Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers

Rationale Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers. Objectives The present study sought to dissociate these two effects of nicotine on reinforcement. Methods For one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever. Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine infusions (NIC only) or VS presentations (VS only) for pressing the active lever. Results Nicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC + VS). Conclusions These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.     

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.     

Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats

Rationale Recent studies have demonstrated that nicotine can enhance operant responding for other nonpharmacological reinforcing stimuli. However, the nature of the reinforcement-enhancing effect of nicotine remains largely unknown. Objective The present study determined the dose dependency of the ability of nicotine to increase lever-pressing responses maintained by a compound visual stimulus (VS) in rats and examined its sensitivity to pharmacological antagonism of nicotinic acetylcholine receptors (nAChRs). Materials and methods Male Sprague–Dawley rats were trained in daily 1-h sessions to lever press for delivery of a VS (1 s lever light on and 60 s house light off) on a fixed ratio 5 schedule. During these sessions, eight scheduled response-independent intravenous infusions of nicotine (total amount: 0, 0.06, 0.12, 0.24, 0.48 mg kg⁻¹ h⁻¹) were delivered. In pharmacological tests, a nonselective nAChR antagonist mecamylamine, α4β2-selective antagonist dihydro-β-erythroidine (DHβE), and α7-selective antagonist methyllycaconitine (MLA) were administered in different groups of rats 30 min before the session. Results The VS maintained a moderate level of lever-pressing responses and nicotine dose-dependently increased responses for the VS presentations. Preteatment of mecamylamine and DHβE but not MLA significantly attenuated the nicotine-enhanced responding. However, mecamylamine had no effect on responding for the VS in rats that received scheduled saline infusions. Conclusions These results demonstrate dose dependency of the reinforcement-enhancing effect of nicotine and suggest that activation of the α4β2- but not α7-containing nAChRs may mediate this effect.     

Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats

Rationale Smoking-related environmental stimuli have been implicated as an important factor in triggering relapse in abstinent tobacco smokers, and recent evidence indicates that drug-associated stimuli can reinstate nicotine-seeking in rats. However, there is little investigation on the factors that contribute to the latter effect. Objective This study examined whether a nicotine-associated visual stimulus (VS) can reinstate nicotine-seeking after extinction in a response-reinstatement model of relapse, and whether the behavioral effects of the VS are sensitive to pharmacological blockade of nicotinic neurotransmission. It also determined whether active lever reassignment after food training influences nicotine self-administration and the VS-induced reinstatement. Methods Male Sprague–Dawley rats were trained to self-administer nicotine (0.03 mg/kg/infusion, IV) and associate a VS with each nicotine infusion in 30 daily 1-h sessions. Half of the animals received nicotine infusions for responding at the same lever that previously delivered food; for the other half, infusions resulted from pressing the previously inactive lever during food training. Then, the nicotine-maintained response was extinguished by saline substitution and withholding the VS. One day after rats reached extinction criterion, the reinstatement tests were conducted where the VS was response-contingent represented without further delivery of nicotine. In pharmacological tests, a nicotinic antagonist, mecamylamine, was subcutaneously administered 30 min before reinstatement sessions. Results Presentation of the nicotine-associated VS significantly reinstated responding at the previously drug-reinforced lever and pretreatment with mecamylamine effectively attenuated the response-reinstating effect of the VS. Additionally, animals showed similar profiles of nicotine-taking and nicotine-seeking behavior regardless of reassignment of the active lever after food training. Conclusions Nicotine self-administration and the VS-induced reinstatement of nicotine-seeking do not result from a lever bias due to prior experience for food reinforcement. Significantly, these results suggest that environmental stimuli associated with nicotine self-administration can effectively elicit nicotine-seeking behavior in abstinent subjects, that this effect is blocked by nicotine antagonism, and that the present procedures may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and relapse.     

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     

The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine,cocaine and food in rats

Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.Objectives The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers.Methods Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1–9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions.Results Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food.Conclusions The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.     

Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716).

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drug-seeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drug-seeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.     

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.     

The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose

Stimuli associated with nicotine (NIC) can acquire new meaning via Pavlovian conditioning. If a stimulus is associated with the primary reinforcing effects of NIC, the new conditional properties of the stimulus should make it a more valuable reinforcer (i.e., increase the motivation to obtain the stimulus), and this value should be based, in part, on the strength or intensity of the primary reinforcer (i.e., NIC dose). The purpose of the present study was to investigate whether NIC-conditioned reinforcement increased motivation to obtain non-NIC stimuli, as reflected by performance on a progressive ratio (PR) reinforcement schedule, and whether this increased motivation was systematically related to NIC dose. Two Paired groups were allowed to nose-poke for NIC (0.03 or 0.09 mg/kg/infusion, IV) accompanied by 15-s illumination of a stimulus light (conditional stimulus or CS). Two Unpaired groups (0.03 or 0.09 mg/kg/infusion) could also make a nose-poke response for the CS; however their NIC infusions were controlled by the Paired group (i.e., yoked design). A fifth group (CS-Only) was allowed to nose-poke for CS presentations and saline infusions. After 29 conditioning sessions the nose-poke operant was prevented by obscuring the receptacle and the CS (accompanied by saline infusion for all groups) was made contingent upon a novel operant response (lever press). During the acquisition of this novel response, each CS/saline infusion earned increased the number of responses required to earn the next CS/saline infusion. Pairings with the primary reinforcing effects of NIC resulted the acquisition of a novel response for the CS. Motivation to obtain the CS depended on salience (dose) of the primary reinforcement (NIC).     

The generality of nicotine as a reinforcer enhancer in rats: effects on responding maintained by primary and conditioned reinforcers and resistance to extinction

Rationale  Nicotine may enhance the reinforcing value of other reinforcers. It is unclear whether nicotine enhances responding maintained by all reinforcers or whether there are limits to this role. Objective  The objective of the study is to test the generality of nicotine-induced increases in reinforced responding by using an observing response procedure, which generated measures of responding maintained by food reinforcers, conditioned reinforcers, and responding during extinction. We also examined whether nicotine increased resistance to extinction and whether nicotine’s effects could be characterized as rate-dependent. Materials and methods  Rats received presession subcutaneous injections of Vehicle (n = 5), 0.3 (n = 6), or 0.56 (n = 6) mg/kg nicotine for 70 sessions. Resistance to extinction was also assessed by removing food for five sessions. Results  Nicotine did not consistently affect food or extinction responding. Both doses of nicotine produced increases in responding maintained by conditioned reinforcers, but did not increase resistance to extinction. Predrug response rates accounted for a small but significant percentage of the variance in the drug effect. Conclusion  Although there was a tendency for nicotine to increase low predrug response rates (i.e., response rates just prior to nicotine administration), 0.3 and 0.56 mg/kg nicotine systematically increased responding maintained by conditioned reinforcers. The results are consistent with a reinforcer-enhancing role of nicotine. However, nicotine did not increase resistance to extinction, nor did it increase food-maintained responses. Nicotine may selectively increase responding maintained by moderately reinforcing stimuli, such as the conditioned reinforcers used in the present study.     

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.     

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 rats on a progressive ratio schedule of reinforcement

Rationale: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. Objective: Here, we attempt to establish and characterize nicotine SA on a PR. Methods: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0.09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. Results: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. Conclusions: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement. Received: 28 December 1998 / Final version: 14 June 1999     

Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training

Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg kg⁻¹ per infusion) before access to higher doses, a slower rate of drug delivery (3-s versus 1-s infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressed for nicotine (0.03-0.4 mg kg⁻¹ per infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-s (FR5TO20) reinforcement schedule and consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice.     

Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone

The rate and pattern of lever pressing were studied in 18 rats during 24-h sessions in which responding resulted in intravenous infusions of nicotine. There were four indications of the positive reinforcing effect of nicotine: (1) a greater number of lever presses when nicotine was response-contingent compared to when saline was available; (2) a greater number of responses on the lever resulting in an infusion of nicotine than on the control lever; (3) systematic decreases in the number of contingent nicotine infusions when nicotine was delivered noncontingently; and (4) systematic changes in the frequency of lever pressing as a function of dose. Under a fixed ratio 1 (FR 1) schedule, the number of infusions first increased and then decreased as the dose of nicotine was decreased (64, 32, 16, and 8 microg/kg infusion) and nicotine intake (mg/kg every 24 h) was directly related to the infusion dose. As the FR size was increased from 1 to 6, the number of lever presses increased and the number of infusions (32 microg/kg) remained stable. At FR values greater than 6, both the number of lever presses and infusions decreased. Presession injections of mecamylamine (0.75, 1.5, and 3.0 mg/kg, s.c.) decreased the number of infusions in a dose-related manner. Presession injections of hexamethonium (1.5 and 3.0 mg/kg, s.c.) or naloxone (0.75, 1.5, and 3.0 mg/kg, s.c.) did not alter the within- or between-session patterns of nicotine self-administration. Under the conditions of the present experiment, nicotine served as an effective reinforcer and the behavior was shown to be sensitive to both FR size and infusion dose. In addition, the results suggest that nicotine self-administration involves central nicotinic receptors and that opioid receptor antagonism has no effect on nicotine's reinforcing effects in rats.     

The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections

We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.4 mg/kg base) or saline injections was tested. The stimulus that supported very low rates of operant responding displayed smaller increases in responding after pre-session injections of nicotine. In Experiment 2 the effect of nicotine injected 5 min before the session was compared to the effect of nicotine injected 1h after the session using the more reinforcing stimulus condition from the first experiment. A control group received only vehicle injections. In contrast to nicotine injected just prior to the session, post-session injections of nicotine had no detectable effect on responding for the more reinforcing stimulus. These results indicate that the reinforcement enhancing action of nicotine depends on the intensity of the primary reinforcer and that enhanced reinforcement by nicotine depends on coincident access to a stimulus with reinforcing properties.     

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.     

Nicotine analog inhibition of nicotine self-administration in rats

RATIONALE: Partial agonists and antagonists of addictive drugs have been useful in the treatment of dependence. OBJECTIVE: The purpose of this study is to determine whether nicotine analogs with partial agonist or antagonist properties at alpha4beta2 nicotinic acetylcholine receptors (nAChRs) inhibit self-administration of nicotine in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained to self-administer nicotine (unit dose 0.017 mg/kg) intravenously contingent upon the completion of five lever presses. Once stable responding was established, rats were administered test agents, either as a subcutaneous injection before the daily session or co-infused with nicotine. RESULTS: The number of nicotine injections taken per session was reduced to approximately 50% of baseline after either pre-treatment with the broad spectrum nicotinic receptor antagonist, mecamylamine, or by substituting saline for nicotine (extinction). 4'-Trans-methyl-nicotine, a strong partial agonist, inhibited nicotine self-administration and substituted for nicotine to support self-administration. Partial agonists, prepared by substitution at the 1'-N-position with either ethyl or cyclopropylmethyl moieties, potently inhibited self-administration. Antagonists formed by 5'-methyl substitution also inhibited self-administration, with the 5'-trans-methyl enantiomer about ten times more potent than the 5'-cis-methyl enantiomer. In contrast, antagonists formed by aryl substitution at the 5 position of the pyridyl ring of nicotine did not inhibit self-administration. Intravenous co-infusions had similar effects to the pre-injections. In most instances, doses of the analogs that reduced nicotine self-administration had no effect on food intake when measured using a similar FR5 protocol. CONCLUSIONS: Nicotine analogs with alpha4beta2 nAChR partial agonist and antagonist efficacies can inhibit self-administration and may be considered as prototypical smoking-cessation agents.     

The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats

Lever-pressing responses of a group of five rats (Group E) were rewarded with i.v. injections of cocaine (0.1 mg/kg) under conditions of continuous access for eleven 24-h sessions. When the rats were partially food-deprived every third day, cocaine infusions more than doubled during that session. When saline was substituted for cocaine, responding diminished over a 10-day period (Extinction Phase), but when the rats were subsequently food-deprived every third day (Testing Phase), for a total of six cycles (20 sessions), high rates of responding for saline were reinstated only during food deprivation sessions. Seven control groups were included to investigate several questions regarding this effect. Group C-1 received cocaine but no food deprivation experience during the Training Phase, and Group C-2 received food deprivation experience without cocaine access. The results showed that simultaneous presentation of both the food deprivation condition and cocaine was necessary to reinstate food deprivation-induced increases in responding during the Testing Phase. To test for the importance of the contingency between responding and cocaine infusions during food deprivation (and satiation) in the Training phase, Group C-3 was yoked to Group E; they received the same number and pattern of infusions during the Training Phase, but infusions were not contingent upon lever-press responses. This group showed only small increases in saline-maintained responding due to food deprivation during the Testing Phase. Groups C-4 and C-5 were treated as Groups C-3 and E, respectively, except they were partially food-deprived during the 10-day Extinction Phase. Three of five rats in Group C-4 and all rats in Group C-5 showed no increases due to food deprivation during the Testing Phase. Group C-6 was pre-exposed to food deprivation before the experiment began, and Group C-7 was exposed to food deprivation only once during the Training Phase. Both procedures weakened the ability of food deprivation to produce high rates of saline-maintained responding. It was concluded that novel interoceptive stimuli related to food deprivation had become associated with the relatively novel reinforcing effects of cocaine and these interoceptive stimuli functioned as conditioned reinforcers to increase the maintenance and reinstatement of drug-seeking behavior.     

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.