Intravenous ethanol/cocaine self-administration initiates high intake of intravenous ethanol alone

ArticleinPharmacology Biochemistry and Behavior 72(4):787-94 · August 2002with29 Reads
DOI: 10.1016/S0091-3057(02)00738-4 · Source: PubMed
Evidence suggests that ethanol (EtOH) preexposure influences the rewarding valence of subsequent EtOH use. This study was conducted to determine if EtOH preexposure through EtOH/cocaine self-administration facilitates the motivational effects of EtOH alone. Rats self-administered intravenous (iv) EtOH/cocaine combinations (EtOH/Cocaine Fading group; EtOH 125.0 mg/kg/inj+Cocaine 0.1-0.75 mg/kg/inj) during a preexposure period. Consequently, these rats self-administered intravenous EtOH alone (62.5, 125.0, 250.0 and 500.0 mg/kg/inj) significantly more than a control group with prior cocaine self-administration experience (0.1-0.75 mg/kg/inj). In addition, at equal EtOH intake levels, locomotor activity was significantly enhanced in the EtOH/Cocaine Fading group but not the Cocaine Control animals (P=.01). The amount of EtOH self-administered in the EtOH/Cocaine Fading group during 1-h sessions (approximately 0.5-2.0 g/kg) corresponded with blood alcohol levels (BAL) ranging from 44 to 221 mg/dl. The highest BALs reported here have not previously been demonstrated after voluntary EtOH intake through any route of administration. These data suggest that preexposure to EtOH during EtOH/cocaine self-administration sessions modified neural substrates underlying both the reinforcing and locomotor responses to EtOH alone. Further studies utilizing intravenous EtOH self-administration will allow identification of various long-term behavioral and neural consequences of voluntary high EtOH intake.
    • "Such experimenter-controlled manipulations allow for neither the examination of the underlying motivation to consume high levels of alcohol nor the neurological underpinnings of human alcohol addiction. Escalated IV ethanol selfadministration has also been demonstrated when rats have either previous or concurrent exposure to other drugs of abuse, such as cocaine (Ikegami et al., 2002) or heroin (Hyytiä, Schulteis, & Koob, 1996). However, such studies similarly fail to answer questions relevant to human alcohol abuse. "
    [Show abstract] [Hide abstract] ABSTRACT: Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally “relevant” effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding “non-pharmacological” effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol’s effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous ethanol self-administration methodology cannot overcome the aversive properties of ethanol via this route in the rat.
    Full-text · Article · Aug 2014
    • "Mechanisms that have been advanced to account for polydrug abuse include interactions that enhance positive effects or diminish negative effects of one or more of the combined drugs (Ellinwood et al. 1976; Kosten et al. 1986; Kreek 1987). Several drug combinations have been studied in the laboratory in humans and non-humans under a variety of conditions, including ethanol/barbiturate (DeNoble et al. 1985; Meisch and Lemaire 1990), cocaine/marijuana (Foltin and Fischman 1990), benzodiazepine/caffeine (Rush et al. 1994), ethanol/cocaine (Ikegami et al. 2002), ethanol/marijuana (Liguori et al. 2002), and dextromethorphan/diphenhydramine (Jun et al. 2003). It is not always clear, however, whether and how results can be accounted for by these broad mechanisms. "
    [Show abstract] [Hide abstract] ABSTRACT: Abuse of drug mixtures is common. Drug interactions that are super-additive in terms of reinforcing effects may contribute to this phenomenon. Although quantitative methods for assessing drug interactions have been developed, they have not been widely applied to the analysis of reinforcing effects. The present experiment was designed to study self-administration of mixtures of drugs with comparable pharmacological mechanisms of action. Our hypothesis was that the drugs would be dose-additive. Rhesus monkeys prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule in baseline sessions. When responding was stable, two mu opioid agonists, alfentanil and remifentanil, were tested alone in one group (n = 5). Two dopamine (DA) uptake blockers, cocaine and RTI-117 were tested in the other group (n = 6). Next, mixtures of doses of the two opioids or the two DA uptake blockers were tested in approximate 1:1, 1:2, and 2:1 ratios of their ED50s. Results were analyzed using isobolographic techniques. All drugs alone and drug mixtures functioned as positive reinforcers in a dose-related manner. There was no difference between experimentally determined ED50 values and predicted additive ED50 values for any mixture. Maximum responding maintained by mixtures, a measure of reinforcing strength, did not differ from that for single drugs. Mixtures of various proportions of two drugs with comparable mechanisms of action were additive, i.e., they did not interact. This result will serve as the basis for comparison to studies of mixtures of drugs with various mechanisms of action.
    Article · Apr 2008
    • "Unfortunately, most of the operant studies with intravenous ethanol in rodents have used doses of ethanol that are much smaller than that needed to produce meaningful blood alcohol levels compared with what is normally achieved after oral selfadministration . There are a few studies using this method that have used reasonable doses to produce significant blood levels and cumulative doses (Grahame & Cunningham, 1997; Grahame et al., 1998; Ikegami et al., 2002; D'Souza et al., 2003; Joharchi et al., 2003). A recent study using larger doses is consistent with the role of dopamine in the initiation of ethanol reinforcement (D'Souza et al., 2003). "
    [Show abstract] [Hide abstract] ABSTRACT: The neurobiological processes by which ethanol seeking and consumption are established and maintained are thought to involve areas of the brain that mediate motivated behavior, such as the mesolimbic dopamine system. The mesolimbic dopamine system is comprised of cells that originate in the ventral tegmental area (VTA) and project to several forebrain regions, including a prominent terminal area, the nucleus accumbens (NAcc). The NAcc has been subdivided into core and shell subregions. Both areas receive converging excitatory input from the cortex and amygdala and dopamine input from the VTA, with the accumbal medium spiny neuron situated to integrate the signals. Although forced ethanol administration enhances dopamine activity in the NAcc, conclusions regarding the role of mesolimbic dopamine in ethanol reinforcement cannot be made from these experiments. Behavioral experiments consistently show that pharmacological manipulations of the dopamine transmission in the NAcc alter responding for ethanol, although ethanol reinforcement is maintained after lesions of the accumbal dopamine system. Additionally, extracellular dopamine increases in the NAcc during operant self-administration of ethanol, which is consistent with a role of dopamine in ethanol reinforcement. Behavioral studies that distinguish appetitive responding from ethanol consumption show that dopamine is important in ethanol-seeking behavior, whereas neurochemical studies suggest that accumbal dopamine is also important during ethanol consumption before pharmacological effects occur. Cellular studies suggest that ethanol alters synaptic plasticity in the mesolimbic system, possibly through dopaminergic mechanisms, and this may underlie the development of ethanol reinforcement. Thus, anatomical, pharmacological, neurochemical, cellular, and behavioral studies are more clearly defining the role of mesolimbic dopamine in ethanol reinforcement.
    Full-text · Article · Sep 2004
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