Saccharin aversions in hamsters as a result of nicotine injections

Golden Syrian hamsters (males, N = 70) showed dose-related conditioned taste aversion (CTA) when saccharin drinking was followed by delayed nicotine injections. Baseline consisted of measuring amounts consumed after 20 minutes of daily access to tap water. Measures were taken for five days. The hamsters were then conditioned by offering them saccharin solution (0.1%, w/v) for 20 minutes; afterwhich a 30 minute delay was imposed. Subsequent to the delay, groups of 10 animals were treated as follows: nicotine injection (1.0, 3.0, or 9.0 mg/kg, IP), saline injection, lithium chloride injection (2% body weight of a 0.15 M solution), sham injection, or left in their cages as handling/stress controls. Following two recovery days with plain water available for 20 minutes, all animals were tested for CTA by offering them saccharin solution. Dose-related CTA was demonstrated in the nicotine animals as measured by a decrease in saccharin consumption compared to drinking measures obtained from animals injected with saline. Lithium chloride produced the same degree of CTA as 9 mg/kg of nicotine, and the aversions had extinguished in all groups by the third test day.     

Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice

Mice of the C56BL/6J strain were trained to discriminate between nicotine (1.2 mg/kg) and saline in a two-lever drug discrimination procedure under a tandem variable-interval 60 s fixed-ratio 10 schedule of food reinforcement. Mice of the same strain were trained in conditioned taste aversion (CTA) experiments where drinking a saccharin or saline solution was paired with injection of nicotine or vehicle. During testing with both flavours presented simultaneously, a reduction in the intake of the nicotine-paired solution indicated CTA. The nicotine discrimination was acquired successfully and nicotine yielded a steep dose–response curve. The competitive nicotinic antagonist dihydro-β-erythroidine (DHβE, 0.6–3.0 mg/kg) shifted the dose–response for the discriminative stimulus effect of nicotine to the right; the 7 nicotinic receptor antagonist methyllycaconitine (MLA, 1.0–10 mg/kg) had no effect. The mice showed strong CTA to 2.0 mg/kg of nicotine and marginally to 0.6 and 1.2 mg/kg of nicotine. DHβE (3.0–5.6 mg/kg) attenuated the CTA while MLA (1.0–10 mg/kg) had no effect. These studies show that nicotine has discriminative and aversive stimulus properties in C57BL/6J mice and that the effects are mediated primarily by receptors sensitive to DHβE; there was no evidence for the involvement of 7 nicotinic receptors.     

Chronic caffeine exposure in rats blocks a subsequent nicotine-conditioned taste avoidance in a one-bottle, but not a two-bottle test.

Two experiments were conducted in order to investigate nicotine-conditioned taste avoidance (CTA) following chronic preexposure to caffeine. Rats were given daily intraperitoneal injections of caffeine anhydrous (0, 10, or 30 mg/kg) for 10 or 30 days. Training of the nicotine-CTA began after the last day of caffeine preexposure. On five separate occasions access to a saccharin solution was followed immediately by an injection of 1.2 mg/kg nicotine hydrogen tartrate salt or saline. Nicotine-CTA readily developed in saline-preexposed controls. That is, paired rats drank less saccharin solution than unpaired rats after repeated saccharin-nicotine pairings. A similar pattern of nicotine-CTA was found for rats preexposed to 30 mg/kg caffeine for 10 days. Following 10 days of preexposure to 10 mg/kg caffeine, however, CTA did not develop under standard testing conditions. Thirty days of caffeine preexposure did not affect the development of a nicotine-CTA even though the anorexic effects of caffeine were evident after exposure to 30 mg/kg for this duration. Thus, caffeine exposure appears to weaken acquisition or expression of the conditioned avoidance properties of nicotine. This effect is sensitive to the dose of caffeine and duration of preexposure. Importantly, the pattern of nicotine-CTA does not appear to be due to nonspecific effects of caffeine.     

Influence of genotype on nicotine-induced increases of plasma corticosterone in mice as a result of acute nicotine pretreatment

Acute exposure to nicotine produces an elevation of plasma corticosterone levels in rodents. The consequences of repeated exposure to nicotine administered intraperitoneally (IP) were examined in three inbred strains of mice, DBA/2Ibg, C3H/2Ibg and A/J. These strains of mice have been shown previously to differ in a variety of behavioral and physiological responses to acute nicotine exposure. Mice were administered saline or 1.00 mg/kg nicotine IP, followed 30 min later by a range of nicotine doses (0.25–1.00 mg/kg). Strain differences were observed for the dose-response to the second injection; however, no effect of acute nicotine pretreatment was demonstrated. The observed lack of desensitization was consistent across genotype. An intragastric administration of a pretreatment dose of nicotine (4.00 mg/kg) also failed to produce desensitization to a subsequent IP nicotine injection in any strain. Increasing the time interval between injections to 45 min did not alter the CCS response. However, at 90 min between injections, a supersensitive CCS response was measured in all strains.     

Visceral cortex lesions block conditioned taste aversions induced by morphine

Rats with bilateral ibotenic acid or sham lesions of the visceral (agranular insular) cortex were tested for a conditioned taste aversion (CTA) to saccharin after five pairings of morphine sulphate injections (15 mg/kg IP) with consumption of a novel solution (0.1% saccharin). Lesioned animals demonstrated no evidence of the morphine-induced CTA that was seen in the sham operated animals. A third group of rats received ibotenic acid lesions but had saccharin consumption paired with saline vehicle injections. This group had the normal preference (seen in naive rats) for saccharin on testing, showing that the visceral cortex lesion had no effect on the ability of the rats to discriminate saccharin from water. In order to test if visceral cortex lesions abolish specifically the CTA induced by morphine, we ran a similar set of CTA experiments using two new novel flavours and either 15 or 75 mg/kg IP lithium chloride (LiCl) as the unconditioned stimuli. Dose dependent CTA's to the LiCl were established in all groups indicating that the visceral cortex plays no role in mediating the aversive effect of LiCl. Using the condition place preference paradigm we investigated the role of the visceral cortex in the expression of morphine's rewarding aspects. Identical place preferences were found in groups of rats with or without visceral cortex lesions suggesting that this cortical region plays no role in either the perception of morphine's rewarding effects or the association of morphine's rewarding properties with sensory stimuli. Visceral cortex lesions also had no effect on the establishment of a conditioned place aversion to a high dose of LiCl (75 mg/kg IP). Thus, visceral cortex appears critical for the establishment of a morphine-induced CTA, but is not crucial for mediating gross taste discrimination, the aversive aspects of LiCl nor the rewarding properties of morphine.     

Nicotine-induced taste aversion: characterization and preexposure effects in rats

Rats were trained to drink their 24 hr water intake during a single daily 30 min period. After stabilization, rats were presented with 0.1% (w/v) of sodium saccharin for 30 min. Immediately after removal of the saccharin solution, the animals were injected with saline, mecamylamine hydrochloride or hexamethonium hydrobromide; thirty minutes later, saline or nicotine, 0.05, 0.16, or 0.50 mg/kg were administered. Twenty-four hr later, rats were allowed access to both water and saccharin. Nicotine caused a dose-related decrease in the proportion of fluid consumed as saccharin solution during the 30 min testing situation. Neither mecamylamine nor hexamethonium alone decreased saccharin preference; however, 3 mg/kg of mecamylamine blocked the decrease of saccharin preference induced by nicotine. Preexposure of drug-naive rats to 0.5 mg/kg of nicotine for 2 or 4 days abolished the nicotine-induced taste aversions to saccharin when tested one day, or one week, after conditioning.     

Preexposure effects of nicotine and acetaldehyde on conditioned taste aversion induced by both drugs

Previous assessments have demonstrated an interaction between ethanol and nicotine in the conditioned taste-aversion (CTA) paradigm. The present study assessed whether acetaldehyde, the primary reinforcing metabolite of ethanol, would interact with nicotine as well. In six experiments, water-deprived male Wistar rats were preexposed to either acetaldehyde (0.2 or 0.3 g/kg, IP) or nicotine (0.8, 1.2, or 2 mg/kg, SC) for 3 consecutive days and then subsequently conditioned, 24 h later, with either nicotine (0.8, 1.2, or 2 mg/kg, SC) or acetaldehyde (0.2 or 0.3 g/kg, IP), respectively. There were 4 conditioning days and 4 drug-free test days, each spaced 72 h apart. On test days, animals were offered a free choice between water and saccharin. The results of the following set of experiments demonstrated a dose-related interaction between nicotine and acetaldehyde, where lower doses of each drug failed to attenuate CTA induced by one another, but a higher nicotine dose (2 mg/kg) attenuated the formation of a CTA induced by acetaldehyde (0.3 g/kg). It was argued that the primary metabolite of ethanol may play a role in the interaction between nicotine and ethanol previously observed.     

Caffeine, nicotine and mecamylamine share stimulus properties in the preexposure conditioned taste aversion procedure

RATIONALE: The present study examined whether nicotine and caffeine, two of the most widely used psychoactive drugs, share stimulus properties in the preexposure conditioned taste aversion (CTA) procedure. OBJECTIVES: To determine whether nicotine would attenuate the formation of a caffeine-induced CTA and further assess whether pretreatment with mecamylamine, a nicotinic receptor antagonist, would reverse nicotine's attenuating effect of a caffeine-induced CTA. METHODS: Male Wistar rats were preexposed with one of three doses of nicotine (0.6, 1.2 and 2.0 mg/kg, s.c.) for three consecutive days, then 24 h following the final preexposure injection were conditioned with caffeine (20 mg/kg and 30 mg/kg, i.p.) in a standard two-bottle test. There were four conditioning trials and four drug-free test days. In a follow-up study, rats were pretreated with mecamylamine (2 mg/kg, i.p.) prior to preexposure injections with nicotine (0.6 mg/kg, i.p.), then subsequently conditioned with caffeine (20 mg/kg, i.p.) as described above. RESULTS: The lowest nicotine dose (0.6 mg/kg) attenuated the caffeine induced CTAs (20 mg/kg and 30 mg/kg) but the higher nicotine doses showed no such attenuating effect. In addition, mecamylamine reversed the nicotine-induced attenuation of the caffeine-induced CTA and also directly attenuated it. CONCLUSIONS: These results suggested that caffeine, nicotine and mecamylamine share overlapping stimulus properties and that the nature of this relationship may involve action at the nicotinic-cholinergic receptor.     

Adipsic,but not anorectic,effect of fluprazine hydrochloride in rats

The present experiment explored the anorectic and adipsic effects of fluprazine hydrochloride, a phenylpiperazine compound. Thirty-eight albino rats were randomly assigned either to a control saline group (six rats) or to groups (eight subjects each) receiving an IP dose of fluprazine in saline (1.25, 2.5, 5 or 10 mg/kg). No anorectic effect of the drug doses was observed 30, 60, 90, 120, 180 and 240 min, and 24 h after drug injection. However, water drinking was significantly decreased 30 min after drug administration, with 5 and 10 mg/kg, compared to saline.     

The NMDA antagonist dizocilpine (M K801) attenuates tolerance to nicotine in rats

The N-methyl-D-aspartate antagonist dizocilpine (MK801) has been shown to attenuate neuroadaptations of the locomotor activity responses seen after chronic nicotine administration in rats. The aim of the present study was primarily to examine the effects of dizocilpine on tolerance to the aversive stimulus effect of nicotine, as measured in a conditioned taste aversion (CTA) paradigm. A second aim was to determine whether the previously reported effect of dizocilpine on tolerance to the locomotor depressant effect of nicotine could be confirmed. CTA was assessed from changes in the consumption of saccharin and salt solutions and locomotor activity was measured during 30 min sessions in photocell cages. In control rats, the administration of nicotine (0.4 mg/kg s.c.) produced strong CTA and a biphasic effect on locomotor activity (depression followed by facilitation). Daily treatment for 7 days with nicotine (0.4 mg/kg s.c.) produced tolerance to the CTA and motor effects. This tolerance was not detectable in rats that had received dizocilpine (0.3 mg/kg s.c.) 30 min before each daily injection of nicotine during the period of chronic treatment. The chronic administration of dizocilpine alone did not prevent locomotor effects and CTA when nicotine was administered subsequently. These results suggest that the NMDA receptor may be involved in adaptation to both unconditioned and conditioned behavioural responses to nicotine.     

Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice.

The present experiments examined the effects of the GABA(B) receptor agonist, baclofen, on the acquisition of ethanol-induced conditioned place preference (CPP) and conditioned taste aversion (CTA) in male DBA/2J mice. Mice in the CPP experiment received four pairings of ethanol (2g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). On intervening days (CS- sessions), mice received saline injections paired with a different floor type. On CS+ days, mice also received one of four doses of baclofen (0.0. 2.5, 5.0, or 7.5 mg/kg) 15 min before an injection of ethanol. For the preference test, all mice received saline injections, and were placed on a half-grid and half-hole floor for a 60-min session. Baclofen dose dependently reduced ethanol-stimulated activity, but did not alter the magnitude of ethanol-induced CPP at any dose. For the CTA experiment, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of saline or baclofen (2.0 and 6.0 mg/kg) 15 min before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Baclofen did not alter the magnitude of ethanol-induced CTA at any dose. In addition, baclofen alone did not produce a CTA. Overall, these studies show that activation of GABA(B) receptors with baclofen reduces ethanol-induced locomotor activation, but does not alter ethanol's rewarding or aversive effects in the CPP and CTA paradigms in DBA/2J mice.     

Caffeine potentiates the discriminative-stimulus effects of nicotine in rats

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.     

Learned taste aversion to saccharin following intraventricular or intraperitoneal administration of d,1-amphetamine

The effects of intracerebroventricular (ICV—160, 250, 500 μg) and intraperitoneal (IP—3,5 mg/kg) administration of d,1-amphetamine were compared using a multiple-bottle CTA procedure. After one conditioning trial animals receiving IP amphetamine exhibited a marked aversion to saccharin. This effect was dose-dependent. With cannulated animals receiving ICV saline the effectiveness of amphetamine at 5 mg/kg IP was equivalent to that of 3 mg/kg IP with unoperated rats. After one conditioning trial amphetamine at 160 μg ICV was ineffective in inducing an aversion to saccharin. Animals receiving 250 or 500 μg ICV exhibited a marked aversion to saccharin after one trial. The 160 μg ICV dose was effective after two conditioning trials. This differential potency of centrally and peripherally administered amphetamine after one conditioning trial indicates that the aversive stimulus properties of amphetamine may not simply be centrally mediated. It is proposed that both central and peripheral amphetamine effects may be necessary for the induction of a CTA with this drug.     

Withdrawal from chronic nicotine fails to produce a conditioned taste aversion to saccharin in rats

Sprague-Dawley rats were maintained on a daily regimen of nicotine, morphine or saline administration for 28 days. Following the discontinuation of the daily drug regimen, rats were given a choice of tap water or a saccharin-water solution. The rats previously receiving morphine drank significantly less saccharin-water solution than did the rats receiving nicotine or saline injections. The failure of the nicotine rats to display a conditioned aversion to the novel saccharin flavor suggests that nicotine did not produce a physiological withdrawal syndrome analogous to morphine withdrawal in this paradigm.     

Effects of naloxone and its quaternary form on fluid consumption in rats

Three studies were performed on albino rats to determine the effects of naloxone and its quaternary derivative, naloxone methylbromide, on fluid consumption. The doses of the quaternary naloxone were equated with naloxone by molarity and effectiveness in order to facilitate direct comparisons. All rats were deprived of food and water for 12 hr and exposed to a 20% sucrose solution for a 2 hr period. In Experiment 1, a low (0.01 mg/kg) dose of naloxone or an equated dose of quaternary naloxone was given ICV and immediate access allowed to the fluid on four consecutive days. Animals receiving naloxone were not significantly different from controls, and rats receiving quaternary naloxone exhibited seizures, resulting in decreased consumption. In Experiment 2, the low dose of naloxone or the equated dose of quaternary naloxone was given IP for four consecutive days and neither was significantly different from controls. In Experiment 3, animals were given an IP dose of either 1 mg/kg naloxone, a 1 mg/kg or 50 mg/kg dose of quaternary naloxone, or saline and tested for a single 2 hr period. The doses of 1 mg/kg naloxone and 50 mg/kg quaternary naloxone produced significantly less drinking than controls. In all studies, the initial 30 min period produced the most drinking. Suppression of drinking by a dose of 50 mg/kg quaternary naloxone suggested, in contrast to other studies, that it may cross the blood-brain barrier at high doses.     

Effects of nicotine on spatial learning in C57BL mice

In the present study, the effects of nicotine on spatial memory in C57BL/6J mice was evaluated. Mice were trained in a water maze during four daily sessions of three trials each. In the first experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered once daily for 4 days, 15 min before the start of daily training: an impairment of performance of the water maze was observed in the group treated with 0.7 mg/kg of nicotine. In the second experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered from the 5 days prior to the beginning of the task and during the 4 days of acquisition. The results indicated an improvement in the rate of learning in the 9-day nicotine treated groups. The comparison between 4-day and 9-day treated groups revealed that the group receiving 0.35 mg/kg of nicotine for 9 days displayed significantly shorter latencies than all the other groups, while the group receiving 0.7 mg/kg of nicotine for 4 days performed significantly worse than all the other groups. The most noteworthy result is that nicotine was more effective after a more prolonged administration than when administered only during the training days.     

Withdrawal from chronic nicotine substitutes partially for the interoceptive stimulus produced by pentylenetetrazol (PTZ)

Rats were trained on an FR10 schedule of food reinforcement to press one lever after pentylenetetrazol (PTZ), 20 mg/kg, IP, and an alternate lever after saline. After acute nicotine, 0.64 mg/kg, SC, 35% of the rats pressed the PTZ-lever. Diazepam, 5 mg/kg, IP, blocked the stimulus produced by PTZ, and mecamylamine, 5 mg/kg, IP, blocked the stimulus produced by nicotine. Training was then suspended and rats were treated with nicotine, at 8-h intervals, 0.64 mg/kg on the 1st day, and 1.25 mg/kg on subsequent days, for 21 days. To determine whether nicotine withdrawal substitutes for the stimulus produced by PTZ, rats were tested with saline at various times after chronic nicotine injections. Data from this part of the study were replicated in another group given nicotine for 15 days. Saline at 8 h after nicotine (five determinations each group) produced a small but stable degree of PTZ lever selection (35±4%). At 48 h after termination of nicotine treatment, the percentage of rats selecting the PTZ lever (50%) was greater than that in a control group tested after an equivalent period without training. The PTZ-like stimulus detected after chronic nicotine was not altered by mecamylamine, was additive with PTZ, and was blocked by diazepam. These data suggest that withdrawal from chronic nicotine produces a weak PTZ-like stimulus, which can be antagonized by an anxiolytic drug.     

Aversive conditioning properties of caffeine in rats

Four experiments tested the conditioning effects of caffeine. Flavor and place cues were paired with IP caffeine injections and followed by tests for cue preference. In Experiment 1A, saccharin was paired with 1.25, 5 or 20 mg/kg of caffeine. In Experiment 1B, caffeine was delivered 30 min before, 5 min before, or 30 min after saccharin. Dose- and time-dependent conditioned taste aversions were produced. In Experiment 2, a place and taste cue were paired simultaneously with 5 or 20 mg/kg of caffeine. Conditioned place and taste aversions developed at 20, but not at 5 mg/kg. In Experiment 3, a place cue alone was paired with 0, 5, or 20 mg/kg of caffeine; dose-dependent conditioned place aversions developed. In Experiment 4, place and taste cues were paired with control treatments: pH-buffered caffeine, purine or vehicle. Caffeine produced taste aversions whereas the purine and vehicle did not. These aversive conditioning effects of caffeine across a variety of situations, doses and temporal arrangements stand in contrast to results obtained with other psychoactive drugs, such as amphetamine and alcohol.     

Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence.

A "gateway" function toward substance abuse has been suggested for early tobacco smoking. Nicotine actually represents an easily available drug for human adolescents, who are very likely to use a number of different psychoactive agents. Surprisingly, the psychobiological factors involved in this age-related willingness have been poorly investigated. In Experiment 1, nicotine consumption was studied in outbred CD-1 mice during Early (postnatal day (pnd) 24 to 35), Middle (pnd 37 to 48) or Late (pnd 50 to 61) adolescence, in an oral self-administration paradigm. During the drinking session (2 h/day), animals had free choice between either tap water or a nicotine solution (10 mg/l). After a 6-day period, a fading study was carried out, in which nicotine concentration was reduced to 7 mg/l (days 7-9) and 5 mg/l (days 10-12), to assess whether animals would compensate by increasing their intake from the nicotine solution. In Experiment 2, psychopharmacological effects on locomotion induced by the nicotine solution (0, 10, 30 mg/l) during the 1-h drinking session were assessed in Early and Late adolescent mice. In Experiment 1, Early adolescents expressed a marked and stable preference for the nicotine solution, showing a daily nicotine intake of 1.15 +/- 0.04 mg/kg. Middle adolescents did not show any preference for either bottle, whereas a tendency toward avoidance for the nicotine solution was found for Late adolescents. In the fading study, Early adolescents were the only group to show increased consumption from the nicotine bottle as far as nicotine concentration was reduced. A time-course analysis of plasma levels of cotinine (the principal biomarker of nicotine consumption) revealed some pharmacokinetic differences between the three age-groups. In Experiment 2, drinking from a nicotine solution produced a prominent hyperactivity in Early adolescents, whereas a quite opposite profile was associated with older subjects. In summary, even if a role for taste factors cannot be completely ruled out, a peculiar spontaneous drive toward oral nicotine consumption, as well as a nicotine-induced arousal, is specific to Early adolescence in mice. The present animal model might be useful to investigate psychobiological determinants involved in early tobacco smoking in human adolescents     

Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine

Rationale Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults.Objectives This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. We also examined age differences in locomotor responses to nicotine.Methods In the CPP paradigm, male periadolescent and adult Wistar rats received nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle prior to place conditioning trials. In the CTA paradigm, in separate groups of rats, periadolescents and adults were exposed to a 0.1% saccharin solution, followed by the administration of nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle. Four saccharin–nicotine pairings were followed by a preference test and three extinction sessions.Results In the CPP paradigm, nicotine produced a dose-dependent place preference in periadolescent, but not in adult, rats. In the CTA paradigm, adult rats expressed a dose-dependent avoidance of saccharin after pairings with nicotine, whereas periadolescents were resistant to CTA formation. With regard to locomotor activity, adults and periadolescents showed comparable locomotor responses to nicotine.Conclusions These results suggest that periadolescent rats find nicotine more rewarding and less aversive, compared to adult rats. This shift in the balance between the rewarding and aversive effects of nicotine may make adolescents more susceptible to continued nicotine use.