Dopamine and opioids interactions in sleep deprivation

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 enviromental 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

Rewarding properties of gamma-hydroxybutyric acid: an evaluation trouth place preference paradigm

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

Intravenous self-administration of gamma-hydroxybutyric acid in drug-naive mice

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. (C) 1998 Elsevier Science B.V./ECNP. All rights reserved

Baclofen antagonizes intravenous self-administration of gamma-hydroxybutyric acid in mice

Gamma -Hydroxybutyric acid (GHB) is a widely used recreational drug known to exert positive reinforcing effects in animals and humans. The GABAB 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-I) 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 GABAB receptor in reward-related mechanisms underlying addictive behaviour. NeuroReport 12:2243-2246 (C) 2001 Lippincott Williams & Wilkins

Effect of isradipine, a Dihydropyridine-calcium antagonist oni.v. self-administration of morphine in rats

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

Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice

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, (C) 1998 LBRO, Published by Elsevier Science Ltd

Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naive mice

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

Effect of the calcium antagonist Isradipine on cocaine intravenous self-administration in rats

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

Sleep deprivation increases dopamine D1 receptor antagonist [3H]SCH 23390 binding and dopamine-stimulated adenylate cyclase in the rat limbic system.

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