weeks (Rommelspacher and Schmidt, 1985);
15) after the rat consumes alcohol chronically for a period of up to 10 months, postmortem levels of salsolinol rise sharply in the limbic-system (Matsubara et al., 1987; Myers et al., 1985a; b; Sjoquist et al.,1982b);
16) alcohol-dependent synthesis of THP in the brain occurs after alcohol is administered to the L-dopa treated rat (Cashew et al., 1987); and
17) a similar lime-dependent rise in an indolealdehyde adduct in the brain of the rat arises after alcohol is ingested (Rommelspacher et al., 1984).
Table 4.1 presents an annotated survey of reports in which an aminealdehyde metabolite significantly alters alcohol drinking [table not here yet].
A Unique Controversy
Shortly after the initial announcement of the new theory, two articles came forth to activate and then sustain a controversy on this new concept on the etiology of alcoholism (Haluska and Hoffman, 1970; Seevers, 1970). Although alcoholics and heroin addicts are indeed differentiated clinically, the sentiments of the critiques were neurochemically premature. Conceming the abyss of ignorance at that time on receptor mecha nisms in the brain controlling vegetative functions such as drinking,
craving for a drug, tolerance and withdrawal, it was remarkable how rapidly minds were made up. Then a decade later, a paper appeared which reported that neither THP nor salsolinol infused ICV had an effect on alcohol drinking in the rat (Smith et al., 1980). In retrospect, however, the differences between procedures of the original experiments (Myers and Melchior, 1977 a; b) and the latter report were so substantial that the study hardly constituted a replication. These differences are enumerated as follows:
1) aseptic surgical procedures were not described;
2) stereotaxic coordinates for intracranial implantation of the THP/salsolinol infusion cannula were dissimilar;
3) the test rats were much smaller thereby affecting the anatomical site of implantation;
4) the purity of the compounds was not ascertained;
5) two drinking tubes instead of three were used for testing alcohol preference;
6) in a part of the study, those rats not consuming 8 ml of 15 % alcohol were eliminated from the study, thus biasing the population sample in favor of genetic drinkers;
7) hydrochloric acid was used to adjust the infused solution to an acid pH;
8) ascorbic acid was not used as an anti-oxidant;
9) in a part of the study, some rats inexplicable doubled their alcohol intake during the baseline period prior to metabolite infusion;
10) the inbred sub-strain of rat was different;
11) baseline alcohol intakes of the metabolite-infused and control groups differed substantially; and
12) Ringers solution rather than an artificial CSF was used as the control vehicle.
In spite of these conspicuous differences in the experimental protocol, the data show that salsolinol infusions seemingly enhanced alcohol intake two-fold, from 2.0 to4.0gm/kg/day (Smithet al., 1980). Nevertheless, the "replication" was interpreted as unsuccessful.
Perpetuation of the Controversy
Without conscientious scrutiny of this report in light of the evidence from experiments presented in Table 4.1, some individuals have "thrown out the baby with the bath water." Skeptics from the 1970s astonishingly pounced on this report to dismiss outright any involvement of an aldehyde metabolite in alcohol or in the etiology of alcoholism. How frightening if the sample of THP had been contaminated! Or if it had been degraded in the brain because of the absence of an anti-oxidant!
At a recent symposium the view was expressed that "...Unfortunately, there is little in the way of solid, consistent data to support this "MultiMetabolite" theory (Smith and Amit, 1987). These authors conclude that " ... further research in this area may be more fruitfully directed to other avenues of investigation." Recently, other individuals have espoused the same viewpoint. In
reviewing neurotransmitter systems implicated in the reinforcing effects of alcohol, for example, Kranzler and Orrok (1989) have deduced from the Smith-Amit paper that "...Despite the high face validity of this mechanism for the reinforcing effects of ethanol, the bulk of available evidence argues against a role for condensation products such as tetrahydroisoquinolines." Nearly, the only conclusion is that the bulk of the vast amount of data readily available, superficially condensed in Table 4.1, has neither been considered nor contemplated in balanced fashion.
To comprehend the reasoning behind a resolute stance of negativity which may promulgate a controversy is indeed challenging. Several explanations are forthcoming. First, the apparent evaluation of the pertinent literature has not been a critical one. Second, the "bulk of evidence" simply has not been analyzed, weighed, and then judged. Third, academic, institutional or other professional pressures conceivably may lead to error or oversight in the review and resultant pondering over the relevant literature. Fourth, it is much simpler intellectually to repudiate a viewpoint out-of-hand than to probe scientifically in-depth into each of the experiments pertaining to the controversy; thus any attempt to reach a reconciliation is nullified.
When the pendulum of controversy swings too far to the point of ultimate negativity, an experimental issue ordinarily is taken out of the realm of science. The consequences can be disastrous. Younger scientists are afraid to venture into a field when a discouraging pronouncement by a well-known scientist is made on a topic. The attitude of rejection of a proposition can even creep into the halls of a governmental granting agency or other institution supporting creative research. Today, this is critical since decisions are made to fund or not to fund projects which are now touched by the controversy. Finally, this sort of swing in a sense represents an obstacle to the fundamental principles of science. The outcome is a tragic loss in the goal of every rational individual involved in the quest for the truth about any complex mechanism in the nature— including the neurobiological mechanisms of alcohol reinforcement.
Clear-cut evidence now exists for alcohol-contingent synthesis in of aminealdebyde metabolites in the brain which are active pharmacologically in altering alcohol drinking. Under the conditions of acute and chronic exposure to alcohol, aldehyde metabolites are readily detectable when appropriate and sensitive analytical techniques are employed. Except for one report from one
laboratory, numerous investigators have demonstrated unequivocally in several species, the significant changes in volitional drinking of alcohol produced by THP, THBC, and other aminealdehyde metabolites. Alterations in alcohol consumption depend on the metabolite selected, genetic background of the individual, the specific dose of the metabolite injected intracerebrally, regimen of administration, and the specific anatomical sites in the brain into which the compound is injected.Although the controversy surrounding the role of these metabolites in the Biological mechanisms of alcoholism may be "in the mind of the beholders history alone will prove the validity of their involvement. The truth will triumph ultimately, but only if well-designed scientific experiments continue.
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