Acute exposure to caffeine selectively disrupts context conditioning in rats

RATIONALE AND OBJECTIVE: Acute caffeine administration has both beneficial and adverse effects on learning and memory; however, the brain regions underlying these effects remain unclear. Several experiments were conducted to examine the effects of acutely administered caffeine on the acquisition and expression of hippocampal-dependent and hippocampal-independent forms of conditioned fear. METHODS: In the first experiment, caffeine (10, 20, or 30 mg/kg; IP) or vehicle was administered to rats 15 min prior to classical fear conditioning, which consisted of ten tone-shock pairings. Freezing to the conditioning context was measured 24 h later, whereas tone-elicited fear was measured 48 h later. A second experiment examined possible state-dependent effects of caffeine by administering caffeine (30 mg/kg) or vehicle 15 min before conditioning and before testing. RESULTS: Pretreatment of acute caffeine severely impaired the acquisition of context conditioning, a hippocampal-dependent task. Tone conditioning, a hippocampal-independent task, was only modestly and non-significantly affected by caffeine (4-21% suppression compared with controls). The disruption of context conditioning was dose-dependent: 10 mg/kg had little effect on context or tone conditioning, whereas doses of 20 and 30 mg/kg caffeine severely disrupted context conditioning (73-87% suppression). In two subsequent experiments, it was found that caffeine's selective disruption of context conditioning could not be attributed to the fact that it is a weaker form of learning than tone conditioning or to state-dependent learning. CONCLUSIONS: Considered together, these results suggest that acute administration of caffeine may preferentially disrupt the acquisition of hippocampal-dependent learning, including context conditioning.     

Differential behavioral effects of nicotine exposure in adolescent and adult rats

Rationale Although the detrimental effects of nicotine in early brain development and the addictive properties in adulthood are well known, little is known about the neurobiological effects of nicotine in adolescence. An important question is whether adolescents and adults differ in the development of nicotine sensitization and drug-cue conditioning.Objective To examine the behavioral effects of multiple, repeated injections of nicotine on both sensitization and drug-cue conditioning in the adolescent rat, and to compare this profile with the adult rat.Methods Sixteen male adolescent (28 day) and 16 young adult (70 day) rats were given injections of either saline or nicotine and tested for motor activity for 90 min for ten consecutive days. Following 4 days of no testing, animals were given a sham injection and placed in the testing apparatus for 90 min. A dose–response curve for nicotine was also generated using two additional groups of ten adolescent and ten adult male rats.Results Adolescent rats, unlike adults, did not exhibit signs of nicotine-cue conditioning, and displayed less robust sensitization to the locomotor effects of nicotine than adults. Dose–response testing revealed differences in adolescent responsivity to nicotine in measures of rearing, but not ambulation. Initial exposure to nicotine resulted in increased sensitivity to the motor-activating effects of nicotine but less sensitivity to the depressant effects of nicotine in rearing in adolescents.Conclusions Adolescent animals display different long-term neuroadaptive responses to nicotine than adult animals, possibly related to immature or still-developing plasticity mechanisms in the prefrontal cortex.Electronic Supplementary Material Supplementary material is available for this article at .     

Aversion instead of preference learning indicated by nicotine place conditioning in rats

Although nicotine is a drug of abuse for millions of smokers, it has been difficult to demonstrate clearly the motivational properties of nicotine with rats using the conditioned place preference (CPP) paradigm. The first experiment attempted to replicate CPPs reported by other researchers using nicotine doses of 0.4, 0.8, and 1.2 mg/kg. There was a trend for all three doses to produce aversions, but it was significant only for the 0.8 mg/kg dose. Exposures to the CS alone extinguished aversions, but a priming dose (0.2 mg/kg) of nicotine given after extinction produced aversions only in animals exposed to 1.2 mg/kg. Experiment 2 tested whether preexposure to morphine or nicotine would sensitize animals to nicotine's reinforcing effects. In this experiment, rats were exposed to either six nicotine (0.6 mg/kg) or morphine (1.0 mg/kg) dosings prior to preference conditioning. Neither preferences nor aversions were observed in any group following subsequent conditioning with 0.6 mg/kg nicotine. The results suggest that previous observations of preference effects may have been due to specific procedural factors or may have depended on negative reinforcement due to stress reduction.     

Nicotine-induced place preferences following prior nicotine exposure in rats

The motivational properties of morphine and nicotine were investigated in an automated conditioned place preference (CPP) procedure using a two-compartment apparatus. The accuracy of the photocell recording system was assessed by correlation with direct observation. In a counterbalanced conditioning design, graded doses of morphine (0.1–3.2 mg/kg SC) produced dose-related CPP. Under similar conditions, a dose of nicotine (0.6 mg/kg SC) previously reported to produce CPP failed to show an effect. Increasing the number of conditioning trials from 4 to 12 did not facilitate CPP with nicotine. After pretreatment with nicotine (0.4 mg/kg SC) daily for 7 days prior to conditioning, nicotine (0.4–0.8 mg/kg) produced increasing magnitudes of CPP. Locomotor activity was assessed during both conditioning and extinction tests. During conditioning, nicotine but not morphine decreased activity in the first conditioning trial, but by the fourth trial, marked stimulation was apparent following administration of either drug. Activity in the drug-paired compartment was not increased during tests for CPP carried out in the undrugged state following 4 conditioning trials with either morphine or nicotine, but there was evidence for conditioned hyperactivity after 12 conditioning trials with nicotine. The results suggest that motivational properties of nicotine can be detected in counterbalanced CPP procedures, but only in subjects with a history of nicotine exposure. The CPP produced by morphine or nicotine does not appear to be an artefact associated with conditioned changes in locomotor activity.     

Adolescent-onset nicotine self-administration modeled in female rats

Rationale Although the great majority of tobacco addiction begins during adolescence, little is known about differential nicotine effects in adolescents versus adults. Objectives A rat model was used to determine the impact of the age of onset on nicotine self-administration. Methods In expt 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01–0.08 mg/kg per infusion) was determined in adolescent (beginning at 54–62 days) versus adult (beginning at 84–90 days). In expt 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In expt 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. Results Adolescent-onset rats showed a significant main effect of increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. Conclusions Adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats, which began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction.     

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.     

Trajectories of criteria of nicotine dependence from adolescence to early adulthood

Background

To identify patterns and correlates of developmental trajectories of DSM-IV nicotine dependence criteria from adolescence to early adulthood.

Methods

The analytical sample of lifetime smokers (N = 877) is from a longitudinal cohort of 6th–10th graders drawn from an urban school system. Subjects were interviewed 5 times at 6-month intervals and once 4.5 years later. Growth mixture models were estimated to identify trajectories of DSM-IV nicotine dependence criteria over ages 12–23.

Results

A four-class solution fitted the data best: No dependence criteria (Class 1, 32.0%); Early onset/Chronic course (Class 2, 26.1%); Early onset/Remission (Class 3, 15.4%); Late onset (Class 4, 26.5%). There appeared to be three critical periods. At ages 12–15, symptoms increased rapidly. As of age 16, the Early onset/Chronic class stabilized at high levels of symptoms, the Early onset/Remission class started its symptomatic decline, and the Late onset class experienced a sharp increase in symptoms. At age 20, there was a convergence in the prevalence of symptoms experienced at high (Classes 2 and 4) and low levels (Classes 1 and 3). Extensiveness of smoking and marijuana use were associated with higher baseline levels of nicotine dependence criteria. Anxiety disorders were associated with all three symptomatic trajectories. Parental smoking and nicotine dependence were associated specifically with the Early/Chronic class, while pleasant initial sensitivity and earlier onset ages of cigarette and marijuana use characterized the two early onset classes (2 and 3).

Conclusions

Trajectories of dependence criteria constitute an advantageous phenotype for research and intervention over static summaries of smoking behaviors.     

Chronic caffeine exposure potentiates nicotine self-administration in rats

The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150–180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking. Received: 11 November 1997/Final version: 28 September 1998     

Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.     

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.     

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     

Adolescent and adult female rats differ in sensitivity to nicotine's activity effects

More than 90% of cigarette smokers begin smoking during adolescence. This between-subjects repeated-measures experiment examined: (1) nicotine's acute effects on activity in adolescent and adult female Sprague–Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on activity when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). The experiment consisted of three separate phases. In Drug Phase I, animals were administered either 0 (saline), 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine via subcutaneous injections for 12 days and horizontal activity was measured daily. During the Interim Phase (no drug phase), activity was measured but nicotine was not administered. During Drug Phase II, the same animals were administered the same nicotine dosages as in Drug Phase I for 12 days and activity was measured daily. Drug Phase I revealed dose–response differences between adolescent and adult female rats. In addition, animals initially exposed to nicotine in adolescence exhibited greater sensitivity to nicotine's activity-increasing effects than did females initially exposed to nicotine in adulthood (i.e., Drug Phase II).     

Synergistic interaction between nicotine and social rewards in adolescent male rats

Rationale  Smoking typically begins during adolescence and is largely reinforced by social cues. During adolescence in rats, sensitivity to both social cues and drugs of abuse is enhanced. Objectives  We have previously demonstrated in adolescent male rats that a low dose of cocaine interacts with social reward to produce an enhanced conditioned place preference (CPP) relative to either reward given alone. The present study further examined the nature of drug–social reward interactions using nicotine. Methods  Dose–effect functions for nicotine-CPP were established using two different routes of administration (vehicle, 0.1, 0.3, and 0.6 mg/kg, SC and vehicle, 0.01, 0.03, and 0.06 mg/kg, IV). The effects of nicotine on social reward-CPP and social play behavior were next examined using parameters presumed to be sub-threshold for establishing social reward- and nicotine-CPP. Results  Dose-dependent nicotine-CPP was observed using both routes of administration. Two pairings of the initially non-preferred side of the apparatus with either SC nicotine or another adolescent rat failed to produce CPP when examined alone, but together produced a robust CPP despite nicotine reducing social play. This interaction effect was not observed with the IV nicotine. A final experiment demonstrated that the enhancement of CPP with the combination of rewards was not due to additive effects of weak, sub-threshold conditioning. Conclusions  These findings suggest that nicotine and social rewards interact synergistically in adolescent rats resulting in a greater, perhaps qualitatively different, reward than either reward given alone. Understanding drug–social reward interactions may provide new directions for development of preventions and interventions of adolescent smoking. Funding sources: This work was supported by grants R01DA11064, R21DA023123, and F31DA023746 from the National Institute on Drug Abuse (NIDA). The content is solely the responsibility of the authors and does not necessarily represent the official view of NIDA or the National Institutes of Health.     

Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction

Rationale Enhanced reinforcing effects of nicotine during adolescence appear to contribute to the rapid development of dependence in this age group. However, the contribution of nicotine withdrawal to dependence in adolescents is unclear.Objective We compared motivational and somatic signs of nicotine withdrawal in adolescent and adult rats.Materials and methods In experiment 1, motivational signs of nicotine withdrawal were compared using intracranial self-stimulation procedures after administration of mecamylamine (1.5 mg/kg, i.p.) in adolescent and adult rats made dependent on nicotine (9 mg/kg/day). Somatic signs of withdrawal were compared in two experiments using various doses of nicotine (adolescent doses: 0, 1.6, 3.2, 4.7 mg/kg/day; adult doses: 0, 1, 2.1, 3.2 mg/kg/day, expressed as nicotine base) to produce dependence and one dose of mecamylamine (1.5 mg/kg, i.p.) to precipitate withdrawal (experiment 2) and in a subsequent experiment, using various doses of mecamylamine (0, 0.75, 1.5, 3.0 mg/kg, i.p.) to precipitate withdrawal and a dose of nicotine (adolescent dose: 4.7 mg/kg/day; adult dose: 3.2 mg/kg/day) that produced equivalent nicotine blood levels in these age groups (experiment 3).Results Adolescents did not display the decreases in brain reward function observed in adults experiencing withdrawal, and displayed fewer somatic signs of nicotine withdrawal relative to adults regardless of the dosing procedure used.Conclusion The negative effects of nicotine withdrawal are lower during adolescence relative to later periods of development. Both the enhanced rewarding effects and the diminished nicotine withdrawal likely contribute to the rapid development of nicotine use during adolescence.     

Prenatal nicotine exposure increased duration of nicotine-induced analgesia in adult rats

The effect of prenatal exposure to nicotine on nicotine-induced analgesia was studied in rats. The analgesic effect of a single dose of nicotine (1 mg/kg SC) was measured by the tail-flick technique, and two subsequent studies were carried out. In the first study, 7-month-old male rats, born to dams chronically treated with nicotine during pregnancy (NIC), exhibited prolonged nicotine-induced analgesia compared to matched controls. The second study was designed to explore whether rats prenatally exposed to nicotine (NIC rats) are born with an increased sensitivity to nicotine and whether there is any sex difference. The analgesic effect of nicotine was tested on control and NIC rats of both sexes once a month from 2 to 7 months of age. At an early age, male but not female NIC rats, exhibited shorter analgesic responses to nicotine than did the matched controls. With increasing age, however, the duration of nicotine analgesia began to be prolonged in NIC rats of both sexes. Significant differences between control and NIC rats were found at the age of 6 and 7 months, in both sexes. Thus, rats prenatally exposed to nicotine are not born with an increased sensitivity to the analgesic effect of a single dose of nicotine. This phenomenon develops later, during the course of life, independently of gender.     

Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats

RATIONALE: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission. OBJECTIVES: The present study examined the impact of nicotine treatment on the reinforcement efficacy of self-administered cocaine and non-reinforced responding for cocaine in rats. METHODS: Rats were trained to self-administer cocaine (i.v.) on a progressive ratio (PR) schedule of reinforcement. Self-administration training continued until stable responding was obtained. Acute nicotine pretreatment consisted of a subcutaneous injection (0.15, 0.3 and 0.6 mg/kg) 3 min prior to cocaine access. In the repeated treatment condition, a separate group of animals was given nicotine (0.6 mg/kg, s.c.) 3 min prior to cocaine access for 14 consecutive days. During extinction trials, these animals were injected with nicotine (0.6 mg/kg, s.c.) after 45 min of non-reinforced responding. RESULTS: Acute nicotine treatment produced an inverted U-shaped dose-response function with lower doses increasing and the highest dose decreasing the number of cocaine infusions obtained during a session. Animals treated repeatedly with the highest dose of nicotine showed a significant increase in the number of cocaine infusions by day 8 of nicotine treatment. During extinction sessions when cocaine was not available, injections of nicotine in these animals caused a reinstatement of the previously rewarded lever-press behavior. CONCLUSIONS: These findings indicate that nicotine can facilitate cocaine reinforcement, may contribute to the transition from moderate drug-taking to an escalation of drug intake which is characteristic of addiction, and may trigger relapse.     

Impaired auditory and contextual fear conditioning in soman-exposed rats

Exposure to soman (GD) can result in prolonged seizures and subsequent neuropathology in a variety of brain regions including the amygdala and hippocampus. Both regions are believed to play important roles in the development and expression of fear conditioning. The purpose of this experiment was to test these conditioning tasks as a possible behavioral correlate of the observed neuropathology. Male rats were exposed to GD (1.0 or 1.2 × LD₅₀) or saline followed with injections of atropine sulfate, the oxime HI-6 and diazepam. Fear conditioning was conducted on post-exposure day (PED) 8 followed by measuring freezing to contextual and auditory conditioned stimuli on PED 9 and 10 respectively. Contextual and auditory fear conditioning was severely impaired in both the 1.0 × LD₅₀ and 1.2 × LD₅₀ GD groups. Both GD groups spent less time freezing than controls when returned to the context in which conditioning occurred. The 1.0 × LD₅₀ and 1.2 × LD₅₀ groups had very low levels of freezing following presentation of the auditory conditioned stimulus. Neuronal fiber degeneration was present in the piriform cortex, thalamus, and amygdala in GD-exposed animals regardless of dose. The present study suggests that contextual and auditory fear conditioning is impaired in GD-exposed rats possibly due to neuropathology observed in the hippocampus, amygdala and thalamus.     

The effect of nicotine and total alkaloids extracted from cigarette smoke on avoidance behavior in rats under extinction procedure

The effect of nicotine and total alkaloids extracted from smoke on the avoidance behavior of rats under extinction procedure has been measured in an experiment extended over a period of three months. There was no significant difference between the two substances, with both inhibiting the extinction of avoidance response to approximately the same degree. Significance against the control was achieved with all treatments, the effect being significantly greater with the dose of 0.2 mg/kg than with the two doses of 0.1 or 0.05 mg/kg.This study was made possible through the help of a research grant from the Swiss Association of Cigarette Manufacturers.     

Effects of developmental nicotine exposure in rats on decision-making in adulthood

Exposure to tobacco smoke during pregnancy is associated with a range of adverse outcomes in offspring, including cognitive deficits and increased incidence of attention deficit-hyperactivity disorder, but there is a considerable controversy with regard to the causal role of tobacco smoke in these outcomes. To determine whether developmental exposure to the primary psychoactive ingredient in tobacco smoke, nicotine, may cause long-lasting behavioral alterations analogous to those in attention deficit-hyperactivity disorder, male Sprague-Dawley rats underwent a chronic neonatal nicotine administration regimen, which models third-trimester human exposure. Male rat pups were administered nicotine (6 mg/kg/day) by oral gastric intubation on postnatal days 1-7. In adulthood, rats were tested in two decision-making tasks (risky decision-making and delay discounting) as well as in free-operant responding for food reward and the elevated plus maze. Chronic neonatal nicotine attenuated weight gain during nicotine exposure, but there were no effects on performance in the decision-making task, and only a modest decrease in arm entries in the elevated plus maze in one subgroup of rats. These data are consistent with previous findings that developmental nicotine exposure has no effect on delay discounting, and they extend these findings to risky decision-making as well. They further suggest that at least some neurocognitive alterations associated with prenatal tobacco smoke exposure in humans may be due to genetic or other environmental factors, including non-nicotine components of tobacco smoke.     

Effects of environmental conditioning on the development of nicotine sensitization: behavioral and neurochemical analysis

We have investigated the effects of environmental conditioning on the induction of nicotine sensitization of locomotion, stereotypy and nucleus accumbens dopamine release. Sprague-Dawley rats, some of which had been previously implanted with a microdialysis guide cannula over the nucleus accumbens, were sensitized with 5 days of repeated nicotine (0.6 mg/kg per day, SC) or saline injections (1 ml/kg per day). During nicotine treatment the drug administration was either paired with the microdialysis/activity monitor testing chamber (conditioned) (n=6) or with the animal's home cage (unconditioned) (n=6) and after 60 min the animal was returned to home cage and received a second injection of saline 15 min later. A third group received saline in the testing apparatus followed by nicotine in the home cage (pseudo-conditioned) (n=6). In the guide cannulated animals, 2 mm microdialysis probes were inserted after completing day 5 of treatment and all animals were tested for their response to nicotine (0.6 mg/kg, SC) on day 6. Both locomotor activity and nucleus accumbens dopamine release showed a larger response subsequent to nicotine challenge in the nicotine versus saline pretreated animals in the conditioned group, but not in the unconditioned group. In the pseudo-conditioned group there was an increase in the stereotypy responses to nicotine, however the locomotor and dopamine release responses were not significantly enhanced. The results from the conditioned group were confirmed in animals which were tested for behavioral activation and dopamine release simultaneously (n=5). These findings indicate that nicotine sensitization of locomotor activity and nucleus accumbens dopamine release (using a 5-day pretreatment protocol) is dependent on conditioning the animal to the testing environment during nicotine pretreatment.