Intravenous ethanol/cocaine self-administration initiates high intake of intravenous ethanol alone.
ABSTRACT 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.
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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.Psychopharmacology 04/2008; 196(4):575-82. · 4.06 Impact Factor
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ABSTRACT: Drugs of abuse are typically discussed in terms of their rewarding effects and how these effects mediate drug taking. However, these drugs produce aversive effects that could have an important role in the overall acceptability of a drug and its likelihood of being self-administered. Rewarding and aversive effects, then, could be interpreted as separate behavioral effects, with the balance of the two determining overall drug acceptability. Interestingly, the role of aversive effects on drug acceptability in the self-administration preparation has received limited attention in this context. This chapter examines the aversive effects of drugs and discusses their role in drug taking. If these aversive effects serve a protective function, manipulations that alter or decrease these effects could have implications for drug taking. Several factors have been reported to alter conditioned taste aversion (CTA) learning, a preparation used in the assessment of the aversive effects of drugs in general. Two of these factors, drug history and strain, are reviewed here. By reviewing these, we intend to demonstrate the protective nature of aversive effects in the initiation and escalation of drug taking and to provide evidence that reductions in aversive effects could produce changes in patterns of drug self-administration that could lead to an increased vulnerability to abuse drugs by altering the reward-aversion balance. The aim of this chapter is not to question the importance of rewarding effects in self-administration but rather to provide evidence that aversive effects are an important factor that needs to be considered in discussions of drug-taking behavior.Annals of the New York Academy of Sciences 02/2010; 1187:247-75. · 4.38 Impact Factor
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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.Alcohol. 01/2014;