Gyula Szabó

OXYTOCIN AND ADDICTION: A REVIEW

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.

Decreased serotonin turnover in the dorsal hippocampus of rat brain shortly after adrenalectomy : Selective normalization after corticosterone substitution

Pargyline-induced accumulation of serotonin (5-HT) was used as an index of 5-HT turnover rate in the dorsal hippocampus. One hour after bilateral removal of the adrenals, 5-HT turnover was significantly reduced when compared to that of the sham-operated controls. A low dose of corticosterone given immediately after adrenalectomy restored the 5-HT response, while the same dose of dexamethasone was ineffective. Pretreatment with dexamethasone blocked the 5-HT response to corticosterone in the acutely adrenalectomized rat. The specificity of the 5-HT response in the hippocampus corresponds to the properties of the glucocorticoid receptor system in rat hippocampal neurons.

Effect of an imidazobenzodiazepine, Ro15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital

The imidazobenzodiazepine, Ro15-4513, which is a partial inverse agonist at brain benzodiazepine receptors, reversed the incoordinating effect of ethanol in mice, as measured on an accelerating Rotarod. This effect was blocked by benzodiazepine receptor antagonists. In contrast, Ro15-4513 had no effect on ethanol-induced hypothermia in mice. However, Ro15-4513 reversed the hypothermic effect of pentobarbital, and, at a higher dose, also reversed the incoordinating effect of pentobarbital in mice. The data support the hypothesis that certain of the pharmacological effects of ethanol are mediated by actions at the GABA-benzodiazepine receptor-coupled chloride channel.

The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity

Cocaine is a widely used drug of abuse. One of the characteristic effects of this stimulant drug in the CNS of mice is the induction of motor hyperactivity. It was demonstrated that cocaine-induced motor hyperactivity could be blocked by pimozide, a dopamine receptor blocker, suggesting that dopamine was involved in cocaine-induced hyperactivity. Oxytocin, a neurohypophyseal neuropeptide, also partially antagonized cocaine-induced motor hyperactivity. Moreover, oxytocin antagonized the increased utilization of dopamine, elicited by cocaine in the nucleus accumbens. The data suggest that oxytocin may influence the behavioural effects of cocaine by affecting dopaminergic neurotransmission in some regions of the brain.

Effects of cholecystokinin octapeptide on striatal dopamine metabolism and on apomorphine-induced stereotyped cage-climbing in mice

The effects of sulfated (CCK-8-SE) and non-sulfated (CCK-8-NS) cholecystokinin octapeptide on striatal dopamine (DA) metabolism have been investigated on mice. CCK-8-NS facilitated the disappearance of striatal DA, measured after synthesis inhibition with 350 mg/kg of alpha-methyl-p-tyrosine. CCK-8-SE did not affect DA disappearance. In vitro uptake of [3H]DA by striatal slices was affected by neither CCK-8-SE, nor CCK-8-NS (10(-5) M). Potassium-induced in vitro release of [3H]DA from striatal slices was significantly increased by 10(-5) M CCK-8-NS: however, CCK-8-SE likewise increased DA release in this model system. Apomorphine-induced (1.0 mg/kg) stereotyped cage-climbing behavior was not affected by CCK-8-SE but was enhanced by CCK-8-NS. This effect could be antagonized by haloperidol, but not by naloxone. The data suggest that CCK-8-NS affects striatal DA release, disappearance and receptor sensitivity in the mouse. Dopaminergic mechanisms should therefore be regarded as a possible mode of action of CCK-8-NS on brain functions.

SELECTIVE ATTENUATION OF COCAINE-INDUCED STEREOTYPED BEHAVIOUR BY OXYTOCIN: PUTATIVE ROLE OF BASAL FOREBRAIN TARGET SITES

The effects of oxytocin (OXT), arginine- and lysine-vasopressin (AVP and LVP) and an OXT-receptor antagonist on cocaine-induced sniffing behaviour were investigated in rats. OXT, but not AVP or LVP injected subcutaneously (s.c.) attenuated cocaine-induced sniffing. The effect of OXT (s.c.) was inhibited by an OXT-receptor antagonist administered intracerebroventricularly (i.c.v.). I.c.v. administration of different doses of OXT in nanogram quantities caused a dose-dependent attenuation of cocaine-induced sniffing. Local cerebral microinjection of OXT into the accumbens nucleus and olfactory tubercle but not into the olfactory nucleus, central amygdaloid nucleus or caudate nucleus, inhibited the cocaine-induced sniffing behaviour. These results demonstrate that OXT selectively attenuates the cocaine-induced stereotyped behaviour through basal forebrain target sites.

Effects of cocaine on the contents of neurohypophyseal hormones in the plasma and in different brain structures in rats

The effects of acute and chronic cocaine treatments on the levels of the neurohypophyseal hormones oxytocin (OXT) and vasopressin (AVP) in the plasma and in different brain structures in rats were measured by radioimmunoassay (RIA). Acute cocaine treatment had no effect on the level of OXT in the plasma or in the amygdala, but increased OXT contents were measured in the hypothalamus and in the hippocampus. The OXT levels in the basal forebrain structures (including the septum and the nucleus accumbens) were decreased by a single dose of cocaine. The acute injection of cocaine increased the level of AVP in the plasma, and decreased contents of OXT were measured in the amygdala and in the basal forebrain. Repeated treatment with cocaine decreased the level of OXT in the plasma, hypothalamus and hippocampus. The AVP contents were decreased in all of the brain structures investigated, but no change was caused in the plasma level of AVP by repeated injections of cocaine. These results demonstrate complex, region-specific interactions between cocaine and the neurohypophyseal hormones in the brain and in the periphery underlying the alteration in behavioral and autonomic functions caused by acute and chronic cocaine exposure.

The involvement of catecholaminergic mechanisms in the behavioural action of vasopressin

The effect of lysine-8-vasopressin (300 mU/kg b.w.) has been tested in a single-trial step-down passive avoidance test. Vasopressin treatment resulted in an improvement of step-down latency in normal rats, but this action disappeared when the animals were pretreated with 80 mg/kg alpha-methyl-p-tyrosine (alpha-MT). Vasopressin treatment decreased the hypothalamic, septal and striatal dopamine (DA) levels. Following vasopressin, the turnover of norepinephrine (NE) increased in the hypothalamus, as did these of DA in the septum and striatum. The data suggest that the cerebral catecholaminergic system might be one of the important mediators of the behavioural action of vasopressin.

Role of endogenous corticotropin- releasing factor in mediation of neuroendocrine and behavioral responses to cholecystokinin octapeptide sulfate ester in rats

The possible involvement of endogenous corticotropin-releasing factor (CRF) in the anxiogenic and pituitary-adrenal-axis-activating effects of cholecystokinin octapeptide sulfate ester (CCK 8) was investigated in rats. Intracerebroventricularly (i.c.v.) administered CCK 8 induced an anxiogenic response in an elevated plus-maze test, and enhanced the plasma corticosterone level. Pretreatment with different dilutions (1:10, 1:20 and 1:100, i.c.v.) of CRF antiserum and different doses of a CRF receptor antagonist, alpha-helical CRF (ahCRF, 0.001-1.0 microgram, i.c.v.) prevented the anxiogenic response to CCK 8 in a dose-dependent manner. None of the doses of CRF antiserum or ahCRF alone produced any alteration in either the elevated plus-maze paradigm or corticosterone level in saline-treated control rats. The results strongly suggest that the anxiogenic and hypothalamo-pituitary-adrenal-activating effects of CCK 8 are mediated via CRF.

Critical role of endogenous corticotropin-releasing factor (CRF) in the mediation of the behavioral action of cocaine in rats

The role of endogenous CRF in the locomotor hyperactivity induced by cocaine was investigated by using the immunoneutralization of endogenous CRF and an antagonist of CRF-receptors (alpha-helical CRF9-41: alpha h-CRF) in rats. Different dilutions of anti-CRF antibody (1:5, 1:20, but not 1:100) injected intracerebroventricularly (i.c.v.) 24 hours before the cocaine treatment blocked the expression of locomotor hyperactivity. Pretreatment with different doses (0.001, 0.01, 0.1, 1.0 micrograms i.c.v.) of alpha h-CRF inhibited the locomotor hyperactivity induced by cocaine dose-dependently. Neither the immunoneutralization nor the receptor blockade for CRF changed the hyperactivity induced by another locomotor stimulant caffeine. These results serve as indirect in vivo evidence of the selective role of endogenous CRF in the cocaine-induced behavioral alterations. The findings have implications as concerns the possible role of CRF in human psychopathological changes induced by cocaine.