Associative and behavioral tolerance to the analgesic effects of nicotine in rats: tail-flick and paw-lick assays

Rationale Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine.Objective We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine.Methods and results Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test.Conclusions The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.     

Analgesia induced by neonatal capsaicin treatment in rats

Twenty-seven rats were treated by 475 mg kg^?1 of subcutaneous capsaicin from 2 to 7 days of their life. After treatment, only 11 rats had survived. Their cutaneous heat, pressure, pricking and visceral hyperosmolarity nociceptive thresholds were measured between 50 and 170 days after treatment. The results showed a considerable, or even total, analgesia to cutaneous as well as to visceral stimuli. The conclusion is that same pathways carried all the nociceptive messages independently of nature or localization of noxious stimuli.     

Effects of continuous nicotine infusion on nicotine self-administration in rats: relationship between continuously infused and self-administered nicotine doses and serum concentrations

Rationale The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. One reason for this limited efficacy may be that typical serum nicotine concentrations provided by NRT do not match the peak arterial nicotine concentrations achieved from smoking.Objective The purpose of the present study was to determine whether continuous nicotine infusion at a rate producing serum nicotine concentrations that match the estimated peak arterial nicotine concentrations associated with nicotine self-administration (NSA) in rats produces greater suppression of NSA than lower infusion rates.Methods The effects of continuous nicotine infusion were studied by intravenously administering nicotine at various rates (1.0, 3.0, and 8.0 mg/kg per day) to rats concurrently self-administering nicotine (0.03 mg/kg per infusion) during 23-h sessions or cocaine (0.17 mg/kg per infusion) during 2-h sessions.Results Continuous nicotine infusion suppressed NSA in a rate-related fashion. NSA was suppressed by 17, 50, and 73% at infusion rates of 1.0, 3.0 and 8.0 mg/kg per day, respectively. The 8.0-mg/kg per day infusion rate, which provided venous serum nicotine concentrations equaling the peak arterial concentrations associated with NSA, suppressed NSA to a greater extent than lower infusion rates. The 8.0-mg/kg per day nicotine infusion rate had no effect on cocaine-maintained responding, demonstrating that its effects were specific for suppression of NSA. This infusion rate provided a mean percentage replacement of nicotine from NSA of more than 700%. Reacquisition of NSA after suppression by the two highest infusion rates was delayed compared with reacquisition after saline extinction.Conclusions Continuous nicotine infusion produced an infusion rate-related suppression of NSA that was greatest when the infusion provided nicotine doses and venous serum concentrations substantially higher than those typically associated with NRT in humans.     

Characteristics of tail-tremor induced by nicotine in rats

To characterize the tail-tremor and locomotor hyperactivity induced by repeated nicotine administration, the effects of nicotinic, -adrenergic and dopaminergic blockers were investigated in rats. Daily administration of nicotine (0.5 mg/kg, s.c.) induced tail-tremor from the 4th day, which became more marked in intensity by subsequent administration. Locomotor hyperactivity was also induced by nicotine, which was enhanced by daily administration. The tail-tremor and locomotor hyperactivity induced by repeated nicotine administration were inhibited by mecamylamine (0.1–1 mg/kg, i.p.) but not by hexamethonium (0.5 and 1 mg/kg, i.p.). Clonidine (0.02 and 0.04 mg/kg, i.p.) and prazosin (0.5 and 1 mg/kg, i.p.) reduced tail-tremor more markedly than hyperactivity. However, haloperidol (0.05–0.2 mg/kg, i.p.) and chlorpromazine (1–5 mg/kg, i.p.) reduced hyperactivity more markedly than tail-tremor. These results suggest that nicotine-induced tail-tremor and hyperactivity are due to an increased susceptibility of central nicotinic receptors of nicotine followed by catecholaminergic mechanisms, and that tail-tremor may be more associated with the noradrenergic system than the dopaminergic system. Correspondence to: Y. Gomita at the above address     

Antinociception induced by atorvastatin in different pain models

Atorvastatin is a statin that inhibits the 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Several landmark clinical trials have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. It is assumed that the beneficial effects of statin therapy are entirely due to cholesterol reduction. Statins have an additional activity (pleiotropic effect) that has been associated to their anti-inflammatory effects. The aim of the present study was to assess the antinociceptive activity of atorvastatin in five animal pain models. The daily administration of 3-100 mg/kg of atorvastatin by oral gavage induced a significant dose-dependent antinociception in the writhing, tail-flick, orofacial formalin and formalin hind paw tests. However, this antinociceptive activity of atorvastatin was detectable only at high concentrations in the hot plate assay. The data obtained in the present study demonstrates the effect of atorvastatin to reduce nociception and inflammation in different animal pain models.     

Dexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol

The antinociceptive activity of dexketoprofen was studied in mice using the acetic acid writhing test (acute tonic pain), the tail flick test (acute phasic pain) and the formalin assay (inflammatory pain). Isobolographic analysis was used to study the antinociceptive interactions between morphine and paracetamol co-administered with dexketoprofen. In the writhing test, the intraperitoneal administration of dexketoprofen or ketoprofen resulted in parallel dose-response curves with equal efficacy, but higher relative potency for dexketoprofen. In the tail flick test, the curves were parallel with similar efficacy and potency. The administration of morphine or paracetamol in both tests resulted in dose-response curves not parallel with that of dexketoprofen, which showed a potency between morphine and paracetamol. In the formalin assay, the antinociceptive activity of morphine during phase I was 122, 295 and 1695 times higher than dexketoprofen, ketoprofen and paracetamol, respectively. Isobolographic analysis demonstrated that the combination of sub-analgesic doses of dexketoprofen with morphine or with paracetamol was strongly synergic in all three tests. Synergistic drug combinations should improve effective pharmacological treatment of pain, minimizing drug specific adverse effects. These findings are undoubtedly worthy of additional controlled clinical trials in severe pain syndromes.     

Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor

RATIONALE: Despite the widespread popularity of opioid analgesics, significant differences in the potency and effectiveness of these drugs are often observed across age groups. OBJECTIVES: The purpose of this investigation was to examine age-related differences in sensitivity to the antinociceptive effects of mu opioids and to identify the conditions under which these differences are most apparent. METHODS: In a warm-water tail-withdrawal procedure, young (3 months) and aged (24 months) male rats were habituated to restraint and the latencies to remove their tails from 50 degrees C (low nociceptive intensity) and 55 degrees C (high nociceptive intensity) water were measured. Opioids possessing a range of intrinsic efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine, nalorphine) were examined. RESULTS: Young and aged rats were equally sensitive to the antinociceptive effects of morphine, levorphanol, and buprenorphine when tested at the low nociceptive intensity. When these drugs were tested at the high nociceptive intensity, differences between the two age groups became apparent, such that aged rats were significantly more sensitive to the antinociceptive effects of these drugs than young rats. Differences between age groups were most apparent when butorphanol, nalbuphine, and nalorphine were tested, in that each of these drugs produced maximal levels of antinociception in aged rats under conditions in which they failed to produce antinociceptive activity in young rats. Under conditions in which lower efficacy opioids failed to produce antinociceptive activity in young rats, they antagonized the effects of morphine in drug combination tests. CONCLUSIONS: These data may be taken as evidence that aged male rats are more sensitive to the antinociceptive effects of mu opioids than young male rats, and that age-related differences in opioid sensitivity are most apparent when lower efficacy opioids and higher nociceptive intensities are employed during behavioral testing.     

Morphometric and biochemical analysis of adrenal medullary hyperplasia induced by nicotine in rats

The administration of nicotine (1 and 4 mg/kg/day, subcutaneously for up to 6 weeks) to male Sprague-Dawley rats first induced a time-and dose-dependent increase in catecholamine (CA) synthesis. This was followed by an increase in endogenous CA levels and in total volume and number of chromaffin cells, as measured by stereological methods on serially sectioned adrenal glands. Thus, continued stimulation of the sympathoadrenal system generated an increase in biosynthetic enzyme activity, and subsequently adrenal medullary hypertrophy and hyperplasia developed as an adaptive reaction. The proposed model is useful for quantifying both biochemically and morphometrically early adrenal changes long before irreversible pathologic alterations are manifested.     

Acute and chronic nicotine effects on working memory in aged rats

Acute and chronic nicotine administration has been repeatedly been found in our laboratory to improve working memory performance of normal adult rats in the radial-arm maze. The current study was conducted to determine if acute or chronic nicotine administration would improve working memory performance in aged rats. Sixteen young adult (3–7 months) and 32 aged (24–28 months) male Sprague-Dawley rats were trained on an eight-arm radial maze. A significant age-related choice deficit was seen during the 21 sessions of training. After training, half of the rats in each age group were implanted with nicotine-containing osmotic minipumps and the other half implanted with vehicle-containing pumps. Consistent with previous work, the young adult rats given chronic nicotine (approximately 5 mg/kg per day as measured as nicotine base) showed a significant improvement in working memory performance. In contrast, the aged rats did not show a significant effect of this dose of chronic nicotine. After a 2 week withdrawal period the remaining rats underwent a series of acute drug challenges with nicotinic and muscarinic agonists and antagonists as well as the dopaminergic antagonist haloperidol. Mecamylamine and haloperidol impaired the memory performance of the young adult rats, whereas the aged rats showed no effect. In contrast, scopolamine impaired performance of both young adult and aged rats in a similar manner. Both pilocarpine and nicotine improved the memory performance of the aged rats, but did not improve the young adult rats, possibly due to a ceiling effect on performance. During the cholinergic agonist drug phase, the aged rats which had previously been given chronic nicotine infusions showed better performance than those which had not. The resistance of the aged rats to chronic nicotine-induced working memory improvements and acute mecamylamine-induced working memory deficits may have resulted from the decline in nicotinic receptors seen with aging. Chronic co-administration of the nicotinic antagonist mecamylamine in a previous study was found to abolish the chronic nicotine-induced working memory improvement. The aged rats were resistant to haloperidol-induced deficits which may have resulted from the decrease in dopaminergic receptors seen with aging. Interestingly, acute cholinergic agonists including nicotine did improve working memory performance in the aged rats and previous chronic nicotine infusion was beneficial during the period of acute cholinergic agonist challenge. This suggests that nicotinic treatment may be of use for treating age associated memory impairments but that special dosing regimens may be required.This work was carried out in partial fulfillment of a BSc (Hons) in Biochemistry at the University of Bath (UK) by D.T.     

Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats

Rationale Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine self-administration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior.Objectives This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus.Methods Initially, male and female rats acquired self-administration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg^–1 inf^–1, freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus.Results While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg^–1 inf^–1 on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses. Combining nicotine infusions with the visual stimulus doubled responding compared to nicotine alone at 0.03 and 0.06, but not at 0.15 mg kg^–1 inf^–1: this effect was significantly greater for female rats.Conclusions These data highlight the prominent contribution of nonpharmacological stimuli to nicotine-reinforced behavior across a range of doses in both male and female rats. They also reveal sex differences in operant responding for nicotine under conditions where a nonpharmacological stimulus is either absent, or combined with drug delivery.     

Antinociception induced by stimulating the anterior pretectal nucleus in two models of pain in rats

1. This study examined whether different parts of the rat anterior pretectal nucleus (APtN) may be involved in the spinal control of brief (tail flick test) or persistent (surgical incision of the plantar aspect of a hind paw) noxious inputs via activation of descending pathways. 2. We have confirmed that stimulation of the dorsal APtN produces a strong antinociceptive effect in the tail flick test, as opposed to a very weak effect obtained from the ventral APtN. Stimulation at the ventral APtN was the most effective part of the nucleus against a persistent incisional pain. 3. The incisional pain was significantly increased following injection of 1 or 2% lignocaine (0.25 microL) into the nucleus, but the effect was more intense after neural block of the ventral rather than the dorsal APtN. Injection of 2% lignocaine (0.10 microL) into the ventral, but not dorsal, APtN significantly increased the perception of the incisional pain. 4. We conclude that the effect of stimulating the APtN depends on the site of stimulation and model of pain used. Sustained noxious stimuli activate pathways from the ventral APtN to reduce further noxious spinal inputs. The noxious stimulation produced during the tail flick test may be not enough to activate the same circuitry, but electrical stimulation at the dorsal APtN is very effective in inhibiting brief thermal noxious inputs at the spinal level.     

Trait differences in response to chronic nicotine and nicotine withdrawal in rats

Introduction

Understanding an individual’s vulnerability to drug addiction has important implications for the development of effective personal treatment plans. Although theories acknowledge impulsive behaviour as a key component of drug addiction, little is known about the influence of trait impulsivity on an individual’s susceptibility to the effects of psychostimulants on impulsivity at critical phases of the addiction cycle.

Methods

This study investigated the short and longer-term effects of chronic nicotine administration on impulsive choice in rats selected for high (HI) and low impulsivity (LI) on a delay discounting task. Rats prepared with subcutaneously osmotic mini-pumps received either nicotine (3.16 mg/kg/day [freebase]) or saline for 7 days. Performance was assessed during chronic treatment, early and late withdrawal, and in response to acute nicotine challenges following prolonged abstinence.

Results

Chronic nicotine increased impulsive choice in LI but not HI animals. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by opposing effects on impulsive choice in HI and LI animals. A transient decrease in impulsivity was observed in HI animals whilst the LI group remained more impulsive for up to 1 week following drug termination. Following normalisation of behaviour, acute nicotine challenges (0.125, 0.25, 0.5 mg/kg, SC) markedly increased impulsive choice regardless of trait impulsivity and drug history.

Conclusion

The results indicate that only LI individuals are vulnerable to chronic drug- and withdrawal-induced impairments in self-control which may increase the likelihood of the transition to, and maintenance of, nicotine dependence.     

Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats

Tobacco use is prevalent in the adolescent population. It is a major concern because tobacco is highly addictive and has also been linked to illicit drug use. There is not much research, however, on the interaction between nicotine and other stimulant drugs in animal models of early adolescence. This study examined the effects of chronic nicotine alone and on cocaine-stimulated activity in male and female periadolescent rats compared to male and female adult rats. During the seven-day nicotine pretreatment period, nicotine increased locomotor activity in all groups compared to vehicle controls. Male and female adult rats and female periadolescent rats developed sensitization to the locomotor-activating effects of nicotine over the 7-day treatment period, while male periadolescent rats did not. All groups treated with nicotine, however, exhibited sensitization to nicotine-induced repetitive motion over the 7-day nicotine treatment period. On day 8, male periadolescent rats pretreated with nicotine were more markedly sensitized to the locomotor-activating effects of cocaine than male adult rats, while female rats pretreated with nicotine were not sensitized to cocaine. In contrast, male and female periadolescent rats, but not adult rats, had increased amounts of repetitive beam breaks induced by cocaine after nicotine pretreatment. Overall, it appears that cross-sensitization to cocaine is greater in periadolescent than in adult rats, and that males are more sensitized than females. Thus, it may be that nicotine use during adolescence carries a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of cocaine abuse after nicotine use. This information should be taken into account so as to help us better understand the development of drug addiction in adolescents compared to adults.     

Inhibition of nicotine-induced seizures in rats by combining vaccination against nicotine with chronic nicotine infusion

The ability of a nicotine vaccine to protect against nicotine-induced seizures was studied in rats. Groups of 10 rats were vaccinated with 3 doses of either a nicotine conjugate vaccine over 6 weeks to elicit high titers of nicotine-specific antibodies or with a control vaccine. Rats were then pretreated with a 1-week subcutaneous infusion of either nicotine 1 mg/kg/day or saline and then received a single 2 mg/kg ip dose of nicotine to provoke seizures. Vaccination reduced the incidence of seizures. The combination of vaccination and pretreatment with nicotine infusion was more effective than either treatment alone. These data suggest that vaccination is protective against this toxic effect of nicotine and that combining vaccination and chronic nicotine administration may provide a novel strategy for blocking some effects of nicotine.     

Analgesia induced by vaginal stimulation in rats is apparently independent of a morphine-sensitive process

Previous studies have suggested that in rats probing against the vaginal cervix with a glass rod is analgesic, for this stimulus elevates the threshold for eliciting vocalization in response to tail shock. In the present studies pretreatment with naloxone HCl (1 or 10 mg/kg), a potent narcotic antagonist, did not antagonize this vaginal stimulation-induced analgesia. Furthermore, vaginal stimulation was found to exert its analgesic effect even in rats made tolerant to, and dependent upon, morphine sulfate. These results suggest that the analgesic effect of vaginal stimulation is not necessarity mediated by an opiatesensitive neural system. However, we hypothesize that even though vaginal stimulation and other analgesic manipulations may act via different neural substrates, they may nevertheless converge onto a final common mechanism for pain suppression.     

Norepinephrine release in amygdala of rats during chronic nicotine self-administration: an in vivo microdialysis study

The essential role of the amygdala in learning and memory, including cue-associated learning, is influenced by local release of norepinephrine (NE). The current study investigated changes in amygdaloid NE secretion in rats learning to self-administer nicotine in an unlimited access model (23 h/day). In vivo microdialysis of NE was performed for 9 h intervals during three phases of nicotine self-administration: acquisition (day 1); early maintenance, when self-administration rates first stabilized (day 8.4+/-0.7); and later, during fully stable maintenance (day 17.6+/-1.0). On day 1, a greater number of self-administration episodes (SAEs) were associated with elevated NE levels in rats bar-pressing for nicotine (88% vs. 39% with saline). By early maintenance, such episodes increased threefold and overall NE levels were greater. During later maintenance, however, bar-pressing behavior was similar and NE was elevated by the first SAE of the day, but total daily NE levels were no longer elevated. In all the three phases, the enhanced NE release during the first daily SAE did not occur in the last SAE 9 h later. Thus, in an animal model of unlimited nicotine self-administration that approximates the human pattern of nicotine consumption via smoking, the amygdaloid NE response to nicotine diminishes over each day and with the stabilization of self-administration. The decline of amygdaloid NE secretion after long-term nicotine self-administration likely reflects desensitization to the pharmacological effects of nicotine. In addition, amygdaloid NE release, which enhances the consolidation of amygdala-dependent memory, may no longer be necessary once self-administration behavior has been established.     

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.     

The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine

Excitatory amino acids (EAAs) and their receptors play a central role in the mechanisms underlying pain transmission. NMDA-receptor antagonists such as MK-801 produce antinociceptive effects against experimental models of chronic pain, but results in acute pain models are conflicting, perhaps due to increased glutamate availability induced by the NMDA-receptor antagonists. Since guanosine and riluzole have recently been shown to stimulate glutamate uptake, the aim of this study was to examine the effects of guanosine or riluzole on changes in nociceptive signaling induced by MK-801 in an acute pain model. Rats received an i.p. injection of vehicle, morphine, guanosine, riluzole or MK-801 or a combined treatment (vehicle, morphine, guanosine or riluzole+MK-801) and were evaluated in the tail flick test, or had a CSF sample drawn after 30 min. Riluzole, guanosine, and MK-801 (0.01 or 0.1 mg/kg) did not affect basal nociceptive responses or CSF EAAs levels. However, MK-801 (0.5 mg/kg) induced hyperalgesia and increased the CSF EAAs levels; both effects were prevented by guanosine, riluzole or morphine. Hyperalgesia was correlated with CSF aspartate and glutamate levels. This study provides additional evidence for the mechanism of action of MK-801, showing that MK-801 induces hyperalgesia with parallel increase in CSF EAAs levels.     

Gender differences and the role of estrogen in cognitive enhancements with nicotine in rats

Research has reported that nicotine can increase accuracy, response times and rates of learning with evidence of different effects on males and females. The goal of our research was to study further sex differences by examining the role played by estrogen in the effects of nicotine on learning and memory in female rats. In experiment 1, 48 male and female rats were administered 0.3 mg or 0.7 mg/kg bwt of nicotine (nic) or vehicle only (veh) and tested in a visual spatial orientation (VSO) paradigm designed to maximize the benefits of nicotine on spatial working memory. Females exposed to 0.3 mg nic performed superior to all other groups of both genders. In experiment 2, ovariectomized females (N = 40) were exposed to 30 µg estradiol/kg bwt (E2), 3 mg nicotine/kg bwt, a combination of both E2 and nic, or veh, and tested as in experiment 1. The rankings of scores in the VSO task by group were E2 + nic > nic alone > E2 alone > veh. The E2 + nic combination group also demonstrated the highest rate of acquisition. Collectively, the findings suggest that estrogen can synergize the ability of chronic nicotine to enhance acetylcholine-hippocampal interactions underlying performance in the VSO paradigm.