Caffeine increases the motivation to obtain non-drug reinforcers in rats

Background: Caffeine is widely considered to be a reinforcer in humans, but this effect is difficult to measure in non-human animals. We hypothesized that caffeine may have dual reinforcing effects comparable to nicotine – limited primary reinforcing effects, but potent reinforcement enhancing effects. The present studies tested this hypothesis by investigating the effect of caffeine on responding for non-drug rewards. Methods: In two experiments, rats were shaped to respond on a progressive ratio (PR) schedule for sucrose solution (20%, w/v; Experiment 1) or a fixed ratio 2 (FR2) schedule for a moderately reinforcing visual stimulus (VS; Experiment 2). Pretreatment with various doses of caffeine (0–50 mg/kg, intraperitoneal injection) were administered prior to tests over successive week days (M-F). In Experiment 1, acute administration of low-moderate caffeine doses (6.25–25 mg/kg) increased responding for sucrose under the PR schedule. This effect of caffeine declined over the initial 15 test days. In Experiment 2, only acute pretreatment with 12.5 mg/kg caffeine increased responding for the visual stimulus and complete tolerance to this effect of caffeine was observed over the 15 days of testing. In follow up tests we found that abstinence periods of 4 and 8 days resulted in incomplete recovery of the enhancing effects of caffeine. Conclusion: The findings suggest that caffeine enhances the reinforcing effects of non-drug stimuli, but that the pharmacological profile of these effects may differ from other psychomotor stimulants.     

Nicotine enhances responding with conditioned reinforcement

Rationale The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes.Objective In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects.Methods After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25–350 µg/kg SC; –5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 µg/kg SC; –20 min) alone, or in combination with nicotine (350 µg/kg SC; –5 min), on conditioned reinforcement was also examined.Results Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 µg/kg SC; –5 min) was selectively blocked by mecamylamine (300 µg/kg).Conclusions These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.     

Intravenous self-administration of nicotine: with and without schedule-induction

In Experiment I, rhesus monkeys were trained to lever press on a concurrent fixed-interval 5-min (food pellets) fixed-ratio 1 (IV nicotine-injection) schedule of reinforcement. All three monkeys self-administered nicotine (0.1-100 micrograms/kg/injection) at two or more doses during the concurrent conditions (Concurrent I or II) at rates that exceeded saline control or rates of nicotine-maintained responding on a simple fixed-ratio 1 schedule (No Food condition). At least one dose of nicotine did maintain FR 1 responding which was greater than saline rates on the single component schedule and these rates were not increased by the addition of a concurrent schedule of food reinforcement. During the concurrent schedule, nicotine-maintained responding occurred throughout the 60-min session in contrast to the No Food (FR 1) condition where most injections of nicotine were self-administered during the initial segments of the session. In general, nicotine injections occurred during the early portions of the interval, although this varied between individual animals. In Experiment II, rhesus monkeys were trained to lever press for intravenous injections of cocaine (50 micrograms/kg/injection) on a fixed-ratio 10 schedule of reinforcement. During testing, doses of nicotine (1-300 micrograms/kg/injection) or saline were substituted for cocaine. Nicotine maintained FR 10 responding at rates that exceeded saline self-administration at one or more doses in all four monkeys. These doses were similar to those that functioned as positive reinforcers in Experiment I. These two experiments demonstrate that nicotine can function as a positive reinforcer to maintain FR 1 or FR 10 responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule

Rationale Nicotine infusions that are self-administered (contingent) or response-independent (noncontingent) increase lever pressing for a reinforcing nonpharmacological stimulus in rats, suggesting that in addition to primary reinforcement, nicotine self-administration may result from nicotine enhancing the reinforcement derived from nonnicotine stimuli. Objectives Based on our previous research, in this study, we tested the hypothesis that contingent and noncontingent nicotine would equally elevate responding for a moderately reinforcing visual stimulus, across a range of nicotine doses on both fixed ratio and progressive ratio reinforcement schedules. Materials and methods The rats lever pressed for a visual stimulus with contingent nicotine, noncontingent nicotine, or contingent saline. Separate groups responded for saline or nicotine without the visual stimulus. Three doses of nicotine (0.01, 0.03, and 0.09 mg/kg per infusion, free base) were tested in a between-groups design. After responding on an escalating fixed ratio reinforcement schedule, the rats were tested on a progressive ratio schedule. Results Compared to responding for the visual stimulus with saline, both contingent and noncontingent nicotine equally elevated lever pressing for the stimulus at each dose on fixed and progressive ratio schedules. In the absence of the stimulus, only the highest nicotine dose sustained self-administration. Conclusions The ability of noncontingent nicotine to elevate responding for a moderately reinforcing visual stimulus occurs across a range of doses, and both self-administered and noncontingent nicotine equally increase motivation to obtain the stimulus, as reflected by performance on a progressive ratio schedule. In the absence of a contingent stimulus, primary reinforcement from nicotine only supports self-administration at high nicotine doses in rats.     

Opposing acute and chronic behavioural effects of a beta-blocker,propranolol, in the rat

Rats were trained over 40 days to lever-press for food reward under a schedule of differential reinforcement of low rates of response with a 20-s criterion (DRL 20), following seven sessions of continuous reinforcement. The effect of injecting a beta-adrenergic blocker, propranolol (5 mg/kg IP), before and at two different delays after each daily session of DRL were investigated. In Experiment I, rats drugged 5–8 min before every session earned fewer reinforcements compared to controls, and showed impaired temporal discrimination. In Experiment II, this result was not replicated, but similar effects were clear in animals drugged pre-session from the 15th day of acquisition. By contrast, an improved temporal discrimination, and increased number of reinforcements were seen in rats drugged 5–8 min after every session. In Experiment III, the postsession effects were replicated and found also in rats drugged 4–5.5 h after each session. These results suggest that propranolol has an acute effect on DRL responding which resembles that of anxiolytics, and a chronic effect which opposes the acute one.     

Repeated nicotine exposure enhances responding with conditioned reinforcement

Rationale Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes.Objective This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion.Methods Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 µg per side) prior to the conditioned reinforcement test.Results Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine.Conclusions These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.     

Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine

Rationale Nicotine self-administration in rats is modest when response-contingent nicotine infusions are delivered alone (primary reinforcement) but robust when nicotine infusions are combined with a mildly reinforcing non-pharmacological stimulus. Furthermore, response-independent (non-contingent) nicotine administration also elevates responding for that same non-pharmacological stimulus, suggesting that in addition to primary reinforcement, nicotine can enhance the incentive value of other reinforcers.Objectives In this study, we tested the hypothesis that the reinforcement-enhancing effects of non-contingent nicotine are more dependent on the reinforcing strength of the non-pharmacological stimulus than are the effects of contingent nicotine.Materials and methods A weakly reinforcing light-tone stimulus was established as a conditioned reinforcer by repeated pairings with sucrose for some rats, or by delivery in an explicitly unpaired design with sucrose to other rats. Subsequently, both groups lever pressed for the stimulus with contingent nicotine, non-contingent nicotine (0.06 mg kg⁻¹ per infusion, freebase), or non-contingent saline, according to fixed ratio and progressive ratio reinforcement schedules.Results Compared to sucrose-unpaired training, repeated association with sucrose established the light-tone stimulus as a robust conditioned reinforcer. Contingent and non-contingent nicotine equally elevated responding for this conditioned stimulus. Conversely, for the less reinforcing (sucrose-unpaired) stimulus contingent nicotine more effectively elevated behavior compared to non-contingent nicotine.Conclusions The reinforcement-enhancing effect of nicotine increases behavior controlled by both conditioned and unconditioned reinforcers; however, for less salient stimuli associative processes derived from the primary reinforcing effects of contingent nicotine may also be important. These data suggest that nicotine present in tobacco may differentially modulate stimulus-driven behavior in smokers.     

Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus

Rationale and objective

Intravenous infusions of nicotine appear to exert little primary reinforcing effects in adult rats but, instead, maintain self-administration behavior at least, in part, by increasing the intrinsic reinforcing effects of drug-paired sensory stimuli. The present study examined instead the impact of a motivationally neutral cue on self-administration.

Methods

Adult male Long-Evans rats were permitted to self-administer nicotine (0.015 mg/kg IV given over 30 s, 2 h/day) or saline presented with or without a sensory stimulus (light, white noise). Fixed and progressive ratio reinforcement schedules of nicotine reinforcement were tested. Experiment 2 determined whether noncontingent nicotine or mecamylamine (nicotinic antagonist) would induce lever pressing for either sensory stimulus. Experiment 3 tested whether the white noise stimulus alone could maintain responding after repeated pairing with self-administered nicotine. Finally, the sensory stimuli were assessed for possible aversive properties.

Results

Nicotine infusions alone were at best weakly reinforcing. The white noise stimulus, presented alone, was neither reinforcing nor aversive, whereas the white light appeared marginally reinforcing. Both stimuli, however, facilitated intravenous nicotine self-administration. Neither nicotine nor mecamylamine challenge rendered the white noise reinforcing. The white noise, after being self-administered with nicotine, failed to maintain self-administration behavior on its own.

Conclusions

Even a motivationally neutral sensory stimulus, lacking detectable primary or secondary reinforcing properties, can facilitate self-administration of nicotine. Possibly, drug-paired stimuli provide a "response marker" or serve as a temporal bridge between the operant response and drug effect. Motivationally neutral stimuli may therefore serve to isolate primary reinforcing effects of nicotine.     

Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine

Rationale Nicotine is widely assumed to convey reinforcing properties upon tobacco-related stimuli through associative learning. We have proposed that the reinforcement derived from these conditional stimuli can be inflated by a nonassociative “reinforcement-enhancing” effect of nicotine. Objectives Experiment 1 investigated whether nicotine could establish a stimulus as a conditioned reinforcer. Using the same subjects, Experiment 2 examined whether responding for a nicotine-associated stimulus was enhanced by response-independent administration of nicotine. Materials and methods Self-administered nicotine (Paired group, 0.03 mg kg¹ infusion⁻¹) or saline (conditional stimulus or CS-Only group) was paired with a stimulus light (CS). An Unpaired group, yoked to the Paired group, received equal exposure to nicotine and the CS, but each event was temporally separated. To test for conditioning, the CS was then made contingent upon a novel lever-pressing response. In Experiment 2, a subset of the paired rats (self-administering) continued to lever press while receiving contingent nicotine and the CS. To determine whether nicotine enhanced responding for the CS, two remaining subsets of the Paired group responded for the CS while receiving nicotine (YNIC) or saline (YSAL) yoked to the self-administering rats. All remaining control groups received response-contingent CS presentations, together with yoked nicotine or saline. Results Pairing self-administered nicotine with the CS promoted the acquisition of a novel response for the CS. In Experiment 2, the Paired YNIC group responded at higher rates than control groups receiving YNIC or YSAL. Conclusions Nicotine can establish stimuli as conditioned reinforcers for which noncontingent nicotine can enhance responding.     

Adolescent exposure to nicotine results in reinforcement enhancement but does not affect adult responding in rats

Background

Adolescence is a period of development associated with a peak in an organism's responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether (1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and (2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood.

Methods

Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (postnatal day 29–42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules.

Results

Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.

Conclusions

Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.     

Reinforcement enhancing effects of nicotine via smoking

Rationale

In animals, nicotine enhances reinforcement from stimuli unrelated to nicotine intake. Human research is suggestive but has not clearly shown a similar influence of nicotine.

Objectives

We assessed acute effects of nicotine via smoking on enhancement of positive (money, music) or negative (termination of noise) reinforcers, or no “reward” (control). These different rewards determined the generalizability of nicotine effects.

Materials and methods

Dependent (n?=?25) and nondependent (n?=?27) smokers participated in three sessions, each after overnight abstinence. Using a within-subjects design, sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) Quest^R brand cigarettes. For comparison, a fourth session involved no abstinence prior to smoking one's own brand to gauge responses under typical nicotine satiation. Reinforcement was assessed by responses on a simple operant computer task for the rewards, each available singly on a progressive ratio schedule during separate trials.

Results

The reinforcing effect of music, but not other rewards, was greater due to the nicotine cigarette, compared to the denicotinized cigarette or no smoking. Reinforcement enhancing effects of nicotine did not differ between dependent and nondependent groups, indicating no influence of withdrawal relief. Responding due to acute nicotine after abstinence was very similar to responding to one's own brand after no abstinence.

Conclusions

Acute nicotine intake per se from smoking after abstinence enhances the reinforcing value of rewards unassociated with smoking, perhaps in a manner comparable to ad lib smoking after no abstinence. Nicotine's reinforcement enhancing effects may be specific to certain rewards, perhaps those sensory in nature.     

Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement

Rationale Current conceptualizations of drug reinforcement assume that drug-taking behavior is a consequence of the contingent, temporal relationship between the behavior and drug reward. However, stimulant drugs also potentiate the rewarding effects of other reinforcers when administered noncontingently. Objectives These studies were designed to determine whether noncontingent nicotine enhances the reinforcing properties of a nonpharmacological reinforcer and whether this direct effect facilitates operant behavior within the context of a nicotine self-administration procedure. Methods Rats self-administered nicotine or food, or received noncontingent nicotine, saline, or food either with or without a response-contingent, unconditioned reinforcing visual stimulus (VS). Results Noncontingent nicotine, whether delivered as discrete injections based on a pattern of self-administered nicotine or as a continuous infusion, increased response rates maintained by the VS. There were no significant differences in responding by animals that received contingent compared with noncontingent nicotine when a VS was available. This increase was not observed in the absence of the VS or as a consequence of noncontingent food delivery. Operant behavior was equally attenuated and reinstated by the removal and subsequent replacement of contingent and noncontingent nicotine. Nicotine supported self-administration in the absence of response-contingent, nicotine-paired stimuli; however, response rates were drastically reduced compared with nicotine self-administration with the VS. Conclusions Nicotine influences operant behavior in two ways: by acting as a primary reinforcer when it is contingent upon behavior, and by directly potentiating the reinforcing properties of other stimuli through a nonassociative mechanism. Nicotine self-administration and smoking may be largely dependent upon this later action. This work was supported by National Institute on Drug Abuse research grants, DA-10464 and DA-12655. "Principles of laboratory animal care" (NIH No. 85-23, revised 1985) were followed throughout all experiments. This research was approved by the University of Pittsburgh Institutional Animal Care and Use Committee, Assurance Number A3187-01     

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers

Rationale Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans.Objectives To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements.Methods Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1–20 min) and FR response requirement (10–1600) were varied in different subjects over consecutive sessions.Results Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings.Conclusions Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.Abstracts of these experiments previously appeared in Pharmacologist 25:219, 1983, and Neurosci Lett 14(Suppl):140, 1983.     

Role of dopamine in the behavioural actions of nicotine related to addiction

Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by dopamine receptor antagonists shows that dopamine is involved in nicotine's discriminative stimulus properties, nicotine-induced facilitation of intracranial self-stimulation, intravenous nicotine self-administration, nicotine conditioned place-preference and nicotine-induced disruption of latent inhibition. Therefore, nicotine depends on dopamine for those behavioural effects that are most relevant for its reinforcing properties and are likely to be the basis of the abuse liability of tobacco smoke. On the other hand, in vivo monitoring studies show that nicotine stimulates dopamine transmission in specific brain areas and in particular, in the shell of the nucleus accumbens and in areas of the extended amygdala. These effects of nicotine resemble those of a reward like food except that nicotine-induced release of dopamine does not undergo single-trial, long-lasting habituation. It is speculated that repeated non-habituating stimulation of dopamine release by nicotine in the nucleus accumbens shell abnormally facilitates associative stimulus-reward learning. Acute effects of nicotine on dopamine transmission undergo acute and chronic tolerance; with repeated, discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine release in the nucleus accumbens core takes place while the response in the shell is reduced. It is speculated that these adaptive changes are the substrate of a switch from abnormal incentive responding controlled by consequences (action-outcome responding) into abnormal habit responding, triggered by conditional stimuli and automatically driven by action schemata relatively independent from nicotine reward. These two modalities might coexist, being utilized alternatively in relation to the availability of tobacco. Unavailability of tobacco disrupts the automatic, implicit modality of abnormal habit responding switching responding into the explicit, conscious modality of incentive drug-seeking and craving.     

Dopamine and conditioned reinforcement

In the conditioned reinforcement paradigm, animals learn a new instrumental response reinforced solely by conditioned reward (a stimulus that has previously been associated with primary reward). It has been shown that psychostimulants potentiate responding for conditioned reward and there is evidence that the nucleus accumbens is involved in this effect. The present experiments extend this work and examine the roles of various striatal subregions in the enhancement of responding for conditioned reward. In the conditioning phase, hungry rats were trained to associate a light/click stimulus with food delivery, with no levers present in the operant chamber. In the test phase, two levers were present and responding on one provided conditioned reward (presentation of the compound stimulus but no food). During this phase, microinjections of d-amphetamine (0, 0.2, 2.0, 20.0 micrograms/0.5 microliters) were made into seven striatal subregions in separate groups of rats. Injection of amphetamine into the nucleus accumbens elicited a dose-dependent, selective increase in responding for CR. Injections into posterior regions of the striatum had no effect. Significant and selective increases in CR responding were noted after injections into two regions neighboring the nucleus accumbens, the anterior dorsal and the ventromedial striatum, although the magnitude of these effects was considerably less than that following accumbens injections. Injections into ventrolateral regions increased responding in some rats, but this effect was very variable and not selective for the CR lever. These results are interpreted as evidence for functional heterogeneity of the striatum with regard to enhancement of conditioned reinforcement. The findings are discussed in relation to the theory that increased dopaminergic activity in the nucleus accumbens results in amplification of the response to a previously learned reward-related signal.     

Nicotine trace discrimination in rats with midazolam as a mediating stimulus

It was shown previously that effects of drugs present prior to training sessions could serve as discriminative stimuli. Further experiments have aimed to determine whether a second drug can serve as a mediating stimulus that increases the strength of stimulus control by such pre-session drug effects. Rats were trained in a two-lever discrimination procedure with food reinforcers presented on a tandem variable-interval fixed-ratio (VI-FR) schedule. Injections of nicotine (0.6 mg/kg) or saline were followed after 5 min by administration of midazolam (0.2 mg/kg) as a putative mediating stimulus. The nicotine antagonist mecamylamine (1.0 mg/kg) was administered 5 min after midazolam, to block effects of nicotine during training sessions, as in previous work on pre-session drug effects. Stimulus control was acquired slowly and to an accuracy of only 75%. Midazolam did not facilitate the acquisition or magnitude of nicotine-induced stimulus control. However, extinction tests showed that the presence of midazolam was required for expression of stimulus control by pre-session effects of the training dose of nicotine. The response to nicotine (0.075-0.6 mg/kg) was dose-related, but the dose-response relationship was not dependent upon the presence of midazolam. In a group of rats trained with nicotine and midazolam as above, but without mecamylamine, stimulus control by nicotine was not dependent upon the presence of midazolam. In all cases, overall rates of responding were very low when tests were carried out without midazolam, suggesting the presence of state-dependent learning. The results imply that under appropriate conditions the discriminative stimulus effects of one drug (nicotine) can be mediated by the action of a second substance (midazolam). This finding can be conceptualized in terms of occasion setting, with nicotine serving as the feature and midazolam as the target stimulus. Furthermore, it appears that even when rates of responding show drug-state dependence, this is not necessarily the case for discriminative stimulus effects.     

Nicotine self-administration in baboons

Two experiments were conducted in which responding maintained by nicotine and cocaine was studied under two different schedules of drug delivery. In Experiment 1, nicotine (0.01–0.32 mg/kg IV) was available under a fixed-ratio 2 timeout 15 sec reinforcement schedule. When nicotine was substituted for cocaine or saline, dose-dependent differences in self-administration were evident across the first five sessions, resulting in an inverted U-shaped dose-effect curve. With continued exposure to each nicotine dose, however, number of injections generally stabilized at levels not very different, if at all, from saline; and the terminal dose-effect functions generally were low and flat. In Experiment 2, nicotine (0.01–0.56 mg/kg IV) was available under a fixed-interval 5 min timeout 60 sec reinforcement schedule. Response rates were considerably lower and response patterning was less likely to be scalloped than when responding was maintained by either cocaine or food, but number of injections was higher than those maintained by saline. When fixed-interval value was varied, number of nicotine reinforcements remained low and virtually constant, but number of food reinforcements increased as the fixed interval decreased. The present results, along with those from previous studies, suggest that the ability of nicotine to serve as a reinforcer appears to be strongly influenced by the conditions of drug availability, perhaps more so than for other drugs of abuse.     

In a low-versus high-dose drug discrimination task, random reinforcement in one drug state alters discriminative control only in that state

This study investigated the effects of introducing random reinforcement training after a drug discrimination between 3.0 and 15.0mg/kg chlordiazepoxide had been acquired in rats; a two-lever food-rewarded operant procedure was used. Matched on the basis of dose-generalization test data, two dose-equisensitive groups were formed (A and B). Group A received 30 daily saline injections, which were followed by a random reinforcement session during which either left or right lever presses were reinforced on a probabilistic basis on each of the trials comprising a session. Group B received saline but no training or testing during this period. Subsequent testing revealed that responding conditioned to the low-dose training condition, but not to the high-dose training condition, was significantly changed in Group A. The randon reinforcement data further suggested that Group A did not discriminate saline from the low training dose. In Experiment 2, Group B of Experiment 1 was submitted to 30 random reinforcement training sessions, each preceded by a high training dose administration. Data showed that responding to the high dose, but not the low dose, was changed. For both experiments, chlordiazepoxide dose generalization following reacquisition was similar to that obtained before the random reinforcement phase. The findings indicate that the response pattern changed only for the stimulus condition present during random reinforcement. The random reinforcement manipulation did not disrupt the original discrimination between the high-and low-dose conditions.     

Effects of acute and chronic nicotine on impulsive choice in rats

Impulsive choice, or preference for small immediate reinforcers over large delayed reinforcers, has been associated with cigarette smoking. The direct effects of nicotine on impulsive choice in laboratory animals are unknown. We examined the effects of acute and chronic nicotine injections, and the termination of injections, on impulsive choice in rats. Five rats made choices between a one- and a three-pellet reinforcer in a discrete trials procedure. The delay to the smaller reinforcer was always 1 s. A computer adjusted the delay to the larger reinforcer until the pattern of choices reflected indifference between the two alternatives. We assessed the effects of acute and chronic nicotine (vehicle, 0.03, 0.1, 0.3 and 1.0 mg/kg nicotine). The latency to make the first response of the session increased under the acute 1.0 mg/kg dose. There were no consistent differences in the effects of acute and chronic nicotine on response latency and lever pressing during the delays between choices. Acute injections of nicotine dose-dependently increased impulsive responding. After chronic injections, impulsive responding was increased equivalently regardless of dose, and it was increased even in the absence of nicotine. After drug injections were terminated, behavior remained impulsive for about 30 drug-free sessions, and then responding gradually returned to baseline levels. The results suggest that increases in impulsive choice were not due to anorectic effects, response biases or changes in conditioned reinforcement. Nicotine may have decreased the value of delayed reinforcers. Chronic nicotine exposure produced long-lasting but reversible increases in impulsive choice.     

Repeated heroin in rats produces locomotor sensitization and enhances appetitive Pavlovian and instrumental learning involving food reward

We tested the hypothesis that sensitization to heroin enhances appetitive motivational processes involving food reward. In Experiment 1, sixteen rats were exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, the rats received either saline or heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. Rats were then tested in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another lever produced a tone stimulus not paired with anything. Heroin produced both significant progressive increases in locomotor activity (sensitization) and significantly enhanced conditioned reinforcement of instrumental lever pressing by the food-associated stimulus. In Experiment 2, thirty-two rats were given Pavlovian discrimination training in a conditioned magazine approach task where one stimulus was associated with food and a second unpaired with food. Rats then received repeated saline or heroin injections as in Experiment 1, before being tested under extinction conditions with the two stimuli without the drug. Chronic heroin had no effect on performance in this test, but it facilitated learning of the reversed discrimination in a subsequent phase. These data suggest that sensitization to heroin enhances appetitive motivational processes involving food reward.