Drug context differently regulates cocaine versus heroin self-administration and cocaine- versus heroin-induced Fos mRNA expression in the rat

Rationale  We have previously reported that cocaine self-administration is facilitated in male rats not residing in the test chambers (Non Resident rats) relative to rats living in the test chambers at all times (Resident rats). Surprisingly, the opposite was found for heroin. Materials and methods  We predicted that, when given access to both cocaine and heroin on alternate days, Non Resident rats would take more cocaine relative to heroin than Resident rats. Heroin (25.0 μg/kg) and cocaine (400 μg/kg), were made alternately available for 14 self-administration sessions, on a fixed ratio (FR) schedule that was progressively increased from FR1 to FR5. Next, some rats underwent a progressive-ratio procedure for heroin and cocaine. The other rats continued to alternate heroin and cocaine self-administration for 12 additional sessions, during which the FR schedule was progressively increased from FR10 to FR100. The second aim of the study was to investigate Fos mRNA expression in Resident and Non Resident rats treated with non-contingent intravenous infusion of “self-administration doses” of heroin (25.0 μg/kg) and cocaine (400 μg/kg). Results  We found that: (1) drug-taking context differentially modulates intravenous cocaine versus heroin self-administration; (2) very low doses of cocaine and heroin are sufficient to induce Fos mRNA expression in the posterior caudate; (3) drug-administration context differentially modulates cocaine- versus heroin-induced Fos mRNA expression. Conclusions  Our study indicates that the context of drug taking can play a powerful role in modulating cocaine versus heroin intake in the laboratory rat. An erratum to this article can be found at     

Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex

Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex. Received: 27 July 1999 / Accepted: 30 November 1999     

Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats

We have previously reported that repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, facilitate instrumental behavior in rats given the choice between operant and free access to water (contrafreeloading: CFL). The goal of the present study was to investigate the effects of repeated daily administrations of quinpirole (0.5 mg/kg i.p.) on the appetitive versus the consummatory component of water-reinforced behavior, under two experimental conditions. Under one condition, the rats were given access to tap water according to an FR3 schedule of reinforcement. Under the second condition, the rats were given the choice between operant and free access to water. Five major findings were obtained. First, acutely quinpirole suppressed operant behavior and, therefore, water intake for at least 1h. Second, upon repeated administrations tolerance developed to the suppressant effect of quinpirole on instrumental behavior but only to a lesser extent to the antidipsic effect, dissociating the appetitive from the consummatory components of water-reinforced behavior. Third, in CFL conditions quinpirole induced a progressively larger preference for the operant access. Fourth, even when the rats were given the choice between free access to highly palatable saccharine (0.05 or 0.01%) solutions and operant access to tap water, quinpirole shifted the animals towards the operant access. Fifth, repeated quinpirole produced lasting consequences on drinking behavior, since after rehydration and under drug-free conditions quinpirole-pretreated rats ingested larger amounts of water than control rats. In conclusion, the repeated activation of D2/D3 receptors appears to induce the rats to perseverate in performing needless instrumental behavior.     

Erratum: Corrigendum: Survival and treatment patterns in elderly patients with advanced non-small-cell lung cancer in Manitoba

[This corrects the article on p. e238 in vol. 18, PMID: 21980255.].     

Modulation of food intake by the kappa opioid U-50,488H: evidence for an effect on satiation

The main goal of the present study was to test the hypothesis that the prophagic effect of the kappa opioid agonist U-50,488H (U50) is primarily due to an effect on satiation. In Experiment 1, the feeding effects of U50 (2.0 and 4.0 mg/kg, i.p.) was tested in animals with ad libitum access to ground food and to three sucrose solutions (1, 4, and 20%). In Experiment 2, a classical "one-bottle" test was utilized to test for the effect of U50 (4.0 mg/kg, i.p.) on the intake of five different sucrose solutions (1, 4, 16, 32, and 40%) over a 30-min period. Finally, in Experiment 3 we evaluated the effect of U50 (2.0, 4.0, and 6.0 mg/kg, i.p.) on extracellular dopamine (DA) concentration in the nucleus accumbens. In Experiment 1, U50 enhanced the intake of ground food but not of sucrose. In Experiment 2, U50 increased the intake of high concentration sucrose solutions whereas it decreased that of low concentration solutions. In Experiment 3, U50 produced a dose-dependent decrease in DA concentrations in the absence but not in the presence of food. The most likely explanation for the present results is that U50 enhances feeding by activating mechanisms that block satiety and satiation. In contrast, we found little evidence for an effect of U50 on palatability.     

Ventral tegmental area opioid mechanisms and modulation of ingestive behavior

In this paper we report on the effects of intra-VTA infusion of opioid agonists on rat ingestive behavior in a variety of experimental contexts. When the animals were tested outside of their home cages surrounded only by food-pellets (Experiment 1), the injection of the mu-opioid agonist DAMGO, but not the kappa-opioid agonist U-50,488H, into the ventral tegmental area facilitated food-related behaviors, decreasing the latency to feed and increasing the number of interactions with food. When, as in Experiment 2, gnawable objects and a drinking tube were also available, intra-VTA DAMGO gnawing and drinking behaviors, whereas the effects on feeding were negligible. These effects intra-VTA DAMGO increased were greatly enhanced in rats that underwent repeated treatments with amphetamine. On the other hand, when food-related behaviors were studied in a home-cage, where access to the food supply was achieved by entry into a tunnel, latency to feed and total food-intake were not enhanced in tests made during either the dark or the light phase (Experiment 3 and 4). This was true whether powdered standard lab chow or a highly palatable food was available. It appears that when a number of alternative incentive stimuli are available, increases in dopamine transmission such as that induced by intra-VTA DAMGO may ultimately have the effect of interfering with behavior normally directed primarily to one of these stimuli, by enhancing the salience of others. These effects bears some resemblance to the effects of tail-pinch and electrical brain stimulation of the medial forebrain bundle-lateral hypothalamic area on the responses to natural incentive stimuli.     

3-Deazaadenosine and MDL29350 differentially affect the methylation of serine- and ethanolamine-derived phosphatidylethanolamine in Hep G2 cells

The effect of 3-deazaadenosine (DZA) and the hypolipidemic drug MDL29350 {2-[3,5-di(t-butyl-4-hydroxyphenyl)thio]hexanoic acid} on the synthesis and methylation of phosphatidylethanolamine (PE) originating from the cytidine diphosphate (CDP) ethanolamine pathway and PE originating from decarboxylation of phosphatidylserine (PS) was investigated. DZA and MDL29350 did not affect the synthesis of PE by either pathway; however, methylation of ethanolamine-derived PE was inhibited by 80% and methylation of serine-derived PE was inhibited by 36% by 20 μmol/L DZA or MDL29350. The differential inhibition of the methylation of PE synthesized via serine or ethanolamine suggests that in Hep G2 cells PE-N-methyltransferase (PENMT) may be segregated into distinct compartments that are differentially accessible to the drugs.