Conditioned taste aversions in rats after intracerebral administration of nicotine

Previous studies suggested that the conditioned taste aversion (CTA) produced by nicotine was of central origin. The aims of the present work were to identify neural substrates that mediate nicotine-induced CTA, and to examine the relationship between the CTA and locomotor depressant effects of nicotine. After two conditioning trials with 0.1 or 0.4mg/kg nicotine (s.c.), significant CTA was apparent. In contrast, CTA was absent when nicotine (4 or 32μg) was administered into a lateral ventricle or when nicotine (4μg) was administered into the fourth ventricle, but decreases in locomotor activity were apparent during the conditioning phase. Nicotine (8μg) produced CTA when administered bilaterally into the nucleus accumbens. This finding was confirmed in a second experiment, but was not found in rats pretreated with the nicotine antagonist mecamylamine (2mg/kg s.c.). Bilateral administration of nicotine into the striatum, ventral tegmental area, dorsal hippocampus or the mesopontine tegmentum failed to produce CTA, and administration of nicotine into the interpeduncular nucleus produced CTA in one of two experiments only. It was concluded that the aversive effects produced by systemically administered nicotine may be mediated in part through nicotinic receptors located in the nucleus accumbens. The locomotor depression associated with intraventricular administration of nicotine could be dissociated from the aversive effect as measured by the CTA procedure.     

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.     

Conditioned taste aversions produced by nicotine in Roman High and Low Avoidance strains of rats

Rats of the RHA/iop and RLA/iop strains have been compared in a conditioned taste aversion procedure using nicotine (0.4 mg/kg SC) as the UCS. The procedure utilised a balanced, within-subject design for assessing discriminative aversions to drug- and saline-paired flavoured solutions. Nicotine produced clear aversions in both strains and there were no detectable differences in acquisition. During extinction, rats of the RHA/iop strain consumed more of the drug-paired flavoured solution than rats of the RLA/iop strain, and this difference became greater as the number of extinction trials proceeded. Differences in total fluid intake were too small to account for these effects that were also shown by changes in proportional intake when both flavoured solutions were presented simultaneously. Aversion was, therefore, rather weaker in RHA/iop rats than in RLA/iop rats. These results suggest that rats of the two strains do not differ in learning ability in a general way, and support interpretations based on differences in emotionality.     

Effects of administering caffeine to pregnant rats either as a single daily dose or as divided doses four times a day

From day 6 to day 20 of pregnancy, rats were treated with caffeine in a total daily dose of 10 or 100 mg/kg by gavage, either as a single bolus dose or as four divided doses given at 3-hr intervals throughout the day. Controls were given distilled water at the same times. Maternal body weight and food and water consumption were reduced in the two groups receiving a total of 100 mg caffeine/kg/day and in the group given 2.5 mg/kg four times daily. Dose-related decreases in foetal weight, placental weight and crown-rump length and dose-related retardation of skeletal ossification were observed. Major foetal abnormalities, mainly ectrodactyly, were seen only in the group given 100 mg caffeine/kg in a single daily dose.     

Conditioned flavor aversions for assessing precipitated morphine abstinence in rats.

Rats receiving twice-daily morphine injections acquired aversions to a saccharin solution which had been presented for 1 hr immediately prior to injections of naloxone. The degree of aversion was related to the maintenance dosage of morphine. Rats maintained on a regimen of daily saline injections did not show significant aversion to saccharin paired with naloxone, even at doses as high as 40 mg/kg. The sensitivity of the technique was such that significant aversions could be demonstrated in rats receiving doses of morphine as low as 1 mg/kg twice daily. It is suggested that conditioned flavor aversions provide a useful method for assessing the aversive quality of abstinence precipitated from low doses of morphine.     

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

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

Nicotine elicits methamphetamine-seeking in rats previously administered nicotine

Research has indicated a high correlation between psychostimulant use and tobacco cigarette smoking in human substance abusers. The objective of the current study was to examine the effects of acute and repeated nicotine administration on responding for intravenous methamphetamine (0.03 mg/kg/infusion) in a rodent model of self-administration, as well as the potential of nicotine to induce reinstatement of previously extinguished drug-taking behavior in male Sprague–Dawley rats. In addition, it was assessed whether nicotine-induced reinstatement of methamphetamine-seeking behavior and nicotine-induced locomotor sensitization require that nicotine be temporally paired with the methamphetamine self-administration session or the locomotor activity chamber. Nicotine acutely decreased methamphetamine self-administration, but did not persistently alter responding during the maintenance of methamphetamine self-administration. However, following extinction of methamphetamine self-administration, nicotine administration reinstated methamphetamine-seeking behavior only in rats that had previously been administered nicotine. Nicotine-induced reinstatement and expression of locomotor sensitization were not dependent on a temporal pairing of nicotine with either the methamphetamine self-administration session or the locomotor activity chamber, respectively. These results indicate that nicotine may be acting, at least in part, through a non-associative mechanism to reinstate methamphetamine-seeking behavior.     

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.     

Conditioned taste aversions as a behavioral baseline for drug discrimination learning: an assessment with phencyclidine

When PCP was given prior to the pairing of saccharin with LiCl (and the PCP vehicle prior to a nonpoisoned exposure to the same saccharin solution), rats rapidly acquired the discrimination, avoiding saccharin consumption following PCP and consuming saccharin following the vehicle after only three conditioning trials. Conversely, when the PCP vehicle was given prior to the saccharin-LiCl pairing and PCP prior to a nonpoisoned exposure to saccharin, other subjects avoided saccharin consumption following the vehicle injection and readily consumed saccharin after an injection of PCP. During dose substitution sessions, animals displayed greater drug-appropriate responding as the dose of PCP increased. When a range of doses of ketamine was given in place of PCP prior to saccharin access, subjects displayed dose-dependent PCP-appropriate responding. When a range of doses of d-amphetamine was substituted for PCP, subjects displayed vehicle-appropriate responding at all doses. The relative efficacy of the taste aversion procedure as a baseline for drug discrimination learning is discussed.     

Conditioned saccharin taste aversion induced by mycotoxins in rats: lack of effect of ochratoxin A

The present study examined the putative aversive action of ochratoxin A (OA) using a conditioned saccharin aversion paradigm. Adult male rats consumed a 0.1% saccharin solution then were treated (IP) with either a 5% NaHCO3 vehicle (negative control), 32 mg/kg LiCl (positive control) or 0.75, 1.5 or 3.0 mg/kg OA. Twenty-four hours later, the rats were given a choice between tap water and the 0.1% saccharin solution. Rats treated with the vehicle or any of the doses of OA exhibited a marked preference for the saccharin solution, whereas the rats treated with LiCl exhibited a marked rejection of the saccharin solution. The implications of these data for an understanding of mycotoxicosis are discussed.     

Comparison studies of chlorazepate administered as a divided daily dose and as a single dose at night

The residual effects of dipotassium chlorazepate administered as either a single daily dose of 20 mg at bedtime or a divided daily dose (5+5+10 mg) were studied in a placebo-controlled, doubleblind trial comprising 12 out-patients. The following tests were used to determine changes in perceptual wakefulness, performance ability, fine motor skills, and coordination: critical flicker fusion test, car driving in a simulator, and the bead and needle tests. In addition, the patients underwent a clinical assessment and also filled out a self-rating scale for judging factors related to the tests. No significant differences were found between the dosage schedules or between the active medication and the placebo. The clinical results were not dependent on the dosage schedule.     

Central inhibition of gastric motility by intravenously administered nicotine in rats

Effects of intravenously (i.v.) administered nicotine on gastric motility were investigated in urethane-anesthetized rats in which an intragastric balloon had been placed. I.v. administered nicotine at 75-300 nmole/kg dose-dependently decreased gastric motility. Decrease in gastric motility induced by nicotine at the dose of 300 nmole/kg was inhibited by intracisternally administered hexamethonium. Gastric motility was also decreased by intracisternally applied nicotine (1-10 nmole). These doses were much smaller than those by the intracerebroventricular route in our previous report. Bilateral vagotomy significantly suppressed basal gastric motility. In bilaterally vagotomized animals, nicotine at 1 mumole/kg but not 300 nmole/kg given i.v. significantly decreased the gastric motility maintained at a normal level by electrical stimulation of the vagus nerve. This nicotine-induced decrease in gastric motility, under conditions of electrical stimulation of the vagus nerve, was inhibited by pretreatment with phentolamine. These results suggest that a smaller dose of nicotine given i.v. activates nicotinic receptors in the brainstem and elicits vagally-mediated inhibition of gastric motility. Activation of peripheral alpha-adrenergic mechanisms together with that of central nicotinic mechanisms may be involved in the decreasing effects of a larger dose of nicotine on gastric motility.     

Paced puffing as a method for administering fixed doses of nicotine

Smokers' ability to regulate nicotine intake by varying topographical parameters such as depth of inhalation and number of puffs makes it difficult to administer standardized doses of nicotine as delivered from smoking. A number of studies have claimed to control these parameters without confirming the effectiveness of such procedures by measures of plasma nicotine. The purpose of the present study was to determine whether specifying onset and duration of each puff would result in accurate dosing. Plasma nicotine boosts for five "paced puffers" were compared across two sessions and with similar data for five "free smokers." Neither between-subject consistency nor within-subject reproducibility was improved by this paced puffing procedure, despite apparent topographical control.     

A comparison of the bronchodilator effect of salbutamol inhaled via Turbuhaler as two consecutive doses or as two divided doses at different time intervals.

The aim of the study was to compare the bronchodilatory effect of 2x50 microg salbutamol inhaled via Turbuhaler(R) as two consecutive doses compared with two divided doses (50+50 microg) at different time intervals. The study was of a randomized, double-blind, crossover design. The patients inhaled two doses of 50 microg salbutamol immediately after each other and with a time interval between the doses of 1.5, 3, 5, or 10 mins. Forced expiratory volume in 1 s (FEV(1)) was measured before the first inhalation and at 1, 2. 5, 4.5, 9.5, 15, 20, 30, and 60 min after the first inhalation. Seventeen asthmatic patients (8 men) with a mean age of 32 years (range: 19-49 years), mean FEV(1) of 2.9 l (range: 1.7-3.9 l) and a mean FEV(1) in percentage of predicted normal value of 77% (range: 63-91%) participated. The mean reversibility 15 min after inhaling 100 microg salbutamol from pMDI was 23% (range: 16-35%). The mean maximum increase in FEV(1) from baseline ranged between 18.6% (consecutive doses) and 21.2% (1.5 min between doses), corresponding to a difference between the treatments of 0.06 l. There were no significant differences in maximum FEV(1) or time to reach maximum FEV(1) between the treatments. We were not able to show any clinically relevant differences in maximal bronchodilating effect, assessed as FEV(1), in stable asthmatics, when therapeutic doses of salbutamol were given via Turbuhaler either as two consecutive doses or as two divided doses separated by different time intervals.     

Conditioned taste aversions and changes in motor activity in lithium-treated rats. Mediating role of the area postrema

The role of the area postrema in mediating taste aversions conditioned with the administration of lithium was examined in experiment 1. Rats with lesions of the area postrema or with sham lesions were given pairings of a novel taste with either intraperitoneally or intragastrically administered lithium chloride (LiCl; 10 mg/kg of a 0.15 M solution of lithium chloride) or a similar concentration of NaCl (control groups). Sham-lesioned rats exhibited strong taste aversions when lithium was used for the conditioning procedure and given intraperitoneally or intragastrically (P less than 0.01). Rats with lesions of the area postrema failed to develop taste aversions after the administration of lithium by either route. In experiment 2, rats with lesions of the area postrema and rats with sham lesions were given 30 min access to a 0.12 M solution of NaCl and 2 days later to a 0.12 M solution of lithium. The sham-lesioned animals drank less lithium than NaCl (P less than 0.02) and exhibited depressions in levels of activity following the ingestion of lithium. Rats with lesions of the area postrema drank more lithium than the sham-lesioned rats (P less than 0.01) and did not show behavioral depression after the ingestion of lithium. These data suggest that in the absence of the chemically-sensitive area postrema intragastrically administered lithium does not produce conditioned taste aversions or depression of activity in rats.     

Disposition of amiodarone in rats after single and multiple intraperitoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p. daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both groups were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using High Performance Liquid Chromatography (HPLC). The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7+/-8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 microg/ml, 1.73 microg/mg and 29.01 microg/mg, respectivelly. The concentrations of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microg/ml, 1.41 microg/mg, 7.63 microg/mg and 65.01 microg/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a month if a patient required discontinuation because of serious adverse effects.     

Effects of chronically administered nicotine and saline on motor activity in rats

This study investigated the differential effects of chronically administered nicotine and saline on motor activity in the rat. Nicotine was administered via a subcutaneously implanted osmotic minipump to effect an 8 hour off, 16 hour on, flow. Subjects were 48 male and 48 female albino rats, each about 165 days old. Activity was monitored every hour for 192 consecutive hours. Results indicated that the female animals were more active than the males, and that animals receiving nicotine were significantly more active on the first two days of drug administration than control animals; however, by the fourth day there were no significant differences between the activity levels of animals that received nicotine and those of control animals.     

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.