OXYTOCIN AND ADDICTION: A REVIEW

Psychoneuroendocrinology, Vol. 23, No. 8, pp. 945 – 962, 1998 © 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0306-4530/98 $ - see front matter

PII: S0306-4530(98)00064-X

OXYTOCIN AND ADDICTION: A REVIEW Ga´bor L. Kova´cs1, Zolta´n Sarnyai2 and Gyula Szabo´3 1

Central Laboratory, Markusovszky Teaching Hospital, Szombathely, H-9701, Markusovszky u. 3, Hungary 2 Laboratory of Neuroendocrinology and Laboratory of Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA 3 Department of Pathophysiology, Albert Szent-Gyo¨rgyi University Szeged, Semmelweis u.1, Hungary

SUMMARY Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS—mainly those located in limbic and basal forebrain structures — are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission— primarily in basal forebrain structures — is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT. © 1998 Elsevier Science Ltd. All rights reserved. Keywords—Neuropeptides; Oxytocin; Opiate; Cocaine; Ethanol; Rapid tolerance; Addiction; Withdrawal.

INTRODUCTION In the last 25 years there has been a great increase in interest in central nervous system (CNS) functions of neuroactive peptides (Ho¨kfelt, 1991). Neuropeptides may function as neurotransmitters as well as neuromodulators. Neurotransmitters are localized in nerve terminals, preferentially in synaptic vesicles. They are released upon nerve stimulation, interact with receptor molecules on the postsynaptic cell membrane, and are subsequently inactivated by enzymatic degradation and re-uptake mechanisms. The response to classic neurotransmitters is rapid and short lasting. Neuromodulation includes a slow time course of action, a more diffuse site of action and an ability to change responses to neurotransmitters (Kow and Pfaff, 1988). In view of these characteristics, neuropeptides may indeed influence a variety of biological functions by acting as neuromodulators. Address correspondence and reprint requests to: Ga´bor L. Kova´cs, Central Laboratory, Markusovszky Teaching Hospital, H-9701, Szombathely, Markusovszky u.3., Hungary (Tel: 36 94 312172; Fax: 36 94 327873; E-mail: [email protected]). 945

946

G. L. Kova´cs et al.

Repeated administration of drugs such as ethanol, opiates or barbiturates leads to the development of tolerance and physical dependence. Tolerance is described as a diminished response to a drug upon repeated exposures. Physical dependence is demonstrated by the occurrence of withdrawal symptoms when drug administration is stopped. Some aspects of functional tolerance to opiates have been considered to be a form of learning (Colbern et al., 1986). The same may hold for tolerance to other compounds such as ethanol. Abused drugs are known to enhance brain reward mechanisms. The mesolimbic dopaminergic projections form a crucial drug-sensitive component of the reward circuitry, which is preferentially activated neurochemically by abusable substances to enhance brain reward. The mesolimbic dopaminergic fibers terminating in the nucleus accumbens appear to be the most crucial reward-relevant components of the ascending mesotelecephalic dopamine system (Koob, 1992; Lowinson et al., 1992). The drug-sensitive dopaminergic components of the reward circuitry are under the modulatory control of a wide variety of other neuronal and hormonal systems. In the present paper we consider the hypothesis that a specific neuropeptide, oxytocin (OXT), acting within the CNS, may modulate the role of dopamine in the reward circuitry. Evidence regarding this hypothesis comes primarily from studies of the role of neuropeptides, and in particular of OXT, on experimental drug addiction in rodents. These studies are reviewed here.

OXYTOCIN AND MORPHINE ADDICTION The Effects of Oxytocin on Opiate Tolerance In recent years it has become increasingly evident that neurohypophyseal neuropeptides (OXT and vasopressin, VP) might play a role in drug addiction processes (Kova´cs, 1986; Kova´cs and Telegdy, 1987b; Krivoy et al., 1974; Van Ree, 1983). For example, desglycinamide9-lysine8-vasopressin (DG-LVP) facilitated the rate at which tolerance to morphine-induced analgesia developed in mice (Krivoy et al., 1974). Van Ree and De Wied (1977a,b) found that the hormonally active VP and a variety of hormonally inactive vasopressin-like peptide fragments increased the rate of tolerance (the analgesic action of opiates was investigated in these studies). OXT, on the other hand, dose-dependently attenuated the development of rapid and chronic morphine tolerance in mice. For example, in animals treated with OXT and then with a high, tolerance inducing dose of morphine (Fig. 1), the analgesic effect of a second morphine injection was greater than in the control animals which did not receive OXT. Interestingly, OXT did not modify the magnitude or the duration of the analgesic effect of the first morphine challenge in drug-naive animals (Kova´cs and Telegdy, 1987a; Kova´cs et al., 1985). Of physiological interest might be the finding that tolerance to the antinociceptive effect of b-endorphin was also attenuated by graded doses of OXT. The dose-response effect of OXT was U-shaped, because medium-high doses of this neuropeptide were more effective than high peptide doses. Since b-endorphin is an endogenous substance in the central nervous system, the results indicate the possibility of a physiological interaction between two different neuronal peptides (OXT and b-endorphin) in the organization of opiate tolerance (Kova´cs and Telegdy, 1987a). Intracerebroventricular (ICV) injections of OXT were considerably more potent than were systemic peptide injections in attenuating analgesic morphine tolerance (Fig. 1). This

Oxytocin and Addiction

947

finding suggests that CNS, and not peripheral mechanisms are involved in this effect of the neurohypophyseal neuropeptide. Local intracerebral microinjections of OXT were even more potent than ICV injections (Ibragimov et al., 1987; Kova´cs et al., 1984; Sarnyai et al., 1988). The most sensitive brain sites were the hippocampus and the basal forebrain (including the nucleus accumbens and the posterior olfactory nuclei). Oxytocinergic nerve terminals (Buijs, 1983; Sawchenko and Swanson, 1985) and binding sites (De Kloet et al., 1985; Ferrier et al., 1983) are present in these brain nuclei. It is remarkable that the interaction of OXT with morphine tolerance could also be observed in non-analgesic effects of the opiate alkaloid. Accordingly, in mice OXT treatment inhibited the development of tolerance in the locomotor hyperactivity that follows the administration of high doses of morphine (Kova´cs and Telegdy, 1987b). Since brain structures involved in the control of pain perception and those responsible for hyperlocomotion are not identical, these data suggest that the effect of OXT on morphine tolerance was not specifically related to the effector (output) mechanisms of these behavioral processes, but rather to more fundamental neuronal mechanisms responsible for the organization of tolerance.

Oxytocin and Morphine Withdrawal The degree of physical dependence to a given narcotic drug is characterized by the severity of withdrawal reactions (e.g. stereotyped jumping due to extrapyramidal incoordination, salivation, loss of body weight as a consequence of intensive diarrhea and urination, decrease in colonic temperature, irritability, etc.). Injections of OXT in graded doses, given prior to the first morphine challenge, attenuated various signs of the

Fig. 1. The effect of OXT on the development of morphine tolerance. Mice were rendered tolerant to/dependent on morphine by the subcutaneous implantation of a morphine pellet (Kova´cs et al., 1981). A single injection of OXT in graded doses was given 2 h prior to the pellet implantation; 48 h later, a test dose of 5 mg/kg morphine was injected and the analgesic effect was measured 30 min later by the heat irradiant tail-flick method. Left curve: ICV OXT treatment; right curve: SC OXT treatment. ICV injections were administered via chronically implanted plastic cannulae. Each point represents the mean ( 9 SE) of eight experimental animals. The horizontal dotted area represents the analgesic effect of 5 mg/kg morphine in the tolerant control animals ( + pB .05; + + pB .01; +++ pB.001 vs. tolerant control animals).

948

G. L. Kova´cs et al.

naloxone-precipitated withdrawal reaction. Low doses of OXT were needed to attenuate the withdrawal-induced hypothermia, while higher doses of the neuropeptide were required to antagonize the withdrawal-induced loss in body weight and the latency of the onset of stereotyped jumping. It is therefore likely that OXT interfered with the development of physical dependence and a lower degree of physical dependence resulted in a secondary manner in the appearance of less severe withdrawal signs. Heroin Self-administration and Neurohypophyseal Peptides Since neurohypophyseal neuropeptides deeply affected the development of tolerance to, and dependence on narcotic drugs (Kova´cs and Telegdy, 1985, 1987b; Van Ree, 1983), their roles in drug-induced reinforcement process also have been studied. Van Ree and De Wied (1977a,b) found that desglycinamide9-arginine8-vasopressin, a behaviorally active fragment of VP, reduced intravenous self-administration of heroin in non-tolerant rats. OXT exerted a different effect in this study: rats treated with this neuropeptide self-administered significantly more heroin (Van Ree and De Wied, 1977a) than did VP-treated animals, but not more than the non-treated control animals. Basically different findings were published more recently (Ibragimov et al., 1987; Kova´cs and Van Ree, 1985; Kova´cs et al., 1985), when the effect of OXT treatment on the development of heroin self-administration was investigated in heroin tolerant rats. OXT dose-dependently reduced the self-injected heroin dose. In non-tolerant rats, on the other hand, systemic injections of OXT did not modify the rate of heroin self-administration. Taken together, these findings suggest that OXT reduced the higher self-administration rate of the heroin-tolerant/dependent rats to a level of self-injection, similar to that of non-tolerant rats (Kova´cs and Van Ree, 1985). These data suggest the hypothesis that the primary action of OXT is not on the reinforcing efficacy of heroin, but rather on the degree of tolerance to, and dependence on heroin. The In6ol6ement of Central Ner6ous Oxytocinergic Receptors Earlier results indicated that endogenous OXT, which is present in oxytocinergic nerve fibres and terminals in the brain (Buijs, 1983; Sawchenko and Swanson, 1985) may have a physiological role in adaptive components of narcotic addiction (Kova´cs, 1986). The description of saturable oxytocinergic binding sites in the limbic system (De Kloet et al., 1985; Ferrier et al., 1983) stimulated research investigating whether receptor antagonists of OXT could effectively block the action of OXT on morphine tolerance (Kova´cs et al., 1987). ICV injections of N-a-acetyl-[2-O-methyltyrosine]-OXT, an antagonist of oxytocinergic receptors (Jost and Sorm, 1971), dose-dependently antagonized the inhibitory effect of OXT on the development of rapid-morphine tolerance in mice. It also has been demonstrated that local microinjections of minute amounts of this receptor antagonist into limbic brain areas is highly effective in inhibiting the effects of OXT on morphine tolerance in mice (Sarnyai et al., 1988), or heroin self-administration in rats (Ibragimov et al., 1987). It is, therefore, likely that endogenous OXT acts on OXT receptors in limbic brain areas to inhibit adaptive mechanisms underlying experimental drug addiction (Kova´cs et al., 1986a). However, it cannot be ruled out that OXT may exert some of its effects on drug addiction through central nervous VP receptors. Receptors in the brain, selective for VP, are presumably of the V1a type (Kira´ly et al., 1986; Shewey and Dorsa, 1988). There is no firm evidence for central V1b or V2 receptors. V1a receptors have been found in various

Oxytocin and Addiction

949

brain areas, including the limbic system (e.g. the anterior olfactory nucleus, lateral septum, nucleus accumbens, central amygdaloid nucleus, and dentate gyrus (Tribollet et al., 1988). Also two types of OXT binding sites have been detected in the central nervous system. One widely distributed throughout the CNS is comparable to the uterus type receptor and a sexually dimorphic slightly different type in the nucleus ventromedialis. Elands et al. (1988), using a highly specific tritiated OXT agonist, showed that the OXT receptor in the ventral hippocampus exhibits properties similar to the OXT receptors in the rat uterus and lactating mammary gland. This receptor also has a high affinity for VP, as does the peripheral OXT receptor, although the bioleogical potency of VP in uterus and mammary gland is low. In the brain, this receptor may mediate central effects of VP and OXT and may thus be regarded as a ‘non-selective’ receptor. The Role of Forebrain Dopamine in Mediating the Effect of OXT Forebrain dopamine plays an important, presumably causal, role in drug addiction processes (Acquas and Di Chiara, 1992; Koob, 1992; Redmond and Krystal, 1984). It was, therefore, of interest to investigate whether OXT could alter dopaminergic neurotransmission in the basal forebrain. In rats the effect of OXT was more pronounced on the nigrostriatal, than on the mesolimbic, dopamine system (Kova´cs and Telegdy, 1983; Van Heuven-Nolsen et al., 1984; Versteeg, 1983). In mice, on the other hand, chronic OXT treatment decreased the utilization and the receptor binding (Kova´cs et al., 1986b) of dopamine in the mesolimbic dopamine system. In the basal forebrain structures, also involving the nucleus accumbens and the posterior olfactory nuclei, chronic treatment with OXT significantly inhibited the high potassium-induced stimulated in vitro release of dopamine in these brain structures (Fig. 2). The basal (low potassium-induced) release of dopamine, on the other hand, was not affected by the same treatment schedule. OXT also interferes with the effect of apomorphine on locomotor activity and modulates the development of receptor supersensitivity following haloperidol treatment (Kova´cs et al., 1986b). These and other findings support the idea that the effect of OXT on narcotic addiction is — at least partly — mediated by dopamine receptors in the basal forebrain.

OXYTOCIN AND COCAINE ABUSE Cocaine is a psychostimulant, which acts primarily through the brain dopaminergic system as an inhibitor of the dopamine transporter, thus resulting in an increase in synaptic dopamine content (Galloway, 1988; Koob et al., 1997). Locomotor hyperactivity, exploratory hyperactivity and stereotyped behavior were investigated as acute behavioral responses to cocaine. Two types of behavioral adaptation to repeated cocaine administration, sensitization and tolerance were chosen to study the interactions of OXT with chronic cocaine exposure. Intracerebroventricular and local intracerebral microinjections of OXT and OXT receptor antagonists were utilized to localize the site/s of action of OXT on cocaine-induced behavioral responses and adaptations. The roles of nigrostriatal and mesolimbic dopaminergic neurotransmission in the mediation of the effects of OXT were studied by neurochemical means. Acute Effects of Cocaine: Locomotor Hyperacti6ity and Stereotyped Beha6ior Locomotor hyperactivity elicited by psychostimulants has been considered to develop through the mesolimbic dopaminergic system. The nigrostriatal dopamine system, on the

950

G. L. Kova´cs et al.

Fig. 2. The effect of OXT treatment on dopamine release in the mouse forebrain. The release of [3H]dopamine was measured in vitro in brain slices of the basal forebrain. The experiments were carried out with low potassium (4.2 mmol/l, control values are indicated by the lower horizontal dotted area) as well as high potassium (30 mmol/l, control values are indicated by the upper horizontal dotted area) concentrations (Kova´cs et al., 1986b) (the former gives information about the basal, the latter about stimulated release of dopamine). Columns A, B, C: low potassium release groups; columns D, E, F: high potassium release groups. Column A: in vitro OXT treatment. The peptide was added to the incubation medium in a concentration of 1 nmol/l. Column B: acute in vivo OXT treatment (0.2 mg/kg OXT SC). Mice were decapitated 1 h after peptide treatment. Column C: chronic in vivo OXT treatment. The peptide was injected for 8 consecutive days in a dose of 0.2 mg/kg SC mice were decapitated 1 h after the last peptide injection. Column D: identical to group A, but the potassium concentration of the incubation medium was high. Column E: identical to group B, but the concentration of potassium was high. Column F: identical to group C, but the concentration of potassium was high. The y-axis indicates the ratio of the DPM of [3H]dopamine in the supernatant, and that of the pellet fraction of the homogenate prepared from forebrain slices ( + pB.05 vs. group D). High ratio indicates increased in vitro release.

other hand, is widely accepted as the neuronal basis of stereotyped behavior (Johanson and Fischman, 1989). However, the situation may be more complex, since the most typical element of stereotyped behavior induced by moderate doses of cocaine, sniffing behavior, could be equally elicited by the local microinjection of cocaine into the mesolimbic dopamine terminals located in the nucleus accumbens and tuberculum olfactorium, as well as by local intrastriatal administration of the drug (Sarnyai, 1993). Grooming behavior, another component of the cocaine-induced behavioral repertoire, on the other hand, could only be elicited by local cocaine microinjection into the caudate nucleus (Sarnyai, 1993). Cocaine produced a long-lasting (: 120 min) locomotor hyperactivity in a familiar environment (measured by an automated, microprocessor-controlled, six-channel motimeter (Kova´cs et al., 1990)). Different doses of OXT (0.2, 1.0 and 5 mg/animal) were given SC 60 min before cocaine (30 mg/kg) administration. OXT (1.0 and 5 mg) dose dependently decreased the cocaine-induced locomotor hyperactivity during both the first and second hour after cocaine treatment. Cocaine-induced hyperlocomotion was not altered by 0.2 mg of OXT. The effect of cocaine in a stressful environment was studied by measuring novel environment-induced exploratory hyperactivity in mice (Sarnyai et al., 1990). Animals were tested in an unfamiliar open-field apparatus. Exposure to the novel environment resulted in an exploratory hyperactivity characterized by increased locomotion interrupted by rearing/sniffing episodes. Cocaine administration (7.5 mg/kg) 10 min prior to exposure to the novel open-field situation produced a 3-fold increase in crossing behavior. Pretreat-

Oxytocin and Addiction

951

ment with graded doses of OXT (0.005–5.0 mg) attenuated the cocaine-induced exploratory hyperactivity with a U-shaped dose-response relationship, an effect rather typical for neuropeptides. OXT was found to be ineffective in altering the behavior of cocaine-naive (saline-treated) control animals in both paradigms. A higher dose of cocaine (15 mg/kg) produced a long lasting, characteristic stereotyped behavioral pattern dominated by sniffing behavior. Peripheral pretreatment with OXT (0.05, 0.5 and 5.0 mg/animal; SC), resulted in a dose-dependent decrease in cocaine-induced stereotyped behavior (Fig. 4(A)) (Sarnyai et al., 1991). Grooming behavior, which was not a prominent behavioral pattern after this dose of cocaine (15 mg/kg), remained unchanged by OXT. It is interesting to note that two neuropeptides structurally related to OXT, arginine-vasopressin and lysine-vasopressin, failed to alter this behavioral response. Chronic Effects of Cocaine: Tolerance and Sensitization Chronic cocaine administration could lead to either tolerance or sensitization, depending on the dose and route of administration, treatment schedule or environmental effects (Hammer et al., 1997; Johanson and Fischman, 1989). The effects of OXT on the development of both tolerance and sensitization to cocaine have been studied in rats and mice (Sarnyai et al., 1992a,b). Repeated administration of cocaine (7.5 mg/kg, 2× a day, for 4 days) produced a behavioral tolerance to the sniffing-inducing effects of cocaine (Sarnyai et al., 1992a) (Fig. 3). This was indicated by a parallel shift to the right of dose – response and time – effect curves of the test doses (1.875, 3.25 and 7.5 mg/kg) injected on the fifth day of chronic cocaine administration (Fig. 3(A)). The relative potency of cocaine to induce sniffing was 6.42× greater in the cocaine-tolerant than in cocainenaive rats, therefore a 6.42× larger dose was required to produce the same effect in cocaine-tolerant rats as in cocaine-naive control animals. The development of tolerance was inhibited by pretreatment with OXT (0.05 mg but not 0.005 mg, SC, and administered 60 min before each daily injection of cocaine). OXT pretreatment in these cocaine-tolerant rats shifted the dose-response curve of a test dose of cocaine back to the level of the non-tolerant control rats. The relative potency of cocaine between the OXT-pretreated cocaine-tolerant versus the peptide-naive cocaine-tolerant groups was 5.3. This effect can be interpreted as an inhibition of the development of tolerance to cocaine. Subchronic administration of cocaine (7.5 mg/kg, SC, and 2 × a day for 5 days) induced behavioral sensitization (gradually increasing hypermotility to a challenge dose of cocaine) (Sarnyai et al., 1992b). It was investigated whether repeated administration of OXT would affect cocaine sensitization. Different doses of OXT (0.005, 0.05 and 0.5 mg/animal) were injected 60 min prior to daily cocaine administration, except on the test day. A higher dose of OXT (0.5 mg) significantly facilitated the development of cocaine-induced behavioral sensitization. Interestingly, arginine-vasopressin (0.005, 0.05 and 0.5 mg) pretreatment inhibited the development of sensitization to cocaine in the same paradigm. Site of Action of OXT: Brain Versus Periphery Inhibitory effects of peripherally administered OXT on acute and chronic behavioral actions of cocaine have been demonstrated. One of the major concerns interpreting the CNS effects of peripherally administered neuropeptides is that peptide molecules do not readily penetrate the blood – brain barrier making difficult to reach a brain target for their actions. Three different approaches were applied to study the site(s) of action of OXT.

952

G. L. Kova´cs et al.

Central Pretreatment with a Specific Oxytocin-receptor Antagonist Followed by Peripheral Oxytocin Administration. If target sites of OXT’s actions are in the brain, an ICV administered OXT antagonist should inhibit the effects of peripheral OXT treatment. It has been hypothesized that a minor amount of subcutaneously (SC) injected peptide (or behaviorally active fragments thereof that can interact with cerebral OXT binding sites) can pass the blood – brain barrier and reach brain target sites. To test this hypothesis, a strategy of central OXT-antagonist/peripheral OXT has been utilized. Cocaine-induced sniffing behavior (Sarnyai et al., 1991) was selected as a test model. N-a-(2-O-methylparatyrosine)-OXT, an OXT-receptor antagonist, was administered ICV at a dose of 50 pg, 15 min prior to SC OXT injection. OXT was administered SC 60 min before acute cocaine injection. The development of cocaine-induced sniffing behavior was inhibited by peripheral pretreatment with OXT in a dose of 0.5 mg. ICV administration of the OXT-receptor antagonist (50 pg) completely abolished the effect of peripherally injected

Fig. 3. Role of hippocampal OXT in cocaine tolerance. (A) Tolerance to sniffing-inducing effect of cocaine and its reversal by SC OXT (0.05 mg/rat) administration; (B) decreased hippocampal OXT content in cocaine-tolerant (TOL) rats; (C) tolerance to sniffing-inducing effect of cocaine and its reversal by intrahippocampal OXT (100 pg/rat) administration. c pB .05 versus CTR (non-tolerant); * p B.05 versus TOL (7.5 mg/kg of cocaine, SC, 2× a day, for 4 days) (Sarnyai et al., 1992a).

Oxytocin and Addiction

953

Fig. 4. Peripheral (A) and central (B) OXT administration attenuate the cocaine-induced stereotyped sniffing behavior in rats. cocaine: 15 mg/kg of cocaine, SC; saline: 0.9% NaCl; * pB .05 versus cocaine-treated animals (Sarnyai et al., 1991).

OXT in this paradigm. This result could be explained by assuming that a minor, but sufficient amount of OXT (or one of its active fragments) administered peripherally might have passed the blood – brain barrier and acted on central nervous system target sites. The OXT-receptor antagonist used in these studies was tested on mammary gland myoepithelial tissue to demonstrate its antagonistic property (Krejci et al., 1973a,b). The same OXT-receptor antagonist injected into the nucleus accumbens potently blocked the effect of ICV administered OXT on novelty-induced grooming behavior (Drago et al., 1991). Caldwell et al. (1986) showed that a structurally different OXT antagonist (having activity on peripheral OXT receptors of the myoepithelial cells), administered into the lateral ventricle, altered novelty-induced grooming behavior modulated by OXT. These data support the hypothesis that central and peripheral OXT receptors may have structural– functional similarities. Intracerebro6entricular Administration of Minute Amounts of Oxytocin. If a very small amount of OXT, which is ineffective when administered to the periphery, were able to act on drug-induced processes after central (ICV) injection, this would suggest that the site of action of OXT be in the brain. Peripheral administration of 0.5 and 5.0 mg OXT effectively attenuated cocaine-induced stereotyped behavior. Lateral ventricular injection of graded doses of OXT (1 – 100 ng) caused a dose-related attenuation in cocaine-induced sniffing (Sarnyai et al., 1991). The effective ICV doses of OXT (10 and 50 ng) were approximately one tenth of the effective peripheral doses (Fig. 4(B)). Local Administration of OXT in a Physiological Dose Range. To investigate brain target sites of OXT’s action on cocaine-induced stereotyped sniffing behavior, OXT was microinjected into basal forebrain regions (nucleus accumbens, tuberculum olfactorium and nucleus olfactorius) and into the caudate nucleus; these brain regions have been implicated in the mediation of sniffing behavior in rats (Sarnyai et al., 1991). The microinjection of OXT (100 pg, 60 min prior to cocaine administration) into the nucleus accumbens resulted in a more than 50% decrease in cocaine-induced sniffing behavior. Cocaine-induced

954

G. L. Kova´cs et al.

sniffing also was significantly attenuated by OXT microinjection into the olfactory tubercle. The dose of OXT used for the local microinjection was 102 × lower than the lowest effective dose injected ICV. In contrast to the active brain sites, microinjections of OXT into some other — occasionally adjacent—brain areas, such as the olfactory nucleus, central amygdaloid nucleus, or caudate nucleus did not alter cocaine-induced stereotyped behavior. The nucleus accumbens and the olfactory tubercle are the site of the termination of the mesolimbic dopaminergic projections (Lindvall and Bjo¨rklund, 1978). The mesolimbic dopaminergic terminals in the nucleus accumbens also are critically involved in cocaine-related behavioral processes (Koob, 1992; Koob and Bloom, 1988). Dopamine-receptors in the tuberculum olfactorium are thought to be responsible for the manifestation of sniffing behavior induced by dopaminergic drugs (Madras, 1984). These data strongly suggest that OXT receptors located in basal forebrain areas mediate the effect of OXT on cocaine-induced stereotyped behavior. Behavioral tolerance to chronic cocaine administration was inhibited by low doses of OXT injected SC Furthermore, chronic cocaine administration resulted in a decrease in immunoreactive OXT content (Fig. 3(B)) in the hippocampus (Sarnyai et al., 1992a). To study the target site of exogenous OXT and the role of hippocampal (endogenous) OXT in the development of cocaine tolerance, OXT was administered into the ventral hippocampus (Fig. 3(C)) (Sarnyai et al., 1992b). Sniffing activity, induced by a test dose of cocaine, was gradually decreased by repeated cocaine treatments, demonstrating the development of behavioral tolerance to cocaine (Fig. 3(A)). Intrahippocampal administration of 100 pg of OXT — given 60 min before each tolerance-inducing cocaine injection— almost completely prevented the development of cocaine tolerance (Fig. 3(C)). This conclusion also is supported by the finding that a test dose of cocaine on the OXT treated cocaine-tolerant animals elicited the same sniffing activity as in saline-treated, non-tolerant controls. On the other hand, chronic intrahippocampal OXT treatment did not alter the sniffing activity induced by a single test dose of cocaine. These data showed that the ventral hippocampus plays a critical role in both the mediation of the effect of OXT and the regulation of adaptive CNS processes related to cocaine tolerance. In conclusion, basal forebrain and limbic structures, such as the olfactory tubercle, nucleus accumbens and the hippocampus are important in the mediation of the effects of OXT on psychostimulant-induced adaptive behavioral changes. Cocaine and Brain Oxytocin Content. In order to determine the adaptive changes of the endogenous brain OXT to cocaine challenge, it is of interest to study the effects of acute and chronic cocaine administration on the levels of OXT in different brain regions. Acute administration of behaviorally effective doses of cocaine (7.5–30 mg/kg) increased the levels of OXT in the hypothalamus and in the hippocampus in rats. On the contrary, OXT levels were decreased in the basal forebrain regions in response to acute cocaine treatment. No change was found in the amygdala (Sarnyai et al., 1992c). The data on the increased hypothalamic OXT level in response to acute cocaine administration is also supported by the in vitro results of Sim and Morris (1992). These authors demonstrated that cocaine and dopamine increased the c-fos activity of OXT cells from a neonatal paraventricular nucleus cell culture. Chronic cocaine administration (7.5 mg/kg, 2× a day, for 4 days), a treatment schedule that can produce behavioral tolerance in rats (Sarnyai et al., 1992a), resulted in a significant decrease in OXT levels in the peripheral blood and in the hypothalamus, indicating an OXT depletion in the hypothalamo–neurohypophyseal system. OXT also was depleted from the hippocampus by chronic cocaine administration

Oxytocin and Addiction

955

(Fig. 3(B)). OXT contents in the basal forebrain and in the amygdala were not different from control values after chronic cocaine administration. These data suggest the plasticity of brain OXT systems in response to cocaine. Furthermore, the decreased OXT levels in the hippocampus in cocaine-tolerant animals together with the inhibitory effects of intrahippocampal OXT injection on cocaine tolerance might indicate a functional role of hippocampal OXT in the regulation of adaptive behavioral processes in response to repeated cocaine administration. Mechanisms of Action: Oxytocin, Cocaine and Dopaminergic Neurotransmission. Dopaminergic neurotransmission in the brain has been considered as a major target system for cocaine. Reinforcing and psychostimulant actions of cocaine are mainly mediated through the mesolimbic dopaminergic system (Koob, 1992; Kuhar et al., 1991). Two characteristic acute effects of cocaine, the locomotor hyperactivity and the stereotyped sniffing behavior, were both inhibited by OXT administration (Kova´cs et al., 1990; Sarnyai et al., 1990, 1991). Locomotor activation by cocaine is mediated through the mesolimbic dopamine structures (nucleus accumbens), but both the nigrostriatal (caudate nucleus) and the mesolimbic (nucleus accumbens and tuberculum olfactorium) structures are responsible for cocaine-induced sniffing (Sarnyai, 1993). Cocaine administration facilitated a-MPT-induced dopamine disappearance in both the nucleus accumbens and the striatum (Kova´cs et al., 1990; Sarnyai et al., 1990). SC administration of OXT, in a dose which effectively antagonized the behavioral effects of cocaine, inhibited the effect of cocaine on dopamine utilization in nucleus accumbens, but not in the striatum (Kova´cs et al., 1990; Sarnyai et al., 1990). Interestingly, although cocaine microinjection (15 and 30 mg) into the nucleus accumbens, tuberculum olfactorium as well as into the caudate nucleus elicited the stereotyped sniffing behavior (Sarnyai, 1993), OXT inhibited this effect of cocaine when it was microinjected into the nucleus accumbens and tuberculum olfactorium, but not into the caudate nucleus (Sarnyai et al., 1991). One possible explanation of the lack of effect of OXT in caudate nucleus might be the relatively low density of OXT binding sites in this structure. This surprisingly close correlation between behavioral and neurochemical data suggest that the mesolimbic dopamine system pays a role in the mediation of the effects of OXT on the acute behavioral actions of cocaine. Chronic cocaine administration produced behavioral symptoms such as tolerance or sensitization. Changes of dopamine neurotransmission as a possible neurochemical basis of chronic cocaine abuse have been extensively studied (Johanson and Fischman, 1989). Chronic inhibitory effects of OXT on dopamine utilization, release and on postsynaptic dopamine receptors in the basal forebrain structures might explain the inhibitory and stimulatory effects of OXT on cocaine tolerance and sensitization, respectively.

OYTOCIN AND ETHANOL ADDICTION Oxytocin and Ethanol Tolerance In the CNS, ethanol tolerance appears to be a combined process with both behavioral and cellular components. Tolerance to ethanol has been shown to involve learning. Some forms of tolerance are dependent on learning. The animals display tolerance only in the environment where ethanol was initially presented and not in a novel environment.

956

G. L. Kova´cs et al.

Development of rapid tolerance to the hypothermic effect of ethanol has been proposed as a reliable model for investigating the above phenomenon. Peripheral administration of OXT (1.5 – 6.0 mg/animal) prevented the development (Fig. 5) of tolerance to ethanol in mice (Szabo´ et al., 1985, 1987b). Central administration of OXT was found to be at least 500 × more potent than peripheral injection at blocking the development of rapid tolerance to ethanol (Szabo´ et al., 1989), which lends support to the theory that OXT acts on CNS mechanisms to influence adaptive responses to drugs. Using other techniques, where ethanol was presented covertly and continuously as a liquid diet or by using inhalation chambers, tolerance developed independent of environmental clues. OXT given peripherally at a high dose (10 mg/animal) either during the induction or dissipation of tolerance was without effect (Hoffman et al., 1978). The Role of Brain Monoamines in Mediating the Effect of Oxytocin on the De6elopment of Rapid Tolerance to Ethanol Central administration of OXT in doses which inhibit the development of rapid tolerance to ethanol increased norepinephrine levels in the hypothalamus, dopamine levels in the striatum and medulla oblongata, and serotonin levels in the hippocampus and striatum (Szabo´ et al., 1988). From measuring steady-state levels of monoamines in the CNS one cannot draw conclusion regarding the effects of OXT on synaptic events (e.g. changes in transmitter uptake release, turnover and/or metabolism). The results, however, can be used as a correlative measure for demonstrating the effect of OXT on neurotransmission as the animals were subjected to biochemical investigation at the conclusion of the behavioral observations. The mechanism of ethanol’s action on CNS neurotransmission is unclear. It appears that primarily serotonergic and dopaminergic neurotransmissions are altered during the inhibition of tolerance development by OXT (Szabo´ et al., 1988).

Fig. 5. Effect of OXT on ethanol-induced hypothermia. Mice were injected with OXT 2 h before injection of ethanol. Rectal temperature was monitored 45 min after ethanol administration. Values represent mean 9SEM for 10–19 animals per group.

Oxytocin and Addiction

957

Table I. Effects of OXT on addiction Effects of OXT on addiction

Route of administration

Dose of OXT (mg/kg)

Reference

Morphine tolerance Morphine tolerance Morphine tolerance

SC ICV IC

100–101 10−3–10−1 10−5

Kova´cs et al. (1981) Kova´cs et al. (1981) Ibragimov et al. (1987) Kova´cs et al. (1987) Sarnyai et al. (1988)

Morphine withdrawal Morphine withdrawal Morphine tolerance

SC

100–101

Kova´cs et al. (1981)

ICV

10−2–100

Kova´cs et al. (1981)

IC

10−5

Kova´cs et al. (1987) Sarnyai et al. (1988)

b-Endorphin tolerance

SC

10−3–10−1

Kova´cs and Telegdy (1987a)

SC Heroin self-administration Heroin self-administra- IC tion

10−3–10−2

Kova´cs and Van Ree (1985)

10−5

Ibragimov et al. (1987)

Ethanol tolerance Ethanol tolerance

SC ICV

100–101 10−5–10−4

Szabo´ et al. (1985, 1987a,b) Szabo´ et al. (1989)

Cocaine sensitization Cocaine sensitization

SC

10−2–10−1

Sarnyai et al. (1991)

ICV

10−4–10−3

Sarnyai et al. (1991)

Effect of Oxytocin on Ethanol Withdrawal Symptoms During ethanol withdrawal, OXT-treated mice displayed milder withdrawal convulsions. This effect is increased in response to increasing doses of the peptide (0.6–6 mg/animal SC) and the rate of lethality also were decreased (Szabo´ et al., 1987a). At a lower dose of OXT (0.06 mg/animal) the animals displayed severe withdrawal signs and increase in mortality.

CONCLUSIONS Recent results from our laboratories (Kova´cs, 1986; Sarnyai and Kova´cs 1994), and other laboratories (Krivoy et al., 1974; Van Ree, 1983; Van Ree and De Wied, 1977a,b) suggest that neurohypophyseal neuropeptides modulate the response to drugs of abuse. In the case of OXT, adaptive components of drug addiction are affected primarily: the neuropeptide inhibits the development of tolerance to, and physical dependence on, morphine and reduces the self-administration of another frequently abused opiate drug, heroin. Development of ethanol tolerance and that of cocaine sensitization also is inhibited by OXT treatment.

958

G. L. Kova´cs et al.

Fig. 6. Effects of OXT on opiate, cocaine and ethanol addiction: a summary OXT may modulate adaptive CNS processes related to opiates, cocaine and ethanol through an interconnected neural circuit, which contains the hypothalamus, ventral hippocampus and ventral striatum.

Peripheral injections of OXT were considerably less potent than ICV or local intracerebral administration of the peptide (Table I), suggesting that the primary site of action of the neuropeptide was in the CNS. It is somewhat striking that peripheral injections of the neuropeptide were not completely ineffective, since the blood–brain barrier is largely impermeable to neurohypophyseal peptides. However, peripheral injections with OXT may also increase the OXT content in the cerebrospinal fluid (Mens, 1982) in drug-naive rats. It has been suggested, that 1% of OXT or OXT-antagonists may pass the blood–brain barrier following peripheral injections (Kastin et al., 1976). In addicted animals, however, the permeability of the blood-brain barrier may also be damaged (Lange et al., 1983), leading to an increased leakage of the peptide from the blood stream to the cerebrospinal fluid. It cannot be ruled out either that peripheral OXT treatment modulates the release of central OXT by nervous or humoral mechanisms. Opiates, cocaine and alcohol act on the CNS through different mechanisms (Lowinson et al., 1992). These differences in neuroanatomical, biochemical, neurochemical and molecular mechanisms are particularly significant between stimulant and depressant drugs. And yet, the neuropeptide OXT inhibits adaptive CNS processes in response to all of these addictive drugs. Since oxytocinergic neuronal transmission and CNS OXT receptors are supposedly involved in these effects, one can hypothesize that central nervous oxytocinergic neurons — primarily those located in basal forebrain and limbic structures—are integral elements of the adaptive response of the brain to addictive drugs. The adaptive response of the CNS to repeated administration of addictive drugs leads to drug tolerance, physical and psychological dependence. Activation of brain oxytocinergic neurotransmission under these circumstances may represent a physiological counterbalance mechanism,

Oxytocin and Addiction

959

which may be of functional significance, especially in early neuronal adaptation, and may prevent the rapid onset of drug tolerance and dependence (Fig. 6). These observations might provide useful insights into the way in which an endogenous neuronal peptide modulates adaptive functions of the CNS by acting through its own receptors and also by modifying the efficacy of a ‘classical’ neuronal transmitter system (e.g. dopamine) in the forebrain. Endogenous neuropeptides following their synthesis and release, similarly to the biological half-life of exogenously administered neuropeptides, are present in the brain and body fluids only for minutes. Their effects on addiction, however, can be detected long after peptide release/administration. Thus neuropeptides set into motion various secondary events in the CNS, that keeps all these changes viable. Further studies may shed light on molecular mechanisms involved in these alterations, i.e. on changes in gene expression involved in mediating adaptive processes of the CNS during drug addiction. Since individual sensitivity of human patients towards addictive drugs largely depends on yet unknown parameters, understanding the role of neuronal peptides in human drug and ethanol addiction would be of outstanding theoretical and practical interest.

REFERENCES Acquas, E. and Di Chiara, G. (1992) Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence. Journal of Neurochemistry 58, 1620 – 1625. Buijs, R. M. (1983) Vasopressin and oxytocin — their role in neurotransmission. Pharmacological Therapy 22, 127–141. Caldwell, J. D., Hruby, V. J., Hill, P., Prange, A. J. and Pedersen, C. A. (1986) Is oxytocin-induced grooming mediated by uterine-like receptors? Neuropeptides 8, 77 – 86. Colbern, D. L., Ritzmann, R. F. and Krivoy, W. (1986) Neurohypophyseal peptides in tolerance and dependence. In: De Wied, D., Gispen, W. H. and Van Wimersma Greidanus, T. J. B. (Eds.). Neuropeptides and Beha6ior, Vol. 2. Pergamon Press, Oxford, pp. 171 – 186. De Kloet, E. R., Rotteveel, F., Vorhouis, T. A. M. and Terlou, M. (1985) Topography of binding sites for neurohypophyseal hormones in rat brain. European Journal of Pharmacology 110, 113–119. Drago, F., Sarnyai, Z. and D’Agata, V. (1991) The inhibition of oxytocin-induced grooming by a specific receptor antagonist. Physiology and Beha6ior 50, 533 – 536. Elands, J. P. M., Barberis, C. and Jard, S. (1988) [3H]-[Thr4,Gly7]OT: a highly selective ligand for central and peripheral OT receptors. American Journal of Physiology 254, 31 – 38. Ferrier, B. M., McClorry, S. A. and Cochrane, A. W. (1983) Specific binding of [3H]oxytocin in female rat brain. Canadian Journal of Physiology and Pharmacology 61, 989 – 995. Galloway, M. P. (1988) Neurochemical interactions of cocaine with dopaminergic systems. Trends in Pharmacological Science 9, 451–454. Hammer, R. P., Egilmez, Y. and Emmett-Oglesby, M.W. (1997) Neural mechanisms of tolerance to the effects of cocaine. Beha6ioral Brain Research 84, 225 – 239. Hoffman, P. L., Ritzmann, R. F., Walter, R. and Tabakoff, B. (1978) Arginine vasopressin maintains ethanol tolerance. Nature 276, 614 – 616. Ho¨kfelt, T. (1991) Neuropeptides in perspectives: the last ten years. Neuron 7, 867 – 879. Ibragimov, R., Kova´cs, G. L., Szabo´, G. and Telegdy, G. (1987) Microinjection of oxytocin into limbic–mesolimbic brain structures disrupts heroin self-administration behavior: a receptor mediated event? Life Sciences 41, 1264 – 1271. Johanson, C. E. and Fischman, M. W. (1989) The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 41, 3–52. Jost, K. and Sorm, F. (1971) The preparation of N-a-acetyl-[2-O-methyltyrosine]-oxytocin, a powerful inhibitor of the uterotonic activity of oxytocin. Collection of Czechoslo6ak Chemical Communications 36, 297.

960

G. L. Kova´cs et al.

Kastin, A. J., Nissen, C., Schally, A. V. and Coy, D. H. (1976) Blood – brain barrier, half-time disappearance, and blood distribution for labeled enkephalin and a potent analog. Life Sciences 32, 295–301. Kira´ly, M., Audigier, S., Tribollet, E., Barberis, C., Dolivo, M. and Dreifuss, J. J. (1986) Biochemical and electrophysiological evidence of functional vasopressin receptors in the rat superior cervical ganglion. Proceedings of the National Academy of Science USA 83, 5335 – 5339. Koob, G. F. (1992) Neural mechanisms of drug reinforcement. Annals of the New York Academy Science 654, 171–191. Koob, G. F. and Bloom, F. E. (1988) Cellular and molecular mechanisms of drug dependence. Science 242, 715–723. Koob, G. F., Caine, S. B., Parsons, L., Markou, A. and Weiss, F. (1997) Opponent process model and psychostimulant addiction. Pharmacology and Biochemical Beha6ior 57, 513 – 521. Kova´cs, G. L. (1986) Oxytocin and behaviour. In: Ganten, D. and Pfaff, D. (Eds.). Current Topics in Neuroendocrinology, Vol. 6. Springer, Berlin, pp. 90 – 128. Kova´cs, G. L., Borthaiser, Z. and Telegdy, G. (1985) Oxytocin reduces intravenous heroin self-administration in heroin-tolerant rats. Life Sciences 37, 17 – 26. Kova´cs, G. L., Faludi, M., Falkay, G. and Telegdy, G. (1986b) Peripheral oxytocin treatment modulates central dopamine transmission in the mouse limbic structures. Neurochemical International 9, 481–485. Kova´cs, G. L., Izbe´ki, F., Horva´th, Z. and Telegdy, G. (1984) Effects of oxytocin and a derivative (Z-prolyl-D-leucine) on morphine tolerance/dependence are mediated by the limbic system. Beha6ioral Brain Research 14, 1–8. Kova´cs, G. L., Sarnyai, Z., Babarczy, E., Szabo´, G. and Telegdy, G. (1990) The role of oxytocin–dopamine interactions in cocaine-induced locomotor hyperactivity. Neuropharmacology 29, 365–368. Kova´cs, G. L., Sarnyai, Z., Izbe´ki, F., Szabo´, G., Telegdy, G., Barth, T., Jost, K. and Brtnik, F. (1987) Effects of oxytocin-related peptides on rapid morphine tolerance: opposite actions by oxytocin and its receptor antagonists. Journal of Pharmacology and Experimental Therapy 241, 569–574. Kova´cs, G. L., Sarnyai, Z., Szabo´, G. and Telegdy, G. (1986a) Development of morphine tolerance is under tonic control of brain oxytocin. Drug and Alcohol Dependence 17, 369 – 375. Kova´cs, G. L., Szonta´gh, L., Bala´spiri, L., Ho´di, K., Bohus, P. and Telegdy, G. (1981) On the mode of action of an oxytocin derivative (Z-Pro-D-Leu) on morphine dependence in mice. Neuropharmacology 20, 647–651. Kova´cs, G. L. and Telegdy, G. (1983) Effects of oxytocin, desglycinamide-oxytocin and anti-oxytocin serum on the a-MPT-induced disappearance of catecholamines in the rat brain. Brain Research 268, 307–314. Kova´cs, G. L. and Telegdy, G. (1985) Role of oxytocin in memory, amnesia and reinforcement. In: Amico, J. A. and Robinson, A. G. (Eds.). Oxytocin Clinical and Laboratory Studies. Elsevier, Amsterdam, pp. 359–371. Kova´cs, G. L. and Telegdy, G. (1987a) Endorphin tolerance is inhibited by oxytocin. Pharmacology and Biochemical Beha6ior 26, 57 – 60. Kova´cs, G. L. and Telegdy, G. (1987b) Neurohypophyseal peptides, motivated and drug-induced behaviour. Frontiers in Hormone Research 15, 138 – 174. Kova´cs, G. L. and Van Ree, J. M. (1985) Behaviourally active oxytocin fragments simultaneously attenuate heroin self-administration and tolerance in rats. Life Sciences 37, 1895 – 1900. Kow, L. M. and Pfaff, D. W. (1988) Neuromodulatory actions of peptides. Annual Re6iews in Pharmacology and Toxicology 28, 163 – 188. Krejci, I., Kupkova´, B. and Barth, T. (1973a) N-a-acetyl-(2-O-methyltyrosine)-oxytocin: a specific antagonist of oxytocin. Acta Physiologia Bohemoslo6enica 22, 315 – 322. Krejci, I., Kupkova, B., Barth, T. and Jost, K. (1973b) N-acetyl-2-O-methyl-tyrosine-oxytocin: a specific antagonist of oxytocin. Physiologia Bohemoslo6enica 22, 315 – 322. Krivoy, W. A., Zimmermann, E. and Lande, S. (1974) Facilitation of development of resistance to morphine analgesia by desglycinamide9-lysine vasopressin. Proceedings of the National Academy of Science USA 71, 1852–1856.

Oxytocin and Addiction

961

Kuhar, M. J., Ritz, M. C. and Boja, J. W. (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends in Neuroscience 14, 299 – 302. Lange, D. G., Roerig, S. C., Fujimoto, J. M. and Busse, L. W. (1983) Withdrawal tolerance and unidirectional non-cross-tolerance in narcotic pellet-implanted mice. Journal of Pharmacology and Experimental Therapy 224, 13–20. Lindvall, O. and Bjo¨rklund, A. (1978) Organization of catecholamine neurones in the rat central nervous system. In: Iversen, L. L., Iversen, S. D. and Snyder, S. H. (Eds.). Handbook of Psychopharmacology, Vol. 9. Plenum Press, New York, pp. 130 – 231. Lowinson, J. H., Ruiz, P., Millman, R. B. and Langrod, J. G. (1992) Substance Abuse. A Comprehensi6e Textbook. Williams and Wilkins, Baltimore. Madras, B. K. (1984) Dopamine. In: Lajtha, A. (Ed.). Receptors in the Central Ner6ous System Handbook of Neurochemistry, Vol. 6. Plenum Press, New York, pp. 71 – 103. Mens, W. B. J. (1982) Neurohypophyseal hormones in blood, cerebrospinal fluid and brain of the rat. Ph.D. thesis. University of Utrecht. Redmond, D. E. and Krystal, J. H. (1984) Multiple mechanisms of withdrawal from opioid drugs. Annual Re6iews in Neuroscience 7, 443 – 478. Sarnyai, Z. (1993) Measurement of cocaine-induced stereotyped behavior in response to neuropeptides. In: Conn, P. M. (Ed.). Methods in Neurosciences Paradigms for the Study of Beha6ior, Vol. 14. Academic Press, San Diego, CA, pp. 153 – 165. Sarnyai, Z., Babarczy, E., Kriva´n, M., Szabo´, G., Kova´cs, G. L., Barth, T. and Telegdy, G. (1991) Selective attenuation of cocaine-induced stereotyped behaviour by oxytocin: putative role of basal forebrain target sites. Neuropeptides 19, 51 – 56. Sarnyai, Z., Bı´ro´, E´., Babarczy, E., Vecsernye´s, M., Laczi, F., Szabo´, G., Kriva´n, M., Kova´cs, G. L. and Telegdy, G. (1992a) Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats. Neuropharmacology 31, 593 – 598. Sarnyai, Z. and Kova´cs, G. L. (1994) Role of oxytocin in the neuroadaptation to drugs of abuse. Psychoneuroendocrinology 19, 85– 117. Sarnyai, Z., Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1990) Oxytocin attenuates the cocaine-induced exploratory hyperactivity in mice. NeuroReport 1, 200 – 202. Sarnyai, Z., Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1992b) Opposite actions of oxytocin and vasopressin in the development of cocaine-induced behavioral sensitization in mice. Pharmacology and Biochemical Beha6ior 43, 491 – 494. Sarnyai, Z., Vecsernye´s, M., Laczi, F., Bı´ro´, E´., Szabo´, G. and Kova´cs, G. L. (1992c) Effects of cocaine on the contents of neurohypophyseal hormones in the plasma and in different brain structures in rats. Neuropeptides 23, 27 – 31. Sarnyai, Z., Viski, S., Kriva´n, M., Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1988) Endogenous oxytocin inhibits morphine tolerance through limbic forebrain receptors. Brain Research 463, 284–288. Sawchenko, P. E. and Swanson, L. W. (1985) Relationship of oxytocin pathways to the control of neuroendocrine and autonomic functions. In: Amico, J. A. and Robinson, A. G. (Eds.). Oxytocin Clinical and Laboratory Studies. Elsevier, Amsterdam, pp. 87 – 104. Shewey, L. M. and Dorsa, D. M. (1988) V1-type vasopressin receptors in rat brain septum: binding characteristics and effects on inositol phospholipid metabolism. Journal of Neuroscience 8, 1671–1677. Sim, L. J. and Morris, M. (1992) Activation of c-fos in PVN oxytocin neurons exposed to cocaine and dopamine. Society for Neuroscience Abstracts 18, 346. Szabo´, G., Kova´cs, G. L., Sze´keli, S. and Telegdy, G. (1985) The effects of neurohypophyseal hormones on tolerance to the hypothermic effect of ethanol. Alcohol 2, 567 – 674. Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1987a) Effects of neurohypophyseal peptide hormones on alcohol dependence and withdrawal. Alcohol and Alcoholism 22, 71 – 74. Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1987b) Nurohypophyseal peptides and ethanol tolerance and dependence. Frontiers in Hormone Research 15, 128 – 137. Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1988) Brain monoamines are involved in mediating the action of neurohypophyseal peptide hormones on ethanol tolerance. Acta Physiologia Hungaricae 71, 459–466.

962

G. L. Kova´cs et al.

Szabo´, G., Kova´cs, G. L. and Telegdy, G. (1989) Intraventricular administration of neurohypophyseal hormones interferes with the development of tolerance to ethanol. Acta Physiologia Hungaricae 73, 97–103. Tribollet, E., Barberis, C., Jard, S., Dubois-Dauphin, M. and Dreifuss, J. J. (1988) Localization and pharmacological characterization of high affinity binding sites for vasopressin and oxytocin in the rat brain by light microscopic autoradiography. Brain Research 442, 105 – 118. Van Heuven-Nolsen, D., De Kloet, E. R. and Versteeg, D. H. G. (1984) Oxytocin affects noradrenaline utilization in distinct limbic-forebrain regions of the rat brain. Neuropharmacology 23, 1373–1377. Van Ree, J. M. (1983) Neuropeptides and addictive behavior. Alcohol and Alcoholism 18, 325 – 330. Van Ree, J. M. and De Wied, D. (1977a) Heroin self-administration is under control of vasopressin. Life Sciences 21, 315–320. Van Ree, J. M. and De Wied, D. (1977b) Effect of neurohypophyseal hormones on morphine dependence. Psychoneuroendocrinology 2, 35 – 41. Versteeg, D. H. G. (1983) Neurohypophyseal hormones and brain neurochemistry. Pharmacological Therapy 19, 297–325.

. .