Concurrent-chains schedules as a method to study choice between alcohol-associated conditioned reinforcers

An extensive body of research using concurrent-chains schedules of reinforcement has shown that choice for one of two differentially valued food-associated stimuli is dependent upon the overall temporal context in which those stimuli are embedded. The present experiments examined whether the concurrent chains procedure was useful for the study of behavior maintained by alcohol and alcohol-associated stimuli. In Experiment 1, rats responded on concurrent-chains schedules with equal variable-interval (VI) 10-s schedules in the initial links. Across conditions, fixed-interval schedules in the terminal links were varied to yield 1∶1, 9∶1, and 1∶9 ratios of alcohol delivery. Initial-link response rates reflected changes in terminal-link schedules, with greater relative responding in the rich terminal link. In Experiment 2, terminal-link schedules remained constant with a 9∶1 ratio of alcohol delivery rates while the length of two equal duration initial-link schedules was varied. Preference for the rich terminal link was less extreme when initial links were longer (i.e., the initial-link effect), as has been previously reported with food reinforcers. This result suggests that the conditioned reinforcing value of an alcohol-associated stimulus depends on the temporal context in which it is embedded. The concurrent-chains procedure and quantitative models of concurrent chains performance may provide a useful framework within which to study how contextual variables modulate preference for drug-associated conditioned reinforcers.     

Effects of negative incentive shifts in food reward on rats' consumption of concurrent ethanol solutions

Frustration stress, typically operationalized as the unexpected loss of reinforcement, has been shown to engender substance use. Abrupt reductions in reinforcer magnitude likely also function as frustration stressors. These negative incentive shifts were previously shown to produce tap‐ and sweetened‐water drinking in rats. The purpose of this study was to investigate whether these shifts in food reward would occasion oral ethanol self‐administration. Nine male Long‐Evans rats operated on a two‐component multiple fixed‐ratio schedule with signaled components producing either a large (4 pellets) or small (1pellet) reinforcer. Components were pseudorandomly arranged to present 4 transitions between past and upcoming reinforcer magnitudes: small‐to‐large, small‐to‐small, large‐to‐large, and large‐to‐small (negative incentive shift). Experiment 1 investigated the effects of negative incentive shifts on consumption of concurrent, freely available 10% sucrose, 10% sucrose plus 10% ethanol, and following sucrose fading, 10% ethanol. Experiment 2 entailed continuation of schedule contingencies with a dose manipulation of 4 ethanol concentrations (0, 5, 10, and 20%) to assess dose‐dependent differences in transition‐type control and consumption. A lever‐press extinction condition was then conducted with 10% ethanol availability. In this novel model of frustration stress, negative incentive shifts prompted ethanol self‐administration at each dose investigated, whereas the other transitions did not.     

小鼠新颖寻求特质对酒精的运动激活效应的影响

新颖寻求(或感觉寻求)特质与许多成瘾药物的易感性密切相关。例如, 高、低新颖寻求动物对可卡因、苯丙胺和吗啡等成瘾药物的奖赏、运动激活、强化效应的反应存在差异。长期饮用酒精也容易成瘾, 但尚未发现关于新颖寻求特质影响酒精成瘾的报道。本实验采用药物成瘾研究中常用的自发活动模型, 考察了高、低新颖寻求动物在酒精急性处理、慢性处理和激发过程中的行为表现。实验过程中首先采用两种新颖寻求模型, 即新颖环境中自发活动模型和新颖客体偏爱模型, 将昆明小鼠分别区分为高、低自发活动组和高、低新颖客体偏爱组, 连续10天给予酒精(2g/kg/d, i.p.)或等量盐水处理, 戒断2天后所有小鼠接受酒精(2g/kg)激发。实验结果表明, 新颖环境低自发活动小鼠比新颖环境高自发活动小鼠对酒精急性、慢性处理导致的运动激活效应更敏感; 在酒精激发期前者的自发活动水平也高于后者。本实验结果说明新颖环境中自发活动特质影响动物对酒精导致的运动激活效应的反应。     

Human coffee drinking: manipulation of concentration and caffeine dose.

In a residential research ward coffee drinking was studied in 9 volunteer human subjects with histories of heavy coffee drinking. A series of five experiments was undertaken to characterize adlibitum coffee consumption and to investigate the effects of manipulating coffee concentration, caffeine dose per cup, and caffeine preloads prior to coffee drinking. Manipulations were double-blind and scheduled in randomized sequences across days. When cups of coffee were freely available, coffee drinking tended to be rather regularly spaced during the day with intercup intervals becoming progressively longer throughout the day; experimental manipulations showed that this lengthening of intercup intervals was not due to accumulating caffeine levels. Number of cups of coffee consumed was an inverted U-shaped function of both coffee concentration and caffeine dose per cup; however, coffee-concentration and dose-per-cup manipulations did not produce similar effects on other measures of coffee drinking (intercup interval, time to drink a cup, within-day distribution of cups). Caffeine preload produced dose-related decreases in number of cups consumed. As a whole, these experiments provide some limited evidence for both the suppressive and the reinforcing effects of caffeine on coffee consumption. Examination of total daily coffee and caffeine intake across experiments, however, provides no evidence for precise regulation (i.e., titration) of coffee or caffeine intake.     

Effects of ethanol on reinforced variations and repetitions by rats under a multiple schedule.

Response sequences emitted by five Long-Evans rats were reinforced under a two-component multiple schedule. In the REPEAT component, food pellets were contingent upon completion of a left-left-right-right (LLRR) sequence on two levers. In the VARY component, pellets were contingent upon variable sequences (i.e., a sequence was reinforced only if it differed from each of the previous five sequences). The rats learned to emit LLRR sequences in the REPEAT component and variable sequences in VARY. Intraperitoneal injections of ethanol (1.25, 1.75, and 2.25 g/kg) significantly increased sequence variability in REPEAT, thereby lowering reinforcement probability, but had little effect on sequence variability in the VARY component. These results extend previous findings that alcohol impairs the performance of reinforced repetitions but not of reinforced variations in response sequences.     

Facilitation of human tobacco self-administration by ethanol: a behavioral analysis.

The effect of ethanol on the cigarette smoking of alcoholic subjects was studied in a residential laboratory. During daily 6-hr sessions, cigarettes were obtained either by request to the ward staff or by operation of a lever (fixed-ratio 5 or 10). In a mixed sequence across days, sessions involved ingestion of either vehicle (orange juice or vehicle plus ethanol (133.7 g). During ethanol sessions, the rate of cigarette smoking increased from 26% to 117% of vehicle levels. A series of control studies eliminated a number of potential behavorial mechanisms for the observed effect and indicated that the ethanol-induced increase in cigarette smoking occurred under a variety of experimental conditions: (1) when smoking could not occur concurrently with ethanol or vehicle consumption; (2) when subjects were not allowed to socialize; (3) when ingestion of ethanol or vehicle was scheduled for a number of consecutive days; (4) when various doses of ethanol were administered under blind conditions. In control experiments, weighing unsmoked tobacco and counting the number of puffs per cigarette indicated the effect was not due to smoking less of each cigarette. The effect was not limited to the experimental sessions alone, since total daily smoking was higher on ethanol days than vehicle days.     

Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems

Repeated cycles of ethanol intoxication and withdrawal associated with dependence induce neuroadaptations in a variety of brain systems. Withdrawal-induced negative emotional states can be ameliorated by ethanol consumption; a learned process termed negative reinforcement. Accordingly, a dependence-induced phenotype is escalated ethanol self-administration. Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade the extracellular matrix to allow for synaptic reorganization and plasticity. To test the hypothesis that an intact MMP system is required for animals to learn about the negative reinforcing effects of ethanol and display escalated self-administration during acute withdrawal when ethanol-dependent, male Wistar rats were trained to self-administer ethanol and then assigned to either acute or chronic MMP inhibition treatment groups. The chronic treatment group received intracerebroventricular (ICV) infusions of the broad spectrum MMP inhibitor FN-439 or artificial cerebrospinal fluid (aCSF) via osmotic minipumps during a 1 month ethanol dependence induction period and subsequent post-dependence induction self-administration sessions that occurred during acute withdrawal. The acute treatment group only received ICV FN-439 or aCSF on the day of self-administration sessions following dependence induction during acute withdrawal. The results showed that inhibition of MMPs attenuated escalated ethanol self-administration following chronic and acute exposure conditions. Furthermore, once learning (i.e., plasticity) had occurred, MMP inhibition had no impact on escalated response patterns and animals previously subjected to MMP inhibition that did not escalate evidenced normal escalations in operant ethanol self-administration once FN-439 treatments were terminated. Thus, the present data identified that an intact MMP system is required for the escalated responding that occurs during acute withdrawal in dependent animals and implicate such escalation as a learned response.     

Conditioned ethanol aversion in rats induced by voluntary wheel running,forced swimming,and electric shock: An implication for aversion therapy of alcoholism

This study was planned to demonstrate rats’ acquisition of aversion to ethanol solution consumed before voluntary running, forced swimming, or electric shock delivery. Wistar rats under water deprivation were allotted to four groups of eight rats each, and all rats were allowed to drink 5% ethanol solution for 15 min. Immediately after the ethanol drinking, rats of Group Run were put into the individual running wheels for 15 min, those of Group Swim were put into the individual swimming pools for 15 min, those of Group Shock received electric shocks for 15 min (15 0.45-mA shocks of 0.7s with the intershock interval of 1 min) in the individual small chambers, and those of Group Control were directly returned back to the home cages. This procedure was repeated for six days, followed by a two-day choice test of ethanol aversion where a bottle containing 5% ethanol solution and a bottle of tap water were simultaneously presented for 15 min. In the test, Groups Run, Swim, and Shock drank ethanol solution significantly less than tap water, while Group Control drank both fluids equally. The effects of running, swimming, and shock were equivalent. The successful demonstration of acquired ethanol aversion induced by exercise (running and swimming) or shock in rats suggests an avenue for clinical application of exercise and shock treatments for human alcoholics, though there are many issues to be resolved before the practical use.     

Matching under nonindependent variable-ratio schedules of drug reinforcement.

Response-contingent deliveries of oral pentobarbital maintained responding of 3 rhesus monkeys during daily 3-hr sessions. Deliveries of pentobarbital were arranged under nonindependent concurrent variable-ratio variable-ratio schedules. Responses to either schedule counted toward completion of both variable-ratio schedule requirements. This schedule is similar in some respects to conventional concurrent variable-interval variable-interval schedules, in which passage of time counts toward completion of the interval value on both schedules. Restricted nonindependent concurrent variable-ratio variable-ratio schedules were also studied. On that schedule, when a drug delivery was assigned to one spout, it had to be collected before responses on the opposite spout again counted toward completion of the schedule requirements. Relative reinforcer magnitude was varied by changing the drug concentration on one schedule while keeping the drug concentration constant on the other variable-ratio schedule. Under both types of concurrent variable-ratio schedules, the relative rate of responding corresponded to the relative drug intake. Unlike earlier studies of concurrent variable-interval variable-interval intravenous cocaine reinforcement, preference was proportionate to concentration, and exclusive preferences did not develop. The relationship between relative rate of responding and relative drug intake was well described by the generalized matching law.     

Historical misrepresentation in science: The case of fetal alcohol syndrome

The history of the fetal alcohol syndrome (FAS) provides a microcosm in which to explore the larger ramifications of historical citations in biomedical publications. Though some historical references such as Biblical writings may hint at a rudimentary understanding of the relationship between maternal drinking and fetal development, no definitive case can be made for an understanding of FAS dating back hundreds of years. Authors who claim an impressive history for FAS misrepresent that history. The modern history of FAS raises a question concerning citations of original discoveries. The first paper describing ethanol-induced damage to the fetus appeared in 1968 yet most researchers cite one of two papers from 1973. Both ancient citations and modern references to original discoveries pose difficult questions for the scientist. Both dilemmas may be solved by a better reading of the literature and a more judicious wording when writing about history. This work was supported in part by Grant # AA10681 to SNP.