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gamma-Hydroxybutyric acid (GHB) is a widely used recreational drug known to exert positive reinforcing effects in animals and humans. The GABA(B) receptor agonist baclofen has been proved to possess antimotivational effect and to inhibit alcohol, cocaine, heroin and nicotine intake. In the present study we evaluated the effect of baclofen on i.v. self-administration of GHB in drug-naive mice under a fixed-ratio (FR-1) schedule of reinforcement and nose-poking-like response as operandum. Results show that baclofen was able to completely prevent GHB seeking behaviour, decreasing the rate of responding to basal values, without showing any reinforcing properties when made contingent on nose-poking response. Our findings demonstrate that baclofen antagonises GHB i.v. self-administration, supporting an important role for the GABA(B) receptor in reward-related mechanisms underlying addictive behaviour.

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The Nottingham Prognostic Index (NPI) is an index, derived from a retrospective multivariate study, that is able to predict survival in patients with breast cancer. The index is based on tumour size, lymph node stage and histological grade and allows the stratification of patients into three different prognostic groups. The aim of this study was to verify, according to our experience with a long-term follow-up, the effect of some prognostic variables on survival and to establish the independent influence of each of them by means of a survival regression analysis. Then we applied the NPI to the same group of patients in order to assess the predictive power and reproducibility of the index. 402 patients treated from January 1979 to December 1987 were evaluated. In multivariate analysis (Cox proportional hazard model), only size, lymph node involvement and histological grade remained independent prognostic factors. The survival curves obtained after applying the NPI are similar to those for the factors with independent prognostic significance derived from our multivariate analysis. Our improved survival rates may be attributed to the administration of adjuvant therapies to a larger number of patients. The NPI allow us to accurately predict prognosis and we advocate its more common use.

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Sentinel node biopsy, in breast cancer, is a promising surgical technique for predicting histological findings in the remaining axillary lymph nodes, especially in patients with clinically node-negative breast cancer. 80 patients with breast cancer were evaluated for enrollment in this study. For mapping procedure 32 patients underwent lymphoscintigraphy in combination with an injection of vital blue dye, while 48 utilized only vital dye. In all patients, after sentinel node (SLN) biopsy, a complete axillary dissection was performed. The mapping procedure was possible in 79 cases (98.7%). The SLNs were positive in 27 (34.1%), in 52 patients SLNs were negative and in 50 of these all axillary nodes were negative. There was concordance in 77/79 cases (97.4%). The false negative rate was 3.8% (2/52). The overall sensitivity of the SNL biopsy was 93.1% (27/29), with a negative predictive value of 96.1% (50/52). This study demonstrates that accurate SLN identification was obtained combining lymphoscintigraphy and blue dye. Moreover, each method requires a suitable learning curve. Further studies are needed to define an accurate patient selection and the most speedy and precise method for intraoperative histological examination of SLNs.

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Gamma-hydroxybutyric acid, an endogenous compound present in mammalian brain and supposed to be a neurotransmitter or neuromodulator, has been shown to affect several aspects of dependence from some drugs of abuse. It has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. The aim of this study was to investigate whether gamma-hydroxybutyric acid possesses rewarding properties by means of conditioned place preference and intravenous self-administration paradigms. In the present study, gamma-hydroxybutyric acid induced conditioned place preference in rats, was intravenously self-administered by drug-naive mice, and altered cocaine intravenous self-administration in rats. Although to date the physiological role of this compound still remains unclear, there is no doubt that gamma-hydroxybutyric acid, in addition to its proved effect on alcohol and opiate dependence, possesses reinforcing properties of its own and may interfere with the neurochemical events in the rewarding effects produced by psychostimulant drugs. Our investigation points out the abuse liability of this drug, suggesting the use of particular precaution in handling gamma-hydroxybutyric acid as a clinically useful drug.

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Pica is a pathologic craving for substances not commonly regarded as foods. In this study the authors report their experience about five cases presented with an acute abdomen following foreign bodies ingestion by patients mentally handicapped. Therapeutic treatment was emergency laparatomy with postoperative morbidity of 40% and mortality of 40%. It is hoped that specific drug therapy with more aggressive surgical treatment will reduce the mortality significantly.

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The effect of the CB1 cannabinoid receptor agonist WIN 55,212-2 on intravenous cocaine self-administration (IVSA) in rats was evaluated. Male Long Evans rats were implanted with silastic catheters through the external jugular vein. The IVSA was conducted in 3-h daily sessions with a fixed ratio (FR1) schedule: the experimental apparatus had a nose-poking response-like operandum. Intravenous pre-treatment with WIN 55,212-2 (0.25, 0.5 and 1 mg/kg) to rats self-administering cocaine (0.25 or 0.5 mg/kg/inj) at stable baseline, reduces cocaine intake in a dose-dependent manner. The CB1 receptor antagonist SR 141716A (3 mg/kg i.p.) completely reversed the WIN 55,212-2-induced decrease of cocaine intake. However, pre-treatment of SR 141716A alone (up to dose of 9 mg/kg i.p.) was unable to modify cocaine IVSA. These results indicate that stimulation of CB1 cannabinoid receptors activates rewarding mechanisms which produce reinforcing effects additional to those induced by cocaine.

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Marijuana is one of the most widely used illicit recreational drugs. However, contrary to the majority of drugs abused by humans, there is a general opinion that rewarding effects are not manifested by animals. We studied a synthetic cannabinoid agonist WIN 55,212-2 using an intravenous self-administration model in drug-naive mice. The results of this study show that WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to a bell-shaped curve. Thus, self-administration of WIN 55,212-2 significantly increased, with respect to the vehicle self-administration control group, at concentrations of 0.5 and 0.1 mg/kg per injection. However, at WIN 55,212-2 concentration of 0.5 mg/kg per injection, self-administration significantly decreased. The results obtained show how WIN 55,212-2 is able to elicit both rewarding and aversive effects depending on the concentration used. Pretreatment of mice with the cannabinoid CB1 receptor antagonist SR 141716A (0.25 mg/kg, i.p.) completely prevented WIN 55,212-2 (0.1 mg/kg per injection) self-administration, indicating that WIN 55,212-2 rewarding effects are specifically mediated by cannabinoid CB1 receptors.

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Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long-Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain. route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

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The reinforcing effects of gamma-hydroxybutyric acid (GHB) were studied by means of intravenous self-administration in drug-naive mice. GHB self-administration was concentration-dependent (0.01-0.5 mg/kg/inj.) according to a bell-shaped curve. Pretreatment with the specific GHB receptor antagonist NCS-382 at a dose of 12.5 mg/kg i.p. completely antagonized the reinforcing effects of GHB. These data suggest that GHB is able to induce reinforcing effects in mice and support the hypothesis of an abuse liability of this drug.

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Gamma-hydroxybutyric acid (GHB), a putative neurotransmitter or neuromodulator found in the mammalian brain, has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. In the present study we used a conditioned place preference (CPP) paradigm to investigate whether GHB possesses rewarding properties in rats. In order to exclude possible artifacts due to experimental design, we evaluated the possibility of a shift in preference when rats are conditioned either on their non-preferred side or on a randomly assigned side of conditioning. In both experiments GHB was seen to induce CPP. Although to date the physiological role of this compound still remains unclear, there is no doubt that GHB, further to its proven effect on alcohol and opiates, possesses rewarding properties of its own. The abuse liability afforded by this drug suggests the use of particular caution in handling GHB as a clinically useful drug.

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The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5-7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.

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The effect of isradipine, a dihydropyridine calcium antagonist, on intravenous self-administration of nicotine in naive mice has been investigated. When nicotine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose poking with respect to animals receiving contingent saline injections or yoked control animals receiving noncontingent nicotine injections. Pretreatment of mice with mecamylamine (2.4 mg/kg) inhibited self-administration of nicotine contingent upon a nose-poke response. The same effect was observed with isradipine (0.5-1.0 mg/kg) in a dose-related manner and stereospecifically. These data suggest that isradipine suppresses the reinforcing properties of nicotine and might be useful for treatment of nicotine abuse.

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The effect of isradipine, a dihydropyridine calcium antagonist, on cocaine intravenous self-administration in rats was investigated. Administration of (+/-)isradipine (1.25-5 mg/kg SC) 2 h before the cocaine self-administration session induced a significant and dose-dependent increase in the number of cocaine injections with respect to basal values. This effect was stereospecific, with the (+) form of isradipine being active, while the (-) stereoisomer was ineffective. These results suggest that isradipine antagonizes the rewarding properties of cocaine, possibly by inhibiting those dopaminergic systems related to reward mechanisms. These results further indicate a possible use of isradipine, or structurally similar compounds, in the treatment of cocaine related disorders.

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To obtain information on human pituitary intermediate lobe activity throughout the perinatal period, plasma alpha MSH immunoreactivity (IR) was measured in 106 newborns at delivery and during the first week of postnatal life. Subjects were divided into groups according to gestational age at birth, mode of parturition, and antenatal state of health. Plasma alpha MSH IR decreased progressively from severe preterm to fullterm neonates born by vaginal delivery (VD; P < 0.001) or cesarean section (CS) with and without prenatal distress (P < or = 0.001 in both cases). alpha MSH IR was due, in all studied conditions, to three major forms: desacetyl alpha MSH, alpha MSH, and diacetyl alpha MSH. Desacetyl alpha MSH was always the most represented form, but it decreased from 75-80% of the total in severe premature to 40-45% in mature infants. In term neonates, total alpha MSH IR values were higher in subjects born by normal VD than by elective CS (P < or = 0.05), in complicated than in normal VD (P < or = 0.01), and in CS performed because of fetal distress than in elective CS (P < or = 0.01). No significant difference was detectable in mature subjects in the percentages of the three alpha MSH forms in relation to the mode of delivery and fetal state during antenatal life or at parturition. Twelve hours after birth, total alpha MSH IR significantly decreased in all groups of term newborns, reaching a plateau of 0.8-1.4 pmol/L. In premature infants, similar concentrations were detectable by the fourth postnatal day. We conclude that 1) alpha MSH IR intermediate lobe secretion progressively decreases throughout the third trimester of pregnancy; 2) stress, including that pertinent to parturition, stimulates alpha MSH IR release; and 3) pituitary intermediate lobe activity declines shortly after birth independently of the maturity reached by the fetus, the mode of parturition, and the presence of antenatal chronic distress, although the process is slightly retarded in premature newborns.

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1. Sleep deprivation induced by the platform technique is considered to be a heavy stressful situation in rats. At the end of the sleep deprivation period (72 hrs) the rat displayed particular behavior characterized by wakefulness, a high degree of motor and exploratory activity, increased alertness and reactivity to environmental stimuli. 2. Our results indicate that this behavior is potently antagonized by the administration of D1 antagonist SCH 23390 and by the opioid antagonist naloxone. 3. We also show that concomitantly to this behavior, an increased number of D1 receptors associated with an increased dopamine-stimulated adenylate cyclase activity is present in the limbic system but not in the striatum of these animals. On the contrary, a decreased Bmax of mu and delta opioid receptors was found in the same brain areas. 4. These data suggest an active role of limbic dopamine and opioid system in the generation of arousal and insomnia related to sleep deprivation-induced stress.

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The effect of isradipine and nimodipine, two dihydropyridine calcium antagonists, on intravenous self-administration of cocaine and morphine in naive mice has been investigated. When morphine or cocaine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose-poking with respect to animals receiving contingent saline injections or yoked control animals, receiving noncontingent cocaine or morphine injections. Pretreatment of mice with isradipine (1.0-3.0 mg/kg, SC) or nimodipine (5-20 mg/kg, SC) inhibited in a dose-related manner self-administration both of cocaine and morphine contingent upon a nose-poke response. The ED50 of isradipine against cocaine and morphine self-administration was 1.7 and 2.1 mg/kg, respectively. The relative values for nimodipine were 14.5 and 11.4 mg/kg, respectively. These data suggest that nimodipine and, especially, isradipine suppress the reinforcing properties of morphine and cocaine and may be an effective pharmacotherapy for treatment of cocaine and heroin abuse.

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Sleep deprivation induced by the platform technique is considered to be a heavy stressful situation in rats. At the end of the sleep deprivation period (72 h) the rat displayed particular behavior characterized by wakefulness, a high degree of motor and exploratory activity, increased alertness and reactivity to environmental stimuli. Our previous results indicated that this behavior was potently antagonized by the administration of the D1 selective antagonist SCH 23390 and by the opioid antagonist naloxone. In this paper we show that concomitantly to this behavior, an increased number of D1 receptors associated with an increased dopamine-stimulated adenylate cyclase activity is present in the limbic system but not in the striatum of these animals. On the contrary, a decreased Bmax of mu and delta opioid receptors was found in the same brain area. These data suggest an active role of limbic dopamine and opioid systems in the generation of arousal and insomnia related to sleep deprivation-induced stress.

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The effect of a dihydropyridine (DHP) calcium antagonist, PN 200-110, on cocaine reinforcing properties was investigated using conditioned place preference paradigm. PN 200-110 in nonsedative doses (0.62-1.25-2.5 mg/kg SC) was able to inhibit cocaine-(10 mg/kg IP) induced place preference with ED50 1.57 (0.88-2.58). The results suggest a possible use of DHPs in the treatment of cocaine-related disorders.

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Sleep deprivation induced by the platform technique is considered to be a heavy stressful situation in rats. At the end of the sleep deprivation period (72 h) the rats displayed particular behaviour characterized by wakefulness, a high degree of motor and exploratory activity, increased alertness and reactivity to environmental stimuli. Our previous results indicated that this behaviour was potently antagonized by the administration of the D1-selective antagonist SCH 23390. In this paper we show that concomitantly to this behaviour, an increased number of D1 receptors associated with an increased dopamine-stimulated adenylate cyclase activity is present in the limbic system but not in the striatum of these animals. These data suggest an active role of limbic D1 receptors in the generation of arousal and insomnia related to sleep deprivation induced stress.

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