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Neurochemical aspects in pathogenesis of alcohol and drug dependence
265
Drug and Alcohol Dependence, 4 (1979) 265 - 273 @ Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
NEUROCHEMICAL ASPECTS DRUG DEPENDENCE
IN PATHOGENESIS
OF ALCOHOL
AND
I. P. ANOKHINA
Central Research
Institute
of Forensic Psychiatry,
Moscow
(U.S.S.R.)
Summary At present, catecholamines are considered to play a significant role in the regulation of psychic function and emotional states. Our investigations have revealed significant changes in peripheral catecholamine metabolism in alcoholic patients. Catecholamine metabolism in the brain and in the periphery are rather autonomous, and thus in our studies we compared the effects of alcohol on dopaminergic and noradrenergic systems in different brain regions as well as in the periphery. We found a significant decrease in noradrenaline levels in different regions of the CNS, particularly midbrain, hypothalamus and hippocampus. In chronic studies with rats, catecholamine metabolism was studied in animals chronically treated with alcohol, those treated with a single dose after chronic treatment, and those animals undergoing withdrawal from alcohol. Neuropharmacological and neurochemical studies were accompanied by electrophysiological monitoring of the effects of alcohol.
In the study of pathogenesis of chronic alcoholism, attention must be directed to the mechanisms of formation of psychic and physical dependence upon alcohol. Several reports provide evidence for a significant role of neurochemical disorders in the development of alcohol dependence [ 1 - 31. At present, catecholamines are considered to have a significant role in the regulation of psychic functions and emotional states [4, 51. The study of catecholamine excretion, such as dopamine, noradrenaline and adrenaline and their precursor DOPA, in the second stage of chronic alcoholism, has revealed overt shifts in the metabolism of the biogenic amines. Urinary excretion of the above substances is considerably increased in chronic alcoholic patients (Fig. 1). Alcohol and the adrenotropic preparations L-DOPA, disulfiram, amphetamine and parnate, which produce various effects, evoke reactions of the catecholamine system in alcoholic patients which are different from those in healthy subjects (Fig. 2). Catecholamine excretion becomes especially elevated in chronic alcoholic patients during
266
1
44
WPA
DA
NA
A
DOPA
AMPHETAMINE
--
AVA
DA
NA
1
2mt
CHRONIC NORMAL
of catecholamines
after
different
drugs.
Abbreviations
F%RNATE
ALCOHOLICS SUBJECTS
Fig. 1. Excretion of biogenic amines by chronic alcoholics. DA, dopamine; naline; A, adrenaline; HVA, homovanillic acid. 100% = control. Fig. 2. Excretion 100% = control.
P)
A
NA, noradre-
as in Fig.
1.
abstinence. In these cases there is a considerable increase in the excretion of dopamine in urine, and its metabolic product, homovanillic acid (HVA), is particularly evident (Fig. 1). Such evidence indicates the presence of overt shifts in the function of peripheral catecholamine systems in chronic alcoholic patients. But the main features of chronic alcoholism are undoubtedly connected with the effect of alcohol on the central nervous system. Alcohol freely penetrates the brain where it is found to be in the same concentration as in blood. The main enzyme that metabolizes alcohol, alcohol dehydrogenase, is found in very small quantities inside the brain, so alcohol directly influences the central nervous system [6] . Catecholamine formation in the brain is independent of that in the periphery, and as demonstrated in our laboratory does not always respond similarly to various pharmacological influences. Taking this into consideration, we compared the effect of alcohol on the concentration of dopamine and noradrenaline in different brain regions and in the adrenals and blood. Results showed that alcohol administration evokes a considerable increase of noradrenaline level in the periphery, while it decreases its concentration in different regions of the central nervous system, most evidently in the subcortical structures of the midbrain, hypothalamus and hippocampus (Fig. 3). Thus, alcohol produces opposite effects on catecholamine metabolism in the brain and in the peripheral nervous system. The nature of metabolism of the midbrain and hypothalamic catecholamines in rats was further studied under the following experimental
267
Fig. 3. Effect of alcohol (2 g/kg) on catecholamine DA, dopamine. 100% = control.
concentration.
NA, noradrenaline;
situations: acute alcohol administration; chronic alcohol administration, lasting up to 100 days, when a clear preference for alcohol is formed; acute administration against the background of chronic alcoholism; deprivation of alcohol, when a withdrawal syndrome appears, and conditions in which the withdrawal syndrome was terminated by the administration of alcohol. Alcohol, in combination with different psychopharmacological preparations that influence synthesis, storage, release and destruction of catecholamines, was used to analyse the mechanism of action of alcohol on brain catecholamines. In the midbrain and hypothalamus, the concentration of the catecholamines, noradrenaline and dopamine, their precursor DOPA, as well as their metabolic products, normetanephrine (NM) and 3-methoxy-4-hydroxyphenethylene glycol (MHPG), were determined. An electrophysiological study demonstrated that acute administration of alcohol, 2 - 3 g/kg, induced two stages: the stage of excitation accompanied by activation of the brain biocurrents, followed by the stage of inhibition characterized by sleep. One hour after administration of alcohol, 2 g/kg per OS, a considerable decrease in the concentration of noradrenaline and dopamine was manifested in the midbrain and hypothalamus, and was accompanied by an increase of the products of noradrenaline breakdown, NM and MHPG (Fig. 4a). Thus, we think that acute alcohol intake evokes an intensified release of noradrenaline in the brain regions mentioned and following its destruction, results in a decrease of catecholamine concentration in the brain. The stages of the effect of alcohol on the central nervous system can be connected with this process, because the abundantly released active noradrenaline carries out the functions of neuromediator, exciting the central adrenergic structures. Following the metabolism of noradrenaline, and due to subsequent decrease in noradrenaline concentration, activity in certain areas of the CNS is suppressed. Under long-term alcohol administration and development of preference for it, noradrenaline concentration in the midbrain and hypothalamus is
268
Fig. 4. Concentration hydroxyphenethylene 100% = control.
of catecholamines in the midbrain of rats, MHPG, 3-methoxy-4glycol; NM, normetanephrine; other abbreviations as in Fig. 1.
slightly higher than with an acute alcohol administration, but it is still lower compared with the norm (Fig. 4b). The constantly decreasing level of neuromediator in the central nervous system evokes corresponding changes in electrophysiological parameters represented as a decrease of the general tonus and excitability. Intake of a moderate dose of alcohol under these conditions evokes an intensified release of the bound noradrenaline (Fig. 4c) that improves activity of the central adrenergic system for a short period of time. Electroencephalographic study of chronic alcoholic patients has shown retardation and synchronization of electrical discharges, and decrease in the reactivity of both the brain biocurrents and vegetative functions to stimuli. Intake of a small dose of alcohol temporarily normalizes these functions [ 71. It is well-known that a moderate alcohol intake improves some functions of the central nervous system in chronic alcoholic patients, for example fulfilment of some tests, etc., but the released noradrenaline is soon destroyed and leads to an even further decrease of its concentration in the central nervous system. Thus, a “vicious cycle” is created. This process could be the basis for the development of a “psychic dependence” upon alcohol which occurs when a patient feels a short-term improvement after alcohol intake, causing him to take in more and more of this substance. Certain of our studies have indicated that during long-term alcohol intake, the increased release and destruction of noradrenaline is accompanied by a compensatory mechanism which is activated to counteract the effect of
269
alcohol on the brain catecholamine system. Pharmacological analysis has demonstrated that such a mechanism is a greatly intensified catecholamine synthesis. Thus, in chronic alcoholism, a balance is created between increased noradrenaline synthesis and increased degradation in the central nervous system. Deprivation of alcohol in chronic alcoholism causes an imbalance in the catecholamine system. Cessation of alcohol intake interrupts intensified noradrenaline destruction, while catecholamine synthesis, being a more torpid process, remains intensified, with the result that there is an overt increase in the level of dopamine and DOPA (Fig. 4d). According to present-day thinking, an increase in the dopamine concentration in the brain can cause sharp vegetative disorders and tremors, which are characteristic of the withdrawal state. It is firmly believed that the development of psychotic states is also connected with an increase in the concentration and disruption of dopamine metabolism in the central nervous system [ 8 - lo] . Thus the occurrence of delirium tremens during the withdrawal state can be evoked simply by an imbalance in the catecholamine system. In fact, our investigations showed that in patients with alcohol delirium, the level of dopamine and HVA was increased to 300 - 400% compared with normal subjects, Alcohol intake during the withdrawal state intensified noradrenaline degradation, leading again to a relative balance in the catecholamine system peculiar to chronic alcoholism (Fig. 4e). The shifts described in catecholamine metabolism of the brain can play a significant role in the development of “physical dependence” upon alcohol, because cessation of alcohol intake induces profound changes in this most important physiological system that are reflected in drastic physical and psychic states. These changes are, however, inhibited by alcohol intake. Thus, according to our hypothesis, the trigger mechanism of complex disorders in functions of the brain catecholamine system that leads to the development of alcoholic dependence is the intensified release and destruction of noradrenaline under the influence of alcohol. To verify the above supposition we made an effort to influence this process pharmacologically with the monoamine oxidase (MAO) inhibitors, iprazide and parnate. In the first series, alcohol, 2 g/kg, was administered per OS to two groups of experimental rats for 75 days. One of those groups was also treated with iprazide. At the end of the experiments, the animals were tested for their alcohol intake. The group that received alcohol and iprazide drank the same amount of alcohol as the control rats, while the group that received only alcohol drank 4 to 5 times as much (Fig. 5). The biochemical study of the catecholamine system in the brain during the withdrawal state has revealed a considerable increase of noradrenaline precursors in the midbrain and hypothalamus (up to 250%) in the animals that received only alcohol. However, the rats that were treated with iprazide displayed only a slight increase of DOPA, while the dopamine content in these animals was normal (Fig. 6). During the second series of our experiments, in which the influence of MAO inhibitors on the development of dependence upon alcohol was
270
00 i
::
control
Fig.
75
5. Voluntary
75 days
daqs alcohol
consumption
by different
groups
of rats.
% 250 210
220
I00
180
(60
MO
i (PO
100
-
1I DOPA
Fig. 6. DOPA control.
and dopamine
(DA)
concentration
in rat midbrain
during
withdrawal.
100% =
studied, the animals had the opportunity to choose between water and a 10% alcohol solution. One of the groups also received parnate. During the first 3 to 4 weeks, both groups showed a slight preference for alcohol. Subsequently alcohol intake by the control group increased up to 8 or 9 times, and then stabilized at that level, while in the group that received pamate, alcohol intake decreased somewhat and remained at a level close to the initial preference. Thus, alcohol dependence did not develop with parnate in animals presented with a choice between alcohol and water. Thus our experiments have confirmed our hypothesis of the significant role of noradrenaline in the pathogenesis of chronic alcoholism and on the neurochemical basis of the withdrawal syndrome. We have shown that alcohol produces a significant effect upon the catecholamine metabolism in the organism. Changes in metabolism of these amines in the central nervous system US. the periphery are different, and the specific effect of alcohol on
271
% 160
DA
NA
““4
I
110 I20 too 60 60 40
n
-
olrohol
EBB
-
borbomil
Fig. 7. Effect of drugs and alcohol DA, dopamine; HVA, homovanillic 100% = control.
m
-
morphine
on catecholamine metabolism in rat hypothalamus. acid; NA, noradrenaline; NM, normetanephrine.
7. 220 200
NR
HVA
DR
160. 160
i
140
NM
I
110
0
- alcohol
ES
-
borbomil
Fig. 8. Effect of drugs and alcohol tions as in Fig. 7. 100% = control.
m
- morpbk
on catecholamine
metabolism
in rat midbrain.
Abbrevia-
central nervous system catecholamines is an important stage in the pathogenesis of chronic alcoholism. It is well-known clinically that other forms of drug dependence are similar in their main manifestations and certain drugs show cross-tolerance or cross-dependence with alcohol [ 11,121. In this connection it was of interest to conduct a comparative study of the effect of narcotic drugs of different chemical structures and alcohol on the central metabolism of catecholamines. An hour after administration of morphine, 15 mg/kg, noradrenaline levels were decreased in the midbrain and hypothalamus, while in the other regions of this animal brain, its level was practically unchanged. Dopamine concentration was lower in midbrain, hypothalamus and cortex, whereas in striatum it was insignificantly higher. An injection of morphine led to a considerable lowering of NM in the cortex, an insignificant increase in the hypothalamus, and a sharp increase of NM in midbrain, striatum and particularly
40
1
0
- DA
m
-
NA
Fig. 9. Noradrenaline (NA) metabolism DA, dopamine; NM, normetanephrine.
m
-
NM
in midbrain during 100% = control.
the effect
of various
drugs.
in the hippocampus. It is important to mention that in all regions of the brain, an injection of morphine increased HVA concentration (Figs. 7 and 8). An injection of barbamil, 25 mg/kg, led to an insignificant increase of dopamine in the striatum and a sharp decrease in the other regions of the brain. HVA increased only in the hippocampus, was practically unchanged in the striatum and cortex and was considerably lower in the hypothalamus and midbrain. Noradrenaline was significantly lower than the control level in the midbrain and hypothalamus, while in other brain regions it was unchanged. The NM level was considerably higher in the midbrain and hypothalamus in the cortex, and it was very near to the control values in hippocampus and striatum (Figs. 7 and 8). With the results obtained from this study of the effect of an injection of morphine on the catecholamine system of the rat brain, we may assume that morphine increases both dopamine and norepinephrine metabolism in the midbrain, hypothalamus, striatum and hippocampus. An injection of barbamil, 25 mg/kg, increased only noradrenaline turnover in the midbrain and hypothalamus and activated dopamine metabolism in the hippocampus. It is difficult to explain now the character of changes in metabolism in the striatum and cortex under the effect of barbamil. The results of the investigation indicate that the other drugs investigated had an essential effect on catecholamine metabolism in different brain regions, though the effect varied with the area of the central nervous system that was investigated. Comparing the effects of narcotics of different chemical structure and alcohol on the brain catecholamine system enabled us to describe common features of their actions. All three drugs (morphine, barbamil and alcohol) decrease noradrenaline and dopamine concentrations in the midbrain and hypothalamus. Simultaneous increase in the NM level enables us to suggest that this decrease is due to intensification of release and metabolism of noradrenaline (Fig. 9). Barbamil and alcohol evoked similar disturbances in
273
dopamine metabolism in the midbrain and hypothalamus, where a decrease in the HVA level was observed. Thus, while the investigated drugs and alcohol have a different effect on catecholamine metabolism in many brain regions, they produce the same types of change in catecholamine metabolism in the midbrain and in the hypothalamus. Our investigations have thus shown that there may be common points of action for these drugs in the central nervous system. These results enable us to suggest that disorders in the catecholamine neurotransmitter system play an important role in the development of dependence on many chemically diverse substances.
References 1 H. Wallgren, Adv. Exp. Med. Biol., 35 (1973) 15 - 31. 2 J. Ewing, Ann. N.Y. Acad. Sci., 273 (1976) 159 - 166. 3 B. Tabakoff, in K. Blum (ed.), Alcohol and Opiates: Neurochemical and Behavioral Mechanisms, Academic Press, New York, 1977, pp. 21 - 39. 4 S. Kety, The Neurosciences, 1 (1967) 444 - 451. 5 G. Breese, B. Cooper and A. Hollister, J. Psychiat. Res., 11 (1974) 125 - 133. 6 B. Tabakoff, R. Anderson and R. Ritzmann, Biochem. Pharmacol., 25 (1976) 1305 1309. 7 I. Anokhina and B. Kogan, J. Neuropathol. Psychiatr., 12 (1975) 1874 - 1883. 8 S. Antelman and A. Caggiula, Science, 195 (1977) 646 - 653. 9 S. Matthysse, J. Psychiat. Res., 11 (1974) 107 - 113. 10 S. H. Snyder, Psychiat. Ann., 1 (1976) 53 - 66. 11 N. Eddy et al., Psychopharmacol. Bull., 3 (1966) 1 - 12. 12 A. Ho, K. Chen and J. Morrison, in K. Blum (ed.), Alcohol and Opiates: Neurochemical and Behavioral Mechanisms, Academic Press, New York, 1977, pp. 189 202.
-
Drug and Alcohol Dependence, 4 (1979) 265 - 273 @ Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
NEUROCHEMICAL ASPECTS DRUG DEPENDENCE
IN PATHOGENESIS
OF ALCOHOL
AND
I. P. ANOKHINA
Central Research
Institute
of Forensic Psychiatry,
Moscow
(U.S.S.R.)
Summary At present, catecholamines are considered to play a significant role in the regulation of psychic function and emotional states. Our investigations have revealed significant changes in peripheral catecholamine metabolism in alcoholic patients. Catecholamine metabolism in the brain and in the periphery are rather autonomous, and thus in our studies we compared the effects of alcohol on dopaminergic and noradrenergic systems in different brain regions as well as in the periphery. We found a significant decrease in noradrenaline levels in different regions of the CNS, particularly midbrain, hypothalamus and hippocampus. In chronic studies with rats, catecholamine metabolism was studied in animals chronically treated with alcohol, those treated with a single dose after chronic treatment, and those animals undergoing withdrawal from alcohol. Neuropharmacological and neurochemical studies were accompanied by electrophysiological monitoring of the effects of alcohol.
In the study of pathogenesis of chronic alcoholism, attention must be directed to the mechanisms of formation of psychic and physical dependence upon alcohol. Several reports provide evidence for a significant role of neurochemical disorders in the development of alcohol dependence [ 1 - 31. At present, catecholamines are considered to have a significant role in the regulation of psychic functions and emotional states [4, 51. The study of catecholamine excretion, such as dopamine, noradrenaline and adrenaline and their precursor DOPA, in the second stage of chronic alcoholism, has revealed overt shifts in the metabolism of the biogenic amines. Urinary excretion of the above substances is considerably increased in chronic alcoholic patients (Fig. 1). Alcohol and the adrenotropic preparations L-DOPA, disulfiram, amphetamine and parnate, which produce various effects, evoke reactions of the catecholamine system in alcoholic patients which are different from those in healthy subjects (Fig. 2). Catecholamine excretion becomes especially elevated in chronic alcoholic patients during
266
1
44
WPA
DA
NA
A
DOPA
AMPHETAMINE
--
AVA
DA
NA
1
2mt
CHRONIC NORMAL
of catecholamines
after
different
drugs.
Abbreviations
F%RNATE
ALCOHOLICS SUBJECTS
Fig. 1. Excretion of biogenic amines by chronic alcoholics. DA, dopamine; naline; A, adrenaline; HVA, homovanillic acid. 100% = control. Fig. 2. Excretion 100% = control.
P)
A
NA, noradre-
as in Fig.
1.
abstinence. In these cases there is a considerable increase in the excretion of dopamine in urine, and its metabolic product, homovanillic acid (HVA), is particularly evident (Fig. 1). Such evidence indicates the presence of overt shifts in the function of peripheral catecholamine systems in chronic alcoholic patients. But the main features of chronic alcoholism are undoubtedly connected with the effect of alcohol on the central nervous system. Alcohol freely penetrates the brain where it is found to be in the same concentration as in blood. The main enzyme that metabolizes alcohol, alcohol dehydrogenase, is found in very small quantities inside the brain, so alcohol directly influences the central nervous system [6] . Catecholamine formation in the brain is independent of that in the periphery, and as demonstrated in our laboratory does not always respond similarly to various pharmacological influences. Taking this into consideration, we compared the effect of alcohol on the concentration of dopamine and noradrenaline in different brain regions and in the adrenals and blood. Results showed that alcohol administration evokes a considerable increase of noradrenaline level in the periphery, while it decreases its concentration in different regions of the central nervous system, most evidently in the subcortical structures of the midbrain, hypothalamus and hippocampus (Fig. 3). Thus, alcohol produces opposite effects on catecholamine metabolism in the brain and in the peripheral nervous system. The nature of metabolism of the midbrain and hypothalamic catecholamines in rats was further studied under the following experimental
267
Fig. 3. Effect of alcohol (2 g/kg) on catecholamine DA, dopamine. 100% = control.
concentration.
NA, noradrenaline;
situations: acute alcohol administration; chronic alcohol administration, lasting up to 100 days, when a clear preference for alcohol is formed; acute administration against the background of chronic alcoholism; deprivation of alcohol, when a withdrawal syndrome appears, and conditions in which the withdrawal syndrome was terminated by the administration of alcohol. Alcohol, in combination with different psychopharmacological preparations that influence synthesis, storage, release and destruction of catecholamines, was used to analyse the mechanism of action of alcohol on brain catecholamines. In the midbrain and hypothalamus, the concentration of the catecholamines, noradrenaline and dopamine, their precursor DOPA, as well as their metabolic products, normetanephrine (NM) and 3-methoxy-4-hydroxyphenethylene glycol (MHPG), were determined. An electrophysiological study demonstrated that acute administration of alcohol, 2 - 3 g/kg, induced two stages: the stage of excitation accompanied by activation of the brain biocurrents, followed by the stage of inhibition characterized by sleep. One hour after administration of alcohol, 2 g/kg per OS, a considerable decrease in the concentration of noradrenaline and dopamine was manifested in the midbrain and hypothalamus, and was accompanied by an increase of the products of noradrenaline breakdown, NM and MHPG (Fig. 4a). Thus, we think that acute alcohol intake evokes an intensified release of noradrenaline in the brain regions mentioned and following its destruction, results in a decrease of catecholamine concentration in the brain. The stages of the effect of alcohol on the central nervous system can be connected with this process, because the abundantly released active noradrenaline carries out the functions of neuromediator, exciting the central adrenergic structures. Following the metabolism of noradrenaline, and due to subsequent decrease in noradrenaline concentration, activity in certain areas of the CNS is suppressed. Under long-term alcohol administration and development of preference for it, noradrenaline concentration in the midbrain and hypothalamus is
268
Fig. 4. Concentration hydroxyphenethylene 100% = control.
of catecholamines in the midbrain of rats, MHPG, 3-methoxy-4glycol; NM, normetanephrine; other abbreviations as in Fig. 1.
slightly higher than with an acute alcohol administration, but it is still lower compared with the norm (Fig. 4b). The constantly decreasing level of neuromediator in the central nervous system evokes corresponding changes in electrophysiological parameters represented as a decrease of the general tonus and excitability. Intake of a moderate dose of alcohol under these conditions evokes an intensified release of the bound noradrenaline (Fig. 4c) that improves activity of the central adrenergic system for a short period of time. Electroencephalographic study of chronic alcoholic patients has shown retardation and synchronization of electrical discharges, and decrease in the reactivity of both the brain biocurrents and vegetative functions to stimuli. Intake of a small dose of alcohol temporarily normalizes these functions [ 71. It is well-known that a moderate alcohol intake improves some functions of the central nervous system in chronic alcoholic patients, for example fulfilment of some tests, etc., but the released noradrenaline is soon destroyed and leads to an even further decrease of its concentration in the central nervous system. Thus, a “vicious cycle” is created. This process could be the basis for the development of a “psychic dependence” upon alcohol which occurs when a patient feels a short-term improvement after alcohol intake, causing him to take in more and more of this substance. Certain of our studies have indicated that during long-term alcohol intake, the increased release and destruction of noradrenaline is accompanied by a compensatory mechanism which is activated to counteract the effect of
269
alcohol on the brain catecholamine system. Pharmacological analysis has demonstrated that such a mechanism is a greatly intensified catecholamine synthesis. Thus, in chronic alcoholism, a balance is created between increased noradrenaline synthesis and increased degradation in the central nervous system. Deprivation of alcohol in chronic alcoholism causes an imbalance in the catecholamine system. Cessation of alcohol intake interrupts intensified noradrenaline destruction, while catecholamine synthesis, being a more torpid process, remains intensified, with the result that there is an overt increase in the level of dopamine and DOPA (Fig. 4d). According to present-day thinking, an increase in the dopamine concentration in the brain can cause sharp vegetative disorders and tremors, which are characteristic of the withdrawal state. It is firmly believed that the development of psychotic states is also connected with an increase in the concentration and disruption of dopamine metabolism in the central nervous system [ 8 - lo] . Thus the occurrence of delirium tremens during the withdrawal state can be evoked simply by an imbalance in the catecholamine system. In fact, our investigations showed that in patients with alcohol delirium, the level of dopamine and HVA was increased to 300 - 400% compared with normal subjects, Alcohol intake during the withdrawal state intensified noradrenaline degradation, leading again to a relative balance in the catecholamine system peculiar to chronic alcoholism (Fig. 4e). The shifts described in catecholamine metabolism of the brain can play a significant role in the development of “physical dependence” upon alcohol, because cessation of alcohol intake induces profound changes in this most important physiological system that are reflected in drastic physical and psychic states. These changes are, however, inhibited by alcohol intake. Thus, according to our hypothesis, the trigger mechanism of complex disorders in functions of the brain catecholamine system that leads to the development of alcoholic dependence is the intensified release and destruction of noradrenaline under the influence of alcohol. To verify the above supposition we made an effort to influence this process pharmacologically with the monoamine oxidase (MAO) inhibitors, iprazide and parnate. In the first series, alcohol, 2 g/kg, was administered per OS to two groups of experimental rats for 75 days. One of those groups was also treated with iprazide. At the end of the experiments, the animals were tested for their alcohol intake. The group that received alcohol and iprazide drank the same amount of alcohol as the control rats, while the group that received only alcohol drank 4 to 5 times as much (Fig. 5). The biochemical study of the catecholamine system in the brain during the withdrawal state has revealed a considerable increase of noradrenaline precursors in the midbrain and hypothalamus (up to 250%) in the animals that received only alcohol. However, the rats that were treated with iprazide displayed only a slight increase of DOPA, while the dopamine content in these animals was normal (Fig. 6). During the second series of our experiments, in which the influence of MAO inhibitors on the development of dependence upon alcohol was
270
00 i
::
control
Fig.
75
5. Voluntary
75 days
daqs alcohol
consumption
by different
groups
of rats.
% 250 210
220
I00
180
(60
MO
i (PO
100
-
1I DOPA
Fig. 6. DOPA control.
and dopamine
(DA)
concentration
in rat midbrain
during
withdrawal.
100% =
studied, the animals had the opportunity to choose between water and a 10% alcohol solution. One of the groups also received parnate. During the first 3 to 4 weeks, both groups showed a slight preference for alcohol. Subsequently alcohol intake by the control group increased up to 8 or 9 times, and then stabilized at that level, while in the group that received pamate, alcohol intake decreased somewhat and remained at a level close to the initial preference. Thus, alcohol dependence did not develop with parnate in animals presented with a choice between alcohol and water. Thus our experiments have confirmed our hypothesis of the significant role of noradrenaline in the pathogenesis of chronic alcoholism and on the neurochemical basis of the withdrawal syndrome. We have shown that alcohol produces a significant effect upon the catecholamine metabolism in the organism. Changes in metabolism of these amines in the central nervous system US. the periphery are different, and the specific effect of alcohol on
271
% 160
DA
NA
““4
I
110 I20 too 60 60 40
n
-
olrohol
EBB
-
borbomil
Fig. 7. Effect of drugs and alcohol DA, dopamine; HVA, homovanillic 100% = control.
m
-
morphine
on catecholamine metabolism in rat hypothalamus. acid; NA, noradrenaline; NM, normetanephrine.
7. 220 200
NR
HVA
DR
160. 160
i
140
NM
I
110
0
- alcohol
ES
-
borbomil
Fig. 8. Effect of drugs and alcohol tions as in Fig. 7. 100% = control.
m
- morpbk
on catecholamine
metabolism
in rat midbrain.
Abbrevia-
central nervous system catecholamines is an important stage in the pathogenesis of chronic alcoholism. It is well-known clinically that other forms of drug dependence are similar in their main manifestations and certain drugs show cross-tolerance or cross-dependence with alcohol [ 11,121. In this connection it was of interest to conduct a comparative study of the effect of narcotic drugs of different chemical structures and alcohol on the central metabolism of catecholamines. An hour after administration of morphine, 15 mg/kg, noradrenaline levels were decreased in the midbrain and hypothalamus, while in the other regions of this animal brain, its level was practically unchanged. Dopamine concentration was lower in midbrain, hypothalamus and cortex, whereas in striatum it was insignificantly higher. An injection of morphine led to a considerable lowering of NM in the cortex, an insignificant increase in the hypothalamus, and a sharp increase of NM in midbrain, striatum and particularly
40
1
0
- DA
m
-
NA
Fig. 9. Noradrenaline (NA) metabolism DA, dopamine; NM, normetanephrine.
m
-
NM
in midbrain during 100% = control.
the effect
of various
drugs.
in the hippocampus. It is important to mention that in all regions of the brain, an injection of morphine increased HVA concentration (Figs. 7 and 8). An injection of barbamil, 25 mg/kg, led to an insignificant increase of dopamine in the striatum and a sharp decrease in the other regions of the brain. HVA increased only in the hippocampus, was practically unchanged in the striatum and cortex and was considerably lower in the hypothalamus and midbrain. Noradrenaline was significantly lower than the control level in the midbrain and hypothalamus, while in other brain regions it was unchanged. The NM level was considerably higher in the midbrain and hypothalamus in the cortex, and it was very near to the control values in hippocampus and striatum (Figs. 7 and 8). With the results obtained from this study of the effect of an injection of morphine on the catecholamine system of the rat brain, we may assume that morphine increases both dopamine and norepinephrine metabolism in the midbrain, hypothalamus, striatum and hippocampus. An injection of barbamil, 25 mg/kg, increased only noradrenaline turnover in the midbrain and hypothalamus and activated dopamine metabolism in the hippocampus. It is difficult to explain now the character of changes in metabolism in the striatum and cortex under the effect of barbamil. The results of the investigation indicate that the other drugs investigated had an essential effect on catecholamine metabolism in different brain regions, though the effect varied with the area of the central nervous system that was investigated. Comparing the effects of narcotics of different chemical structure and alcohol on the brain catecholamine system enabled us to describe common features of their actions. All three drugs (morphine, barbamil and alcohol) decrease noradrenaline and dopamine concentrations in the midbrain and hypothalamus. Simultaneous increase in the NM level enables us to suggest that this decrease is due to intensification of release and metabolism of noradrenaline (Fig. 9). Barbamil and alcohol evoked similar disturbances in
273
dopamine metabolism in the midbrain and hypothalamus, where a decrease in the HVA level was observed. Thus, while the investigated drugs and alcohol have a different effect on catecholamine metabolism in many brain regions, they produce the same types of change in catecholamine metabolism in the midbrain and in the hypothalamus. Our investigations have thus shown that there may be common points of action for these drugs in the central nervous system. These results enable us to suggest that disorders in the catecholamine neurotransmitter system play an important role in the development of dependence on many chemically diverse substances.
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