Lobeline does not serve as a reinforcer in rats

Abstract Rationale. Previous results demonstrated that pretreatment with lobeline attenuates d-methamphetamine self-administration in rats. Objective. The present experiments determined if lobeline serves as a reinforcer, if it decreases d-methamphetamine-induced reinstatement of d-methamphetamine self-administration, and if it activates the mesolimbic and nigrostriatal dopamine (DA) pathways in Sprague-Dawley male rats. Methods. The ability of intravenous (IV) lobeline (0.015–0.15 mg/kg per infusion) to engender responding and the ability of lobeline (0.015 and 0.05 mg/kg per infusion) to substitute for d-methamphetamine was determined using the self-administration paradigm. Experiments were also performed to determine if lobeline (1.0 and 3.0 mg/kg) reinstates responding for d-methamphetamine or alters the ability of d-methamphetamine (1.0 mg/kg per infusion) to reinstate responding following extinction. The effect of lobeline (3.0 mg/kg) or d-methamphetamine (1.0 and 3.0 mg/kg) on DA and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and striatum were also determined. Results. Lobeline was not self-administered and did not substitute for d-methamphetamine. Also, lobeline did not reinstate responding for d-methamphetamine following extinction nor did it alter d-methamphetamine-induced reinstatement. Furthermore, lobeline did not alter DA or DOPAC levels in the either the nucleus accumbens or striatum. Conclusions. Taken together, the present results indicate that lobeline decreases d-methamphetamine self-administration by decreasing reward, not by acting as a substitute reinforcer. Electronic Publication     

Modafinil does not serve as a reinforcer in cocaine abusers

The purpose of this double-blind, randomized, outpatient study was to evaluate the reinforcing and subjective effects of modafinil (200, 400, or 600 mg) in cocaine abusers. Twelve participants (2 female, 10 male) completed this study, consisting of 3 blocks of 7 sessions; each block tested a difference dose of modafinil. During the first 2 sessions of each block, participants “sampled” 1 of the doses of modafinil, and placebo. These doses of modafinil and placebo were available for the subsequent five choice sessions of the block. In each choice session, participants had an opportunity to administer active or placebo capsules. Modafinil administration did not differ from placebo administration, and subjective-effects ratings were not systematically altered as a function of modafinil dose. Results suggest that modafinil does not have abuse liability in cocaine abusers.     

The failure of cocaine to serve as an orally self-administered reinforcer in Lewis rats

The aim of this study was to develop a procedure to establish orally delivered cocaine as a reinforcer for rats. Several procedures that have proven reliable in other studies were instituted. (1) Food-induced drinking: food was presented to engender high rates of drinking, then cocaine solutions replaced water, and finally the food was removed. Peak drug intakes ranged from 9.4 to 13.8mg/kg. (2) Ethanol-fade: ethanol was established as a reinforcer, cocaine was gradually added to the ethanol, and the ethanol was gradually removed. Peak cocaine intakes ranged from 3.6 to 5.2mg/kg. (3) Modified food-induced drinking: food was presented, but was followed by a timeout period, allowing digestion to progress prior to cocaine drinking. Peak drug intakes ranged from 12.9 to 18.6mg/kg. However, cocaine was not established as a reinforcer with any of these methods. High cocaine doses may be necessary, but are not sufficient, to establish oral cocaine self-administration in rats.     

Characterization of nicotine's ability to serve as a negative feature in a Pavlovian appetitive conditioning task in rats

Rationale Pavlovian feature negative discriminations have been widely used to understand inhibitory conditioning processes using exteroceptive stimuli. Comparatively little is known about inhibitory conditioning processes using a drug state as a negative feature. A negative feature signals that presentation of a conditional stimulus (CS) will not be paired with an unconditioned stimulus. Objectives The present research examined whether nicotine served as a negative feature and started characterizing its properties. Methods and results In acquisition, rats received intermixed saline and nicotine (0.4 mg/kg, base) sessions. On saline sessions, a 15-s light CS was paired with 4-s access to sucrose; the CS was presented on nicotine sessions, but sucrose was withheld. The discrimination was acquired with more goal tracking during the CS on saline sessions. Nicotine's inhibition of this conditioned response (CR) was sensitive to nicotine dose (ED₅₀=0.225) and injection to testing interval (CR returned at 200 min). Mecamylamine pretreatment, but not hexamethonium, produced a loss of inhibitory control by nicotine suggesting a role for central nicotinic acetylcholine receptors. Amphetamine, bupropion, arecoline, and chlordiazepoxide, but not caffeine, substituted for the nicotine feature. However, in locomotor tests, amphetamine and bupropion increased activity; arecoline and chlordiazepoxide decreased activity. For this reason, the motor effects of these ligands could not be dissociated from substitution via shared stimulus properties. Conclusions This feature negative task provides a preclinical model for studying how drug states inhibit responding, although identifying the process(es) mediating CR inhibition will require further research.     

Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans

The effects of diazepam (DZ) (0, 10, and 20 mg) and caffeine (CAF) (0, 200, 400, and 600 mg) alone and in combination were examined in nine healthy male subjects using a within-subject experimental design in which all subjects received all twelve possible dose combinations. Drug effects were assessed using various psychomotor and cognitive performance tasks, staff (observer) ratings of subject behavior, and subject ratings of mood and drug effect. DZ treatment alone impaired performance on all tasks and produced staff and subject ratings indicative of sedative drug effects. CAF treatment alone facilitated performance on two psychomotor tasks requiring rapid reaction speed and increased staff ratings of subject restlessness and subject ratings of tension, alertness, arousal, and CAF symptoms. CAF generally antagonized the DZ-induced ratings of sedation and impairment of psychomotor performance; however, CAF did not consistently antagonize the DZ impairment of immediate recall or delayed recognition memory performance. DZ antagonized the CAF-induced staff-rated restlessness, and subject-ratings of tension, alertness, arousal and CAF symptoms. The results generally support the hypothesis that DZ and CAF produce antagonistic effects through functionally opposing mechanisms, however, the observed effects of drug combinations are dependent on the specific doses being tested and on the measures of drug effect being examined.     

Effect of caffeine on physiological sleep tendency and ability to sustain wakefulness at night

Marked sleepiness occurs during typical night shift work hours and this reduced alertness is associated with marked performance deficits. The effect of caffeine (versus placebo) upon sleepiness at night was studied using objective measures of physiological sleep tendency and ability to sustain wakefulness. Both measures show caffeine to reduce sleepiness at a single dose roughly the equivalent of two to four cups of coffee. Despite impressive objective differences in alertness with caffeine, subjects did not consistently differentiate between drug conditions on subjective alertness assessments. The use of CNS stimulants to promote alertness during night shift hours should be considered, particularly for occupations for which alertness is critical.     

Genetic differences in the establishment of ethanol as a reinforcer

Ethanol, self-administered orally, has been shown to serve as an effective reinforcer in several species. Self-administration studies have also illustrated that ethanol-drinking behavior can be conceptualized as a specific type of operant behavior. The use of inbred and selectively bred animals in other areas of alcohol research has provided valuable information about the contribution of genetic factors to ethanol-related behaviors. Our research was designed to study genetic differences in oral self-administration in the ALKO AA (Alcohol Accepting) and ANA (Alcohol Non-Accepting) rat lines, selected for ethanol preference. Thus, we applied a behavior genetic analysis to aid in determining the contribution of genetic factors to behavior, specifically drug-seeking behavior. The results of our experiments indicate that genetic differences are important factors contributing to the establishment of a drug as a reinforcer. At least in the case of ethanol, the drug did not act as a reinforcer in non-preferring animals. Conversely, in preferring animals, ethanol was readily established as a reinforcer.     

Tramadol acts as a weak reinforcer in the rat self-administration model, consistent with its low abuse liability in humans

Rodent models of abuse potential are considered to represent a false positive with respect to the low risk of abuse liability associated with the atypical opioid analgesic tramadol. This may reflect either the predictive limitations of the models used to formulate this proposition (drug discrimination and conditioned place preference) or the predictive ability of the rodent per se. To address this concern, we used the rat self-administration model to examine the reinforcing properties of tramadol (0.3-3 mg/kg/infusion) under fixed (FR) and progressive-ratio (PR) schedules of reinforcement. Comparisons were made with the typical opioid analgesics morphine (0.03-0.3 mg/kg/infusion) and remifentanil (0.001-0.03 mg/kg/infusion). All three compounds maintained responding under an FR3 schedule of reinforcement, although clear differences were observed in the rates of responding between compounds. Under a PR schedule, morphine and remifentanil maintained comparable break points, while break points for tramadol did not differ from vehicle. Thus, when examined in the self-administration model, tramadol acts as a relatively weak reinforcer in rodents. These data are consistent with the low risk of tramadol abuse liability in humans and highlight the value of using multiple abuse potential models for assessing abuse liability.     

Effects of administering caffeine to pregnant rats either as a single daily dose or as divided doses four times a day

From day 6 to day 20 of pregnancy, rats were treated with caffeine in a total daily dose of 10 or 100 mg/kg by gavage, either as a single bolus dose or as four divided doses given at 3-hr intervals throughout the day. Controls were given distilled water at the same times. Maternal body weight and food and water consumption were reduced in the two groups receiving a total of 100 mg caffeine/kg/day and in the group given 2.5 mg/kg four times daily. Dose-related decreases in foetal weight, placental weight and crown-rump length and dose-related retardation of skeletal ossification were observed. Major foetal abnormalities, mainly ectrodactyly, were seen only in the group given 100 mg caffeine/kg in a single daily dose.     

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine. Eight healthy volunteers were included in our study. A total of 300 mg of caffeine was given on 2 occasions, once alone and once during the coadministration of 300 mg propafenone. Serial blood samples were collected and pharmacokinetic parameters were estimated using a population pharmacokinetic approach. A one-compartment PK model with first-order absorption and elimination described plasma concentration profiles. Concomitant administration of propafenone decreased caffeine oral clearance from 8.3 +/- 0.9 L/h to 5.4 +/- 0.7 L/h (P < 0.05). Elimination half-life of caffeine was also increased 54% by propafenone. One of our volunteers was a poor metabolizer of CYP2D6. Concomitant administration of propafenone to this volunteer caused the greatest increase in caffeine plasma concentrations. These results support the concept of competitive inhibition between propafenone and caffeine. Our results suggest that propafenone causes significant inhibition of CYP1A2 activity leading to a decrease in the clearance of caffeine. Caffeine has intrinsic proarrhythmic effects; thus, its coadministration with an antiarrhythmic agent such as propafenone should be used with caution, especially in patients with poor CYP2D6 activity.     

Medication take-home as a reinforcer in a methadone maintenance program

The opportunity to take methadone doses home from the clinic can be used as a reinforcer in contingency management procedures to promote desirable behavior among a population of methadone maintenance clients. This was demonstrated by delivering take-home privileges contingent upon attendance at counseling sessions. Sixteen methadone maintenance clients were selected on the basis of their low attendance rates at individual counseling sessions. During five successive 2-month periods, weekend (2 days) medication take-home privileges were either contingent upon attendance at a weekly counseling session lasting at least 45 min or were given to clients non-contingently. During periods of contingent delivery of the take-home privilege, counseling attendance increased significantly above levels observed during period of non- contigent delivery.     

Factors affecting the ability of caffeine to improve the short-term memory in man

Caffeine is known to improve both visual and aural memory in healthy humans. This caffeine effect correlates with the mental work capacity and depends on a number of variable factors. In particular, the effect is more pronounced in the evening and in females.     

The effects of a low dose of caffeine on cognitive performance

There is little evidence concerning the effects of caffeine in doses typical of one cup of tea. The present study investigated the effect of 60 mg caffeine, consumed in either tea or hot water, on performance on a subset of the CANTAB test battery. Eight males participated in a practice session and four test sessions. In each test session, the participant consumed a different hot beverage and then, over approximately 90 min, completed nine tests from the CANTAB battery. The four beverages were created by crossing beverage identity (tea or hot water) and caffeine dose (0 or 60 mg). Significant speeding of reaction time by caffeine consumption was found in pattern recognition, delayed match to sample, and match to sample visual search. The effect on reaction time of 60 mg caffeine can be detected, and may be evident within minutes of consumption. Received: 16 March 1998/Final version: 27 July 1998     

Orally delivered methadone as a reinforcer in rhesus monkeys

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625–0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625–0.4 mg/ml) combined with ethanol (0.0325–2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.     

Brain stimulation as the reinforcer in alcohol-saline discrimination

Male Wistar rats were trained to discriminate intraperitoneal injections of 1 g/kg alcohol from saline injections. The reward that reinforced correct choices was an electrical brain stimulation which the animals self-administered according to a FR10 schdule of bar pressing; the stimulation was given in the postero-lateral hypothalamus. Quantitative generalization experiments revealed a mean ED 50 of 0.39 g/kg. The main advantages of this method using direct intracranial stimulation as the reward would seem to be: (1) quantitative and qualitative generalization experiments can be carried out in non-deprived rats having a normal body weight and (2) the possibility of estimating, in addition to the analysis of their discriminative properties, the effects of drugs on self-stimulation rate.     

Effect of propranolol, d-amphetamine and caffeine on ethanol as a discriminative cue

Rats were trained to escape a shock in a three-compartment chamber contingent upon their ability to discriminate between two drug states, namely, 1.5 mg/kg ethanol and 0.9% saline. This discriminative ability was found to be dose responsive and was tested after pretreatment with 1, 5, 10 and 20 mg/kg propranolol, 4.0 mg/kg d-amphetamine sulphate and 100 mg/kg caffeine. The results of the pretreatment experiments showed that, of the three possible antagonists, only amphetamine significantly decreased the rat's ability to discriminate between ethanol and saline.     

Rapid establishment of ethanol as a reinforcer for rats

Daily 6-h sessions were run during which each lever press by rats produced brief access to water, or to 8?/0 (W/V) ethanol on experimental days. Food pellets were presented noncontingently on a 1 min fixed-time schedule during the last, 4 h of each session. A stable baseline of water responding developed, characterized by little or no responding during the first 2 h followed by high rates and schedule-induced polydipsic drinking during the last 4 h. Following the development of a stable water baseline, 8% (W/V) ethanol was substituted for water on alternate days. After one previous session with ethanol, rats' responding for ethanol during the first 2 h of a session substantially exceed water baseline rates, indicating that ethanol had been established as a reinforcer. Subsequently, when food pellet presentations were discontinued, and the ethanol concentration was increased from 8 to 16 to 32% (W/V), ethanol intake persisted at values exceeding water control levels; these results confirm that ethanol was functioning as a reinforcer.     

含咖啡因某维生素功能饮料对机体运动行为能力影响分析

目的探讨含咖啡因某维生素功能饮料对人体运动行为能力的影响。方法 2015年3月选取某高校35名学生为受试者,随机将其分为对照组(去咖啡因的某维生素饮料)16例和咖啡因干预组(含咖啡因的某维生素功能饮料)19例。所有受试者干预前后开展PWC170机能试验、血清β-内啡肽水平测定、疲劳程度指数测定、背肌力和握力测试、15 s反弹跳测试及模拟篮球比赛测定。结果干预前,所有受试者PWC170、β-内啡肽水平、疲劳程度指数、背肌力、右手和左手握力、弹跳次数、弹跳最高高度及弹跳总高度、模拟篮球比赛中移动距离、平均速度、平均移动速度和最快速度比较,差异均无统计学意义(P>0.05);干预后,咖啡因干预组受试者PWC170、15 s反弹跳测试中弹跳最高高度、模拟篮球比赛中平均移动速度均较对照组显著增加,差异均有统计学意义(P<0.05)。结论饮用含咖啡因的维生素功能饮料可以适当提高人体运动行为能力。     

Nicotine as a reinforcer in human subjects and laboratory animals

Results are summarized from 17 studies in which intravenous nicotine was evaluated in self-administration paradigms. Six species, ranging from the albino rat to the human, have been tested under a variety of schedules of reinforcement, and as a function of several pharmacologic manipulations. Under certain environmental conditions, it is clear that nicotine can serve as a reinforcer. However, nicotine differs from many other drugs of abuse in that the range of environmental conditions under which it serves as a reinforcer appears to be more restricted.