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Pharmacology of drug self-administration
Alcohol. Vol. 7, pp. 193-197. ©Pergamon Press plc, 1990. Printed in the U.S.A.
0741-8329/90 $3.00 + .00
Pharmacology of Drug Self- Administration G E O R G E F. K O O B A N D F R I E D B E R T W E I S S
Research Institute of Scripps Clinic, Department of Neuropharmacology 10666 North Torrey Pines Road, BCR 1, La Jolla, CA 92037
KOOB, G. F. AND F. WEISS. Pharmacologyof drugself-administration. ALCOHOL 7(3) 193-197, 1990.--Limited access to drugs provides a reliable model for their acute-reinforcing effects and a means by which to explore neuropharmacological mechanisms involved in these effects. In limited access situations intravenous self-administration rates of opiates and psychomotor stimulants is inversely related to dose, and competitive antagonists at low doses increase the number of injections self-administered. Competitive agonists decrease drug self-administration. However noncompetitive antagonists tend to produce decreases in self-administration and the specificity of these results are difficult to interpret. A limited access procedure of ethanol (10% v/v) self-administration using a sucrose or saccharin fade out procedure resulted in reliable and stable ethanol (10% v/v) and water self-administration in a concurrent choice situation using nondeprived unselected Wistar and alcohol preferring P-rats. As observed by others, the opiate antagonist naloxone decreased fluid intake in both strain of rats. However, contrary to earlier results naloxone did not produce a selective decrease in ethanol preference. The serotonin antagonist methysergide had no significant effect on fluid intake or ethanol preference. However, the long-acting dopamine agonist bromocriptine decreased ethanol intake and increased water intake producing a significant decrease in ethanol preference. The results with naloxone suggest that opiate interactions with ethanol may reflect a more general effect on consummatory behavior and the results with bromocriptine suggest that the reinforcing effects of low doses of ethanol may involve a dopaminergic component. Future studies should explore further the interactions of ethanol with competitive antagonists (if possible), and fluid intake or ethanol preference with limbic-extrapyramidal circuitry involved in mediating the reinforcing actions of other drugs of abuse. Self-administration
Psychomotor stimulants
Opiates
Cocaine
PHARMACOLOGY OF DRUG SELF-ADMINISTRATION
to the drug dose (see Fig. 1). Using the model, pharmacological antagonism results in a shift to the right of the dose effect function (Fig. 2) and an increase in drug self-administration. Limited access to ethanol can also maintain stable levels of ethanol intake in nondeprived rats. Using taste adulteration (sucrose substitution) reliable and sustained operant responding for 10% ethanol was obtained (30). In extensions of these studies, rats were trained to work for ethanol using a two-lever situation and two small drinking wells. A pump was used which delivers a tenth of a milliliter of ethanol or water in these two wells. A sucrose fade out procedure was employed to train animals to selfadminister ethanol as described by Samson and colleagues (30). A sweet solution that has no nutritional value actually works quite well in these fade out procedures and similar results have been obtained using a saccharin fade out procedure. Thus nutrition, per se, does not have to be a factor. To establish the two-lever concurrent access situation the reinforcer on each lever was alternated every day. Sessions were 30 minutes in duration and the animals were tested at the beginning of the dark cycle (4:00 p.m.-4:00 a.m.). Nonfood-depfived animals of the unselected Wistar strain from Charles River, Kingston, NY and P-rats, genetically selected for
Animal Models of Drug Reinforcement Development of animal models for ethanol self-administration has been impeded by conceptual issues regarding proper animal models of alcoholism. However, other drugs of abuse, like opiates and cocaine, show reinforcing properties without the necessity that the animals become physically dependent. Opiate self-administration in nondependent people called " c h i p p e r s " is characterized by limited bouts of drug intake without physical dependence. Similarly social drinking of ethanol without dependence and alcoholism is indeed effectively " c h i p p i n g . " In humans, the drug is definitely being taken for its reinforcing properties; although intoxication is sometimes only mild. One of the major contributions of recent work on ethanol self-administration has been the development of an animal model of "social drinking," or of the reinforcing properties of social drinking. This is not unlike the models that have been used for intravenous drug self-administration. In intravenous drug self-administration, rats are allowed limited access to psychomotor stimulants such as cocaine or opiates such as amphetamine. In a typical 3-hour session animals will develop stable levels of drug intake that are inversely proportional
IThis is publication number 6155-NP from the Research Institute of Scripps Clinic, La Jolla, CA.
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KOOB AND WEISS
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mglkg Cocaine FIG. 1. Dose-response relationships for cocaine and heroin self-administration in rats. Rats were allowed daily 3-hour access to cocaine (bottom; 0.75 mg/kg per injection) or heroin (top; 0.06 mg/kg per injection) on a continuous reinforcement schedule. After baseline, stable responding ( +__20 percent mean for 3 days) was established and rats were subjected to a doubling of the dose, followed by a return to baseline, followed by a halving of the dose on three successive test days. Results are expressed as mean+-SEM, n=4. [Taken with permission from Koob al. (16)].
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relatively high preference for ethanol solutions, obtained from T. K. Li and Larry Lumeng at the Indiana University School of Medicine, were tested. Using the Samson sucrose fade out procedure, sucrose (initially 5%) is faded out, and ethanol is faded in gradually over test sessions, at 5 percent, 8 percent and 10 percent. Both unselected Wistar rats and the P-rats attained meaningful blood alcohol levels (see Fig. 3) and these blood alcohol levels correlated well with the quantity of lever presses for ethanol. There was a good bit of variability associated with the intake of the Wistar rats. Similar results in training unselected Wistar rats to self-administer ethanol were obtained using a saccharin fade out procedure. Again there was a very good relationship between the intake as measured by lever presses and the blood alcohol concentration (26).
quaternary derivative of naloxone (methylnaloxonium) and with direct intracerebral injections of methylnaloxonium into the region of the nucleus accumbens (34,35). Naloxone and methylnaloxonium in these dose ranges did not alter intravenous cocaine self-administration (5). There is also a substantial literature suggesting that the opiates interact with ethanol self-administration, and one of the bases for this literature is that the opiate antagonists, naloxone or nattrexone. will suppress ethanol intake in a drinking situation (7,25), However. naloxone is an aversive agent to rats since it produces taste and place aversions (10,33). Animals will avoid substances that have been paired with naloxone, and naloxone decreases fluid intake and food intake in rats at low doses (2,323. These data question whether the effect of opiate antagonists on ethanol intake is specific to ethanol or related to a more general decrease in consummatory motivation. Naloxone injected prior to testing produced a significant decrease m fluid intake in Wistar rats and alcohol preferring P-rats, This decrease was reflected in a decrease in both ethanol and water intake (37) and when a preference ratio was calculated there was no significant selective effect of naloxone on ethanol preference (37). The preference ratio was calculated by dividing ethanol lever presses by total lever presses: (ethanol/ethanol ~water) x 100. In the P-rats, the effects of naloxone were even more dramatic. There was no change in preference ratio and a dose-dependent decrease in intake of both ethanol and water (37).
OPIATE ANTAGONIST EFFECTS ON DRUG SELF-ADMINISTRATION
Naloxone at low doses (0.05-0.2 mg/kg) increased heroin self-administration when injected systemically (5,15). At higher doses (10-30 mg/kg) these drugs produced transient decreases in heroin self-administration (see Fig. 4). Similar effects were observed with intracerebroventricular injections of a nonlipophilic
THE EFFECTS OF SEROTONIN,ANTAGONISTS ON DRUG SELF-ADMINISTRATION
Serotonergic systems have been implicated in psychomotor stimulant self-administration, Decreases in amphetamine self, administration have been observed with administration of seroto-
SELF-ADMINISTRATION OF DRUGS
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THE EFFECTS OF DOPAMINE ANTAGONISTS AND AGONISTS, ON DRUG SELF-ADMINISTRATION :
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FIG. 3. Mean ( ---SEM) number of presses (lines and symbols) and mean ethanol intake in ml (histograms) during the single-solution-training phase. Numbers above frequency polygons (ml/30 min) indicate mean (___SEM) blood alcohol levels taken on days 20 and 52. Both alcohol-preferring (P) and genetically heterogeneous Wistar rats developed stable levels of responding for 10% (v/v) ethanol by day 52 of single-solution selfadministration.
nin antagonists (17) however, decreases have also been observed with systemic administration of serotonin agonists (17). Thus, serotonin may modulate psychostimulant reward but the exact nature of that modulation is at present unknown. Previous studies have shown that serotonin reuptake blockers can decrease ethanol preference (1, 2 1 , 2 9 ) [see (31) this volume]. Methysergide, a serotonin receptor antagonist (in doses of 2.5, 5.0 and 10 mg/kg), failed to alter fluid intake or the preference ratio in unselected Wistar rats or ethanol-preferring P-rats (37).
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Low doses of dopamine antagonists increased amphetamine and cocaine self-administration (5, 16, 27, 28, 38, 39). Again these effects were interpreted as reflecting a partial blockade of the reinforcing properties of psychomotor stimulants. Decreases in opiate and ethanol self-administration have been observed with these dopamine antagonists (5,31). The interpretation of these effects is controversial and may involve either nonspecific motor effects or some attenuation of the reinforcing properties of these drugs. Interestingly, bromocriptine dose dependently decreases cocaine self-administration in nondependent animals that are allowed 3 hours daily access to cocaine (11). Bromocriptine is a D-2 dopamine agonist that has been used to treat hyperprolactinemia in humans (6). It is also a drug that has been used preliminarily as a possible treatment for cocaine withdrawal (4). Of particular interest is that the interinjection interval for cocaine self-administration gets longer after pretreatment with bromocriptine, as if there is a specific pharmacological interaction (11 ). One interpretation of this effect is that bromocriptine is in some way substituting for cocaine similar to the ability of methadone to substitute for heroin. Bromocriptine's interaction with ethanol self-administration was explored in a two-lever choice procedure for ethanol and water. Bromocriptine produced a dose-dependent decrease in ethanol intake in the unselected Wistar rats. At the same time, there was a significant decrease in ethanol preference (37). This occurred primarily because of a decrease in ethanol responding with little change in water responding. The results were more dramatic for the P-rats, where there was a dose-dependent decrease in ethanol intake and a dose-dependent increase in water intake and thus a major effect on the ethanol preference (37). A mixed D-l, D-2 dopamine agonist (Sandoz 205-152) produced similar results in unselected Wistar rats. There was no effect on water responses, but there was a significant decrease in ethanol self-administration (26). These data reinforce the view that dopamine agonists tend to suppress ethanol intake.
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FIG. 4. Effects of systemic administration of naloxone, methylnaloxonium chloride, naltrexone and naltrexone methobromide on responding over the total 3-hour test session for rats self-administering heroin. Data are expressed as mean -+ SEM of the total infusions for 3 hours. Asterisks indicate that the treatment dose was reliably different from the saline (SAL) pretreatment condition, p<0.05 paired t-test. Number of rats and observations the same as Fig. 1. [Taken with permission from Koob et al. (15)].
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KOOB AND WEISS
DISCUSSION In summary, pharmacological manipulation of opiate, serotonin and dopaminergic receptors can alter drug self-administration. When the pharmacological challenge is competitive in the case of naloxone versus heroin or dopamine receptor antagonists versus cocaine then the animals tend to increase self-administration to compensate for the blockade. However, noncompetitive antagonism is more likely to result in decreases in drug self-administration and such decreases are more difficult to interpret. Similarly receptor agonists will decrease self-administration presumably reflecting a competitive substitution for the self-administered drug (methadone for heroin; bromocriptine for cocaine). More difficult to interpret are the effects of noncompetitive agonist interactions (bromocriptine in ethanol self-administration). It is clear that reliable limited access self-administration of ethanol can be obtained in nondeprived, nonmotivationally constrained rats using a sucrose or saccharin fade out procedure. Blood alcohol levels range from 25 to 230 mg percent in the P-rats and 25-75 mg percent in the Wistar rats, reflecting a mild intoxication range. There is a reasonably good correlation between the number of lever presses, and the blood alcohol level obtained suggesting the animals are consistently drinking the ethanol delivered. In animals trained in this procedure, drugs influencing opiate, serotonergic and dopaminergic systems were examined for their effects on ethanol reinforcement. The opiate antagonist naloxone produced a dose-dependent decrease in fluid intake in both unselected Wistars and P-rats, but no specific effect on ethanol drinking. The serotonin antagonist methysergide produced no significant effect at the doses employed except for a slight hint of a facilitation in preference in the unsetected Wistar rats at a low dose. The dopaminergic agonist bromocriptine selectively decreased ethanol self-administration and either had no effect or an increase in water intake. The results with naloxone are consistent with a number of studies showing that naloxone even in low doses decreases consummatory behavior (2). For example, naloxone suppresses tk~od and water intake over a wide range of doses (2). Naloxone also decreases oral intake of sucrose solutions and sweetened milk solutions (3,32). Several studies showed a selective decrease in ethanol intake with naloxone (7,25). However, most of these studies involved a forced-choice situation in fluid-restricted animals. In this situation a nonspecific suppressive effect of naloxone may not be measured since rats have to meet their daily water requirements during the time of testing for ethanol choice. A serotonergic role in ethanol reinforcement has been suggested by studies showing that serotonin reuptake blockers, or even central administration of serotonin reduce voluntary ethanol intake (1,20, 29). Also, the levels of serotonin and 5 hydroxyiw doleacetic acid (5-HIAA) in the P-rats have been shown to be 10-30 percent lower than for the alcohol nonpreferring (NP) rats in various forebrain areas (18,19). Similar reductions in serotonin were seen in another line of rats selectively bred for high alcohol drinking (HAD) versus the low alcohol drinking (LAD) (8), The failure of methysergide to increase ethanol preference in the present experiment with the P-rats may relate to the phenomenon of a "floor" effect resulting from the already hypothesized deficient central serotonin system in these rats. However, there still should have been an increase in ethanol preference in the
unselected Wistar rats. There was a slight increase observed at the lower dose suggesting that perhaps other doses should be ex plored (37). An alternative explanation for the methysergide resutt~ may be the interaction of ethanol with the renin-angiotensin system Administration of angiotensin II potently reduces ethanol intake (9), and brain serotonin potently stimulates the renin-angiotensin system (36). Thus it is possible that the reduction in ethanol self-administration produced by serotonin reuptake inhibitors is mediated by an increase in activit5 of the renin-angiotensin system. Conversely, decreases in the rcnin-angiotensin activity may be associated with increased ethanol preference, but serotonin receptor blockade by methysergide may not produce enough of a decrease in renin-angiotensin activity to increase ethanol intake~ The decrease in ethar.q intake produced by bromocriptine b. consistent with results by Samson and colleagues using d-amphetamine and apomorphine (22-24). Both drugs dose dependently decrease ethanol self-administration i~ both food restricted and freely feeding rats. As noted above, bromocriptine produced a dose-dependent decrease in cocaine self-administration (l I). This decrease was accompanied by a regular increase in the interiNection interval which suggested that bromocriptine blunts the reinforcing actions of cocaine by substituting for its dopamineenhancing action. Given the hypothesis that low doses of ethanol may activate central dopamine neurotransmission to produce their reinforcing effects, one might speculate that bromocriptine re~, duced ethanol preference by substituting for this low dose effect. In support of this hypothesis systemic administration of ethanol has been shown to produce significant increases in extraceltula~ dopamine in the region of the nucleus accumbens (12). AIs~, the alcohol preferring P-rats have shown to have higher dopamine metabolites in the nucleus accumbens compared to the nonpreferring (NP) rats (13), Interestingly, dopamine receptor antagonists also decrease ethanol self-administration (24). While superficially this shows that both dopamine agonists and antagonists can decrease ethanol self-administration, recent work by Samson and colleagues (31~ suggests that dopamine agonists produce a different pattern of suppression of ethanol intake than dopamine antagonists. Dopamine agonists disrupt the usual sustained high rate of responding at the beginning of the session. Dopamine antagonists produce no alteration in initial response rates, bu~ the duration of the initial sustained responding is decreased. Finally, it is worth speculating tha~ the same neuronal cucuitry inw)lved in mediating the reinforcing actions of other dnlgs of abuse such as cocaine and heroin may be involved in the reinforcing actions of ethanol. Low doses of ethanol may activate the release of dopamine in the nucleus accumbens, but the nucleus accumbens is situated at a juncture ',~f the limbic and striata[ circuitry such that actions on othm neurotransmitters may also impact on these effects, For example, the brain sites particularly sensitive to the ethanol drinking produced by tetrahydropapaveroline include major parts of this Circuitry such a,,; the nucleus accumbens, olfactory tubercle, lateral septum, stria terminalis and medial forebrain bundle (21L Also, unknown at this time is what effect ethanol has on glutamate, neurotensin, GABA or cholecys-tokinin in the region of the nucleus accumbens, Thus, a logical site to pursue the neurobiology of ethanol reinforcement may be the limbic-extrapyramidal circuit thought to be involved in the reinforcing properties of other drugs of abuse (t4).
ACKNOWLEDGEMENTS This paper was supported by NIAAA grant AA 06420. I would like to thank Diane Braca for manuscript preparation and superb assistance
SELF-ADMINISTRATION OF DRUGS
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0741-8329/90 $3.00 + .00
Pharmacology of Drug Self- Administration G E O R G E F. K O O B A N D F R I E D B E R T W E I S S
Research Institute of Scripps Clinic, Department of Neuropharmacology 10666 North Torrey Pines Road, BCR 1, La Jolla, CA 92037
KOOB, G. F. AND F. WEISS. Pharmacologyof drugself-administration. ALCOHOL 7(3) 193-197, 1990.--Limited access to drugs provides a reliable model for their acute-reinforcing effects and a means by which to explore neuropharmacological mechanisms involved in these effects. In limited access situations intravenous self-administration rates of opiates and psychomotor stimulants is inversely related to dose, and competitive antagonists at low doses increase the number of injections self-administered. Competitive agonists decrease drug self-administration. However noncompetitive antagonists tend to produce decreases in self-administration and the specificity of these results are difficult to interpret. A limited access procedure of ethanol (10% v/v) self-administration using a sucrose or saccharin fade out procedure resulted in reliable and stable ethanol (10% v/v) and water self-administration in a concurrent choice situation using nondeprived unselected Wistar and alcohol preferring P-rats. As observed by others, the opiate antagonist naloxone decreased fluid intake in both strain of rats. However, contrary to earlier results naloxone did not produce a selective decrease in ethanol preference. The serotonin antagonist methysergide had no significant effect on fluid intake or ethanol preference. However, the long-acting dopamine agonist bromocriptine decreased ethanol intake and increased water intake producing a significant decrease in ethanol preference. The results with naloxone suggest that opiate interactions with ethanol may reflect a more general effect on consummatory behavior and the results with bromocriptine suggest that the reinforcing effects of low doses of ethanol may involve a dopaminergic component. Future studies should explore further the interactions of ethanol with competitive antagonists (if possible), and fluid intake or ethanol preference with limbic-extrapyramidal circuitry involved in mediating the reinforcing actions of other drugs of abuse. Self-administration
Psychomotor stimulants
Opiates
Cocaine
PHARMACOLOGY OF DRUG SELF-ADMINISTRATION
to the drug dose (see Fig. 1). Using the model, pharmacological antagonism results in a shift to the right of the dose effect function (Fig. 2) and an increase in drug self-administration. Limited access to ethanol can also maintain stable levels of ethanol intake in nondeprived rats. Using taste adulteration (sucrose substitution) reliable and sustained operant responding for 10% ethanol was obtained (30). In extensions of these studies, rats were trained to work for ethanol using a two-lever situation and two small drinking wells. A pump was used which delivers a tenth of a milliliter of ethanol or water in these two wells. A sucrose fade out procedure was employed to train animals to selfadminister ethanol as described by Samson and colleagues (30). A sweet solution that has no nutritional value actually works quite well in these fade out procedures and similar results have been obtained using a saccharin fade out procedure. Thus nutrition, per se, does not have to be a factor. To establish the two-lever concurrent access situation the reinforcer on each lever was alternated every day. Sessions were 30 minutes in duration and the animals were tested at the beginning of the dark cycle (4:00 p.m.-4:00 a.m.). Nonfood-depfived animals of the unselected Wistar strain from Charles River, Kingston, NY and P-rats, genetically selected for
Animal Models of Drug Reinforcement Development of animal models for ethanol self-administration has been impeded by conceptual issues regarding proper animal models of alcoholism. However, other drugs of abuse, like opiates and cocaine, show reinforcing properties without the necessity that the animals become physically dependent. Opiate self-administration in nondependent people called " c h i p p e r s " is characterized by limited bouts of drug intake without physical dependence. Similarly social drinking of ethanol without dependence and alcoholism is indeed effectively " c h i p p i n g . " In humans, the drug is definitely being taken for its reinforcing properties; although intoxication is sometimes only mild. One of the major contributions of recent work on ethanol self-administration has been the development of an animal model of "social drinking," or of the reinforcing properties of social drinking. This is not unlike the models that have been used for intravenous drug self-administration. In intravenous drug self-administration, rats are allowed limited access to psychomotor stimulants such as cocaine or opiates such as amphetamine. In a typical 3-hour session animals will develop stable levels of drug intake that are inversely proportional
IThis is publication number 6155-NP from the Research Institute of Scripps Clinic, La Jolla, CA.
193
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KOOB AND WEISS
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relatively high preference for ethanol solutions, obtained from T. K. Li and Larry Lumeng at the Indiana University School of Medicine, were tested. Using the Samson sucrose fade out procedure, sucrose (initially 5%) is faded out, and ethanol is faded in gradually over test sessions, at 5 percent, 8 percent and 10 percent. Both unselected Wistar rats and the P-rats attained meaningful blood alcohol levels (see Fig. 3) and these blood alcohol levels correlated well with the quantity of lever presses for ethanol. There was a good bit of variability associated with the intake of the Wistar rats. Similar results in training unselected Wistar rats to self-administer ethanol were obtained using a saccharin fade out procedure. Again there was a very good relationship between the intake as measured by lever presses and the blood alcohol concentration (26).
quaternary derivative of naloxone (methylnaloxonium) and with direct intracerebral injections of methylnaloxonium into the region of the nucleus accumbens (34,35). Naloxone and methylnaloxonium in these dose ranges did not alter intravenous cocaine self-administration (5). There is also a substantial literature suggesting that the opiates interact with ethanol self-administration, and one of the bases for this literature is that the opiate antagonists, naloxone or nattrexone. will suppress ethanol intake in a drinking situation (7,25), However. naloxone is an aversive agent to rats since it produces taste and place aversions (10,33). Animals will avoid substances that have been paired with naloxone, and naloxone decreases fluid intake and food intake in rats at low doses (2,323. These data question whether the effect of opiate antagonists on ethanol intake is specific to ethanol or related to a more general decrease in consummatory motivation. Naloxone injected prior to testing produced a significant decrease m fluid intake in Wistar rats and alcohol preferring P-rats, This decrease was reflected in a decrease in both ethanol and water intake (37) and when a preference ratio was calculated there was no significant selective effect of naloxone on ethanol preference (37). The preference ratio was calculated by dividing ethanol lever presses by total lever presses: (ethanol/ethanol ~water) x 100. In the P-rats, the effects of naloxone were even more dramatic. There was no change in preference ratio and a dose-dependent decrease in intake of both ethanol and water (37).
OPIATE ANTAGONIST EFFECTS ON DRUG SELF-ADMINISTRATION
Naloxone at low doses (0.05-0.2 mg/kg) increased heroin self-administration when injected systemically (5,15). At higher doses (10-30 mg/kg) these drugs produced transient decreases in heroin self-administration (see Fig. 4). Similar effects were observed with intracerebroventricular injections of a nonlipophilic
THE EFFECTS OF SEROTONIN,ANTAGONISTS ON DRUG SELF-ADMINISTRATION
Serotonergic systems have been implicated in psychomotor stimulant self-administration, Decreases in amphetamine self, administration have been observed with administration of seroto-
SELF-ADMINISTRATION OF DRUGS
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nin antagonists (17) however, decreases have also been observed with systemic administration of serotonin agonists (17). Thus, serotonin may modulate psychostimulant reward but the exact nature of that modulation is at present unknown. Previous studies have shown that serotonin reuptake blockers can decrease ethanol preference (1, 2 1 , 2 9 ) [see (31) this volume]. Methysergide, a serotonin receptor antagonist (in doses of 2.5, 5.0 and 10 mg/kg), failed to alter fluid intake or the preference ratio in unselected Wistar rats or ethanol-preferring P-rats (37).
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Low doses of dopamine antagonists increased amphetamine and cocaine self-administration (5, 16, 27, 28, 38, 39). Again these effects were interpreted as reflecting a partial blockade of the reinforcing properties of psychomotor stimulants. Decreases in opiate and ethanol self-administration have been observed with these dopamine antagonists (5,31). The interpretation of these effects is controversial and may involve either nonspecific motor effects or some attenuation of the reinforcing properties of these drugs. Interestingly, bromocriptine dose dependently decreases cocaine self-administration in nondependent animals that are allowed 3 hours daily access to cocaine (11). Bromocriptine is a D-2 dopamine agonist that has been used to treat hyperprolactinemia in humans (6). It is also a drug that has been used preliminarily as a possible treatment for cocaine withdrawal (4). Of particular interest is that the interinjection interval for cocaine self-administration gets longer after pretreatment with bromocriptine, as if there is a specific pharmacological interaction (11 ). One interpretation of this effect is that bromocriptine is in some way substituting for cocaine similar to the ability of methadone to substitute for heroin. Bromocriptine's interaction with ethanol self-administration was explored in a two-lever choice procedure for ethanol and water. Bromocriptine produced a dose-dependent decrease in ethanol intake in the unselected Wistar rats. At the same time, there was a significant decrease in ethanol preference (37). This occurred primarily because of a decrease in ethanol responding with little change in water responding. The results were more dramatic for the P-rats, where there was a dose-dependent decrease in ethanol intake and a dose-dependent increase in water intake and thus a major effect on the ethanol preference (37). A mixed D-l, D-2 dopamine agonist (Sandoz 205-152) produced similar results in unselected Wistar rats. There was no effect on water responses, but there was a significant decrease in ethanol self-administration (26). These data reinforce the view that dopamine agonists tend to suppress ethanol intake.
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I~.
KOOB AND WEISS
DISCUSSION In summary, pharmacological manipulation of opiate, serotonin and dopaminergic receptors can alter drug self-administration. When the pharmacological challenge is competitive in the case of naloxone versus heroin or dopamine receptor antagonists versus cocaine then the animals tend to increase self-administration to compensate for the blockade. However, noncompetitive antagonism is more likely to result in decreases in drug self-administration and such decreases are more difficult to interpret. Similarly receptor agonists will decrease self-administration presumably reflecting a competitive substitution for the self-administered drug (methadone for heroin; bromocriptine for cocaine). More difficult to interpret are the effects of noncompetitive agonist interactions (bromocriptine in ethanol self-administration). It is clear that reliable limited access self-administration of ethanol can be obtained in nondeprived, nonmotivationally constrained rats using a sucrose or saccharin fade out procedure. Blood alcohol levels range from 25 to 230 mg percent in the P-rats and 25-75 mg percent in the Wistar rats, reflecting a mild intoxication range. There is a reasonably good correlation between the number of lever presses, and the blood alcohol level obtained suggesting the animals are consistently drinking the ethanol delivered. In animals trained in this procedure, drugs influencing opiate, serotonergic and dopaminergic systems were examined for their effects on ethanol reinforcement. The opiate antagonist naloxone produced a dose-dependent decrease in fluid intake in both unselected Wistars and P-rats, but no specific effect on ethanol drinking. The serotonin antagonist methysergide produced no significant effect at the doses employed except for a slight hint of a facilitation in preference in the unsetected Wistar rats at a low dose. The dopaminergic agonist bromocriptine selectively decreased ethanol self-administration and either had no effect or an increase in water intake. The results with naloxone are consistent with a number of studies showing that naloxone even in low doses decreases consummatory behavior (2). For example, naloxone suppresses tk~od and water intake over a wide range of doses (2). Naloxone also decreases oral intake of sucrose solutions and sweetened milk solutions (3,32). Several studies showed a selective decrease in ethanol intake with naloxone (7,25). However, most of these studies involved a forced-choice situation in fluid-restricted animals. In this situation a nonspecific suppressive effect of naloxone may not be measured since rats have to meet their daily water requirements during the time of testing for ethanol choice. A serotonergic role in ethanol reinforcement has been suggested by studies showing that serotonin reuptake blockers, or even central administration of serotonin reduce voluntary ethanol intake (1,20, 29). Also, the levels of serotonin and 5 hydroxyiw doleacetic acid (5-HIAA) in the P-rats have been shown to be 10-30 percent lower than for the alcohol nonpreferring (NP) rats in various forebrain areas (18,19). Similar reductions in serotonin were seen in another line of rats selectively bred for high alcohol drinking (HAD) versus the low alcohol drinking (LAD) (8), The failure of methysergide to increase ethanol preference in the present experiment with the P-rats may relate to the phenomenon of a "floor" effect resulting from the already hypothesized deficient central serotonin system in these rats. However, there still should have been an increase in ethanol preference in the
unselected Wistar rats. There was a slight increase observed at the lower dose suggesting that perhaps other doses should be ex plored (37). An alternative explanation for the methysergide resutt~ may be the interaction of ethanol with the renin-angiotensin system Administration of angiotensin II potently reduces ethanol intake (9), and brain serotonin potently stimulates the renin-angiotensin system (36). Thus it is possible that the reduction in ethanol self-administration produced by serotonin reuptake inhibitors is mediated by an increase in activit5 of the renin-angiotensin system. Conversely, decreases in the rcnin-angiotensin activity may be associated with increased ethanol preference, but serotonin receptor blockade by methysergide may not produce enough of a decrease in renin-angiotensin activity to increase ethanol intake~ The decrease in ethar.q intake produced by bromocriptine b. consistent with results by Samson and colleagues using d-amphetamine and apomorphine (22-24). Both drugs dose dependently decrease ethanol self-administration i~ both food restricted and freely feeding rats. As noted above, bromocriptine produced a dose-dependent decrease in cocaine self-administration (l I). This decrease was accompanied by a regular increase in the interiNection interval which suggested that bromocriptine blunts the reinforcing actions of cocaine by substituting for its dopamineenhancing action. Given the hypothesis that low doses of ethanol may activate central dopamine neurotransmission to produce their reinforcing effects, one might speculate that bromocriptine re~, duced ethanol preference by substituting for this low dose effect. In support of this hypothesis systemic administration of ethanol has been shown to produce significant increases in extraceltula~ dopamine in the region of the nucleus accumbens (12). AIs~, the alcohol preferring P-rats have shown to have higher dopamine metabolites in the nucleus accumbens compared to the nonpreferring (NP) rats (13), Interestingly, dopamine receptor antagonists also decrease ethanol self-administration (24). While superficially this shows that both dopamine agonists and antagonists can decrease ethanol self-administration, recent work by Samson and colleagues (31~ suggests that dopamine agonists produce a different pattern of suppression of ethanol intake than dopamine antagonists. Dopamine agonists disrupt the usual sustained high rate of responding at the beginning of the session. Dopamine antagonists produce no alteration in initial response rates, bu~ the duration of the initial sustained responding is decreased. Finally, it is worth speculating tha~ the same neuronal cucuitry inw)lved in mediating the reinforcing actions of other dnlgs of abuse such as cocaine and heroin may be involved in the reinforcing actions of ethanol. Low doses of ethanol may activate the release of dopamine in the nucleus accumbens, but the nucleus accumbens is situated at a juncture ',~f the limbic and striata[ circuitry such that actions on othm neurotransmitters may also impact on these effects, For example, the brain sites particularly sensitive to the ethanol drinking produced by tetrahydropapaveroline include major parts of this Circuitry such a,,; the nucleus accumbens, olfactory tubercle, lateral septum, stria terminalis and medial forebrain bundle (21L Also, unknown at this time is what effect ethanol has on glutamate, neurotensin, GABA or cholecys-tokinin in the region of the nucleus accumbens, Thus, a logical site to pursue the neurobiology of ethanol reinforcement may be the limbic-extrapyramidal circuit thought to be involved in the reinforcing properties of other drugs of abuse (t4).
ACKNOWLEDGEMENTS This paper was supported by NIAAA grant AA 06420. I would like to thank Diane Braca for manuscript preparation and superb assistance
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