Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters.

There is strong evidence supporting the deleterious effects of aging on learning and memory and behavioral parameters in normal mice. However, little is known about the Ames dwarf mouse, which has a Prop-1 gene mutation resulting in deficiencies in growth hormone, thyroid-stimulating hormone, and prolactin. These mice are much smaller and live significantly longer than their normal siblings. Using the elevated plus-maze, locomotor activity meters, and an inhibitory avoidance learning task, the present study compared Ames dwarf mice to their normal siblings. Results showed that Ames dwarf mice did not experience an age-related decline in locomotor activity when compared to their young counterparts. Furthermore, old dwarf mice did not differ from the young groups in inhibitory avoidance retention, while old normal animals performed more poorly than both young groups on this test. Elevated plus-maze behavior did not differ in the old normal versus dwarf groups, but the old groups did differ from the young. Results indicate that both old groups experienced a significant decline in anxiety with age. Taken together, these results indicate that multiple hormone deficiencies resulting from a lack of primary pituitary function have beneficial effects on cognitive function and locomotor behavior in advanced age. In fact, the Ames dwarf mouse may provide a model for studies of delayed mental as well as physical aging.

Nicotine patches improve mood and response speed in a lexical decision task.

The effects of smoking a cigarette or wearing a transdermal nicotine patch on mood and lexical decision-making were tested in eight smokers. Each participant was tested after 4 hours of smoking abstinence, under 4 conditions: placebo (very low nicotine) cigarette, nicotine cigarette, placebo patch, and nicotine patch. Relative to placebo, wearing the nicotine patch reduced Profile of Mood States (POMS) Total Mood Disturbance and Fatigue/Inertia scores, while increasing the speed of some types of lexical decisions. Smoking a nicotine cigarette did not affect reaction times, but unexpectedly decreased the accuracy of Word/ Nonword lexical decisions. Thus, transdermal nicotine may improve mood and facilitate longterm memory search and/or attentional processes in nicotine-deprived smokers.

EEG, physiology, and task-related mood fail to resolve across 31 days of smoking abstinence: relations to depressive traits, nicotine exposure, and dependence.

Changes in task-related mood and physiology associated with 31 days of smoking abstinence were assessed in smokers, 34 of whom were randomly assigned to a quit group and 22 to a continuing-to-smoke control group. A large financial incentive for smoking abstinence resulted in very low participant attrition. Individuals were tested during prequit baselines and at 3, 10, 17, and 31 days of abstinence. Abstinence was associated with decreases in heart rate and serum cortisol, a slowing of electroencephalogram (EEG) activity, and task-dependent and trait-depression-dependent hemispheric EEG asymmetries. Differences between the quit group and the smoking group showed no tendency to resolve across the 31 days of abstinence. Trait depression and neuroticism correlated with increases in left-relative-to-right frontal EEG slow-wave (low alpha) activity at both 3 and 31 days of abstinence. In contrast, prequit nicotine intake and Fagerström Tolerance scores correlated with alpha asymmetry and with greater EEG slowing only at Day 3. Thus, the effects of smoking abstinence appear to last for at least several months.

Low body temperature in long-lived Ames dwarf mice at rest and during stress.

Among homeothermic animals, larger species generally have lower metabolic rates and live longer than do smaller species. Because Ames dwarf mice (dwarfs) live approximately 1 year longer than their larger normal sex- and age-matched siblings (normals), we hypothesized that they would have lower body core temperature (Tco). We, therefore, measured Tco of six dwarfs and six normals during 24-h periods of ad lib feeding, 24-h food deprivation, and emotional stress induced by cage switching. With ad lib feeding, Tco of dwarfs averaged 1.6 degrees C lower than normals; during food deprivation, Tco of both dwarfs and controls was significantly lower than when food was available ad lib; and following cage switch, Tco was elevated in both groups. However, during all three experiments, Tco was significantly lower in dwarfs than in normals. These data support the hypothesis that Ames dwarf mice, which live longer than normal size controls, maintain lower Tco than normals. Because dwarfs are deficient in thyroid stimulating hormone (TSH) and growth hormone (GH), their low Tco may be a result of reduced thermogenesis due to lack of those hormones. However, whether low Tco per se is related to the increased longevity of the dwarf mice remains an interesting possibility to be investigated.

Effects of cigarette smoking on lexical decision-making.

10 habitual smokers, aged 19-25 yr., were randomly assigned to smoke either a very low nicotine "Placebo" cigarette (.05-mg nicotine delivery as estimated by the FTC method) or a Nicotine cigarette (.7-mg estimated nicotine delivery). Each participant was asked to abstain from smoking for 4 to 7 hr. prior to testing. After completing a presmoking test of lexical decision-making, participants smoked either a Nicotine or Placebo cigarette and were then retested for reaction times and accuracy on the lexical decision test. When presented the most difficult lexical decisions, participants responded significantly faster after smoking a Nicotine cigarette than they did before smoking; smoking a Placebo cigarette did not affect reaction times. Response accuracy was unaffected by smoking either kind of cigarette. These results suggest that smoking a nicotine cigarette may improve attention or memory retrieval after several hours of smoking abstinence.

Inhibitory avoidance and appetitive learning in aged normal mice: comparison with transgenic mice having elevated plasma growth hormone levels.

Groups of 25-month-old ("old") B6C3 hybrid male mice, 6-month-old ("young") normal males, and their age-matched transgenic (TG) siblings overexpressing the bovine growth hormone gene were given an inhibitory avoidance training trial (0.20-mA electric shock, 1.0-s duration). The old B6C3 hybrids and the young TG mice displayed poorer retention (shorter latencies to enter the shock compartment) 24 h and 42 days after training than did the young normal mice. In a subsequent multiple-trial acquisition test, young TG and old normal mice required more trials to reach the criterion of complete inhibition of step-through responding for 300 s than did young normal mice. Young normal and young TG mice did not differ in trials to extinction, but TG mice met the extinction criterion sooner than did old normal mice, suggesting poorer longterm retention. In tests of T-maze appetitive learning, young normal, old normal, and young TG mice did not differ in acquisition or 24-h retention. Contrary to expectation, TG mice acquired T-maze reversal learning in fewer trials than did young normal or old normal mice. The TG and young normal mice did not differ in retention when retested 44 days after initial training, but old normal mice showed poorer retention than did the young normals. Results of locomotor activity and shock response tests suggested that learning impairments were not due to differences in locomotor activity or shock response thresholds in these animals. Tests in an elevated plus maze indicated that young TG mice were less anxious in a novel environment than their normal siblings, which may contribute to their impaired inhibitory avoidance learning. These findings suggest that 6-month-old TG mice overexpressing the bovine growth hormone gene display alterations in inhibitory avoidance (but not appetitive) learning similar to those occurring in 25-month-old normal mice. The neurobiological mechanisms mediating inhibitory avoidance and T-maze appetitive learning in these animals may be largely dissociated.

Copulatory behavior and fertility in transgenic male mice expressing human placental growth hormone gene.

Male transgenic (TG) mice overexpressing the human placental growth hormone (GH) variant gene (hGH-V) exhibit reproductive deficits in spite of normal testosterone levels and normal sperm counts. To evaluate the relationship of copulatory behaviors to fertility, we first measured mount, intromission, and ejaculation indices in 2-5-month-old mice (10 TG and 10 normal litter mate controls) during 1 hour tests with ovariectomized, estrogen-, and progesterone-primed females. After eight tests, each male was housed with three intact females for 27 consecutive days. Females were checked daily for vaginal plugs and sacrificed 14 days after insemination to determine the numbers of corpora lutea and live and dead fetuses. Relative to their normal siblings, TG mice mounted less often and intromitted sooner after the initial mount, made marginally more intromissions (with and without ejaculation), and were slower to ejaculate. In subsequent fertility tests, TG males inseminated fewer females and sired fewer live fetuses per insemination than non-TG controls. Across TG and normal males, the length of interval between initial mount and initial intromission was inversely correlated with the number of live offspring sired. This suggests that reduced fertility in hGH-V transgenic male mice may be related to altered copulatory behavior, including a rapid progression from first mount to first intromission.

Noise stress does not modulate effects of smoking/nicotine on beta-endorphin, cortisol, ACTH, glucose, and mood.

Noise-dependent effects of smoking multiple cigarettes on subjective state and blood concentrations of ACTH, beta-endorphin, cortisol, and glucose were assessed in a repeated measures design where noise level (high versus minimal) was crossed with nicotine dose (quasi-ad lib own brand versus 1.0 mg FTC nicotine machine-delivered dose versus 0.05 mg FTC nicotine machine-delivered dose). Cortisol and ACTH were increased by nicotine, but not by noise and there was no noise by dose interaction. In contrast, nicotine did not increase beta-endorphin in either noise condition and there was no dose by noise interaction for beta-endorphin. However, noise was associated with a modest increase in beta-endorphin. The effects of nicotine on blood glucose varied as a function of the number of cigarettes smoked. However, the effects of nicotine on glucose, hormones, and subjective state did not vary as a function of noise stress.

Systemically administered gonadotrophin-releasing hormone enhances copulatory behaviour in castrated, testosterone-treated hyperprolactinaemic male rats.

Hyperprolactinaemic male rats exhibit deficits in copulatory behaviour which can be reversed by a single injection of GnRH. We tested whether systemically administered GnRH can stimulate copulatory behaviour independently of LH-mediated increases in plasma testosterone levels. Gonadectomized, pituitary-grafted adult male Fischer 344 rats bearing implants of 5, 10 or 20 mm capsules of testosterone were administered a single injection of 500 ng GnRH or saline s.c., 30 min prior to copulation tests. Pituitary-grafted castrates displayed copulatory deficits, relative to sham-operated castrates with identical levels of testosterone replacement. Administration of 500 ng GnRH to pituitary-grafted castrates bearing 10 mm testosterone implants significantly increased the proportion of rats that mounted, intromitted and ejaculated during a 30 min test. This treatment also reduced significantly the latency of intromission and ejaculation, and increased significantly the frequency of intromission. The copulatory behaviour of the sexually unresponsive, pituitary-grafted castrates bearing 5 mm testosterone implants, or of the more sexually responsive castrates bearing 20 mm testosterone implants, was not altered significantly by GnRH injections. These results support the hypothesis that copulatory deficits in moderately hyperprolactinaemic rats are due in part to reduced hypothalamic GnRH release, and suggest that GnRH can stimulate sexual behaviour in these animals via mechanisms that are independent of luteinizing hormone-induced testosterone release. However, a threshold level of testosterone (achieved with 10 mm implants) appears to be required for GnRH to elicit this effect.

Immune function in cigarette smokers who quit smoking for 31 days.

A group of 28 healthy, white, male, light-to-moderate smokers, 21 to 35 years of age, were offered a financial inducement to abstain from smoking for 31 days. A matched control group of 11 smokers were paid to continue smoking during the same period. Nonspecific parameters of immune system function were monitored before and at various times after smoking abstinence. Abstinence increased natural killer cell cytotoxic activity but did not alter mitogen-induced T-lymphocyte proliferation as measured by responses to concanavalin A or phytohemagglutinin. Serum cortisol concentrations also decreased after smoking cessation; however, changes in immune function were not correlated with serum cortisol change, nor with indices of smoking such as plasma nicotine and cotinine levels. Responses to concanavalin A and phytohemagglutinin were positively correlated with change in self-reported alcohol ingestion during smoking abstinence. Results indicate that elevation in natural kill cell cytotoxic activity is detectable within 1 month of smoking cessation, even in light-to-moderate smokers. However, elevation in natural killer cell cytotoxic activity appears not to be directly related to cessation-induced reductions in plasma nicotine, cotinine, or circulating cortisol levels.

Ethanol and nicotine consumption and preference in transgenic mice overexpressing the bovine growth hormone gene.

Transgenic mice overexpressing the phosphoenolpyruvate carboxykinase/bovine growth hormone (PEPCK/bGH) hybrid gene and normal (nontransgenic) littermate controls (10 males + 10 females/group) were given access to tapwater and an ascending series of concentrations of ethanol (1.0-22.0%), then a similar ascending series of concentrations of nicotine (1.0-40.0 micrograms/ml), in a two-bottle choice test. Male transgenic mice consumed more and exhibited greater preferences for ethanol and nicotine than control males; transgenic females consumed less and showed lower preferences for ethanol, but not nicotine, than control females. These results suggest that chronic exposure to high levels of bGH may modulate the rewarding effects of ethanol and nicotine in mice in a gender-specific fashion.

Ethanol, nicotine, amphetamine, and aspartame consumption and preferences in C57BL/6 and DBA/2 mice.

Using a two-bottle choice paradigm, adult C57BL/6 and DBA/2 mice (11 males an 10 females per strain) were given access to tapwater and an ascending series of concentrations of ethanol, nicotine, amphetamine, and th artificial sweetener, aspartame. The C57 mice consumed more ethanol, nicotine, and amphetamine, and showed greater preferences for these substances, than did the DBA/2 mice. In contrast, DBAs consumed more and showed greater preference for aspartame than C57s. However, measures of drug and aspartame consumption and preference were moderately intercorrelated when the effects of gender and strain were controlled for. This pattern of results suggests that factors modulating differences between C57BL/6 and DBA/2 mice in ethanol consumption and preference also modulate differences in consumption of nicotine and amphetamine.

Subjective correlates of cigarette-smoking-induced elevations of peripheral beta-endorphin and cortisol.

Two experiments assessed subjective and hormonal effects of smoking cigarettes with three different nicotine deliveries. In experiment 1, 12 males smoked two cigarettes on three different occasions: (1) nicotine-free; (2) their own brand (1.0 mg FTC-estimated nicotine delivery); or (3) 2.4 mg FTC nicotine cigarettes. In experiment 2, 12 males smoked cigarettes of comparable nicotine yield using a quantified smoke delivery system (QSDS). Blood was sampled 2 min after each cigarette completion. Relative to nicotine-free smoking, plasma beta-endorphin (BE) and serum cortisol concentrations increased after quasi-ad libitum smoking of 2.4 mg, but not after 1.0 mg nicotine cigarettes. Self-reported malaise (nausea, sickness, and unpleasantness) also increased after smoking 2.4 mg nicotine cigarettes; subjective distress was correlated with changes in blood BE and cortisol. Smoking 1.0 mg cigarettes did not increase BE or cortisol, or subjective distress. QSDS smoking produced hormonal and subjective effects similar to quasi-ad libitum smoking; however, correlations between neuromodulator concentrations and mood were non-significant. These findings suggest that the elevated levels of plasma BE and cortisol reported in some smoking studies may not be characteristic effects of normal smoking.

Hormonal and subjective effects of smoking the first five cigarettes of the day: a comparison in males and females.

The effects of smoking normal-nicotine-delivery cigarettes on serum cortisol, plasma beta-endorphin (BE), and mood were measured in 8 male and 8 female smokers; 8 male and 8 female nonsmokers served as sham-smoking controls. Smoking five cigarettes of the smokers' usual type after overnight deprivation, either ad lib or via a quantified smoke delivery system, produced small but reliable elevations in serum cortisol concentrations; BE was elevated somewhat after two, but not after four or five cigarettes. Smoking-induced elevations in serum cortisol were correlated with decreases in self-reported drowsiness after two and five cigarettes. Additionally, female smokers reported more drowsiness at baseline and after smoking nicotine-free cigarettes than did male smokers or female nonsmokers. Results suggest that smoking-induced elevations in serum cortisol, which persist for at least the first five cigarettes of the day, may modulate the arousing effects of smoking under conditions of low arousal. Also, nicotine-deprived female smokers may experience subnormal arousal compared to male smokers or female nonsmokers.

Characterization of a dose-response curve for nicotine-induced conditioned taste aversion in rats: relationship to elevation of plasma beta-endorphin concentration.

In the first experiment a conditioned taste aversion paradigm was used to characterize a dose-response curve for the aversive properties of nicotine in male Sprague-Dawley rats. Doses of nicotine ranging from 0.01 to 0.46 mg/kg, 2.0 ml of 0.47 M lithium chloride, or saline were injected, ip, 10 min after exposure to a novel saccharin solution. Amount of saccharin consumed in a two-bottle test was assessed 72 h later. Nicotine doses of 0.046 mg/kg and above produced a significant degree of conditioned taste aversion. In a second experiment, four groups of 10 rats each were injected with saline, 0.022 mg/kg nicotine, 0.46 mg/kg nicotine, or 2.0 ml 0.47 of M LiCl. Doses of 0.46 mg/kg nicotine and 0.47 M LiCl elevated plasma beta-endorphin concentrations significantly above saline control values. The 0.022 mg/kg dose, the highest dose that did not produce conditioned taste aversion in Experiment 1, did not significantly increase plasma beta-endorphin concentrations. This finding suggests that doses of nicotine that produce conditioned taste aversion also promote the release of pituitary stress hormones. Taken together these data suggest that some of the pharmacological and behavioral effects attributed to nicotine, including the release of endogenous neuromodulators, may be dose-dependent concomitants of the aversive effects of nicotine in nicotine-naive animals.

Tolerance and sensitization to chronic and subchronic oral caffeine: effects on wheelrunning in rats.

Twenty-four male Sprague-Dawley rats were tested for wheelrunning in conjunction with chronic (continuous) or subchronic (alternate day) oral caffeine administration. As expected, chronic administration led to complete tolerance to caffeine's locomotor stimulant effect, while subchronic administration produced sensitization. Results confirm earlier reports of enhanced stimulation with spaced administration of caffeine and tolerance with chronic administration.

A system for administering quantified doses of tobacco smoke to human subjects: plasma nicotine and filter pad validation.

A new, automated system for administering quantified doses of cigarette smoke to human subjects is described and results of two studies demonstrating the reliability and validity of the system are presented. To overcome the large variability in nicotine and tar delivery associated with previous means of controlling smoke delivery, an automated quantified smoke delivery system was constructed. The system increases the precision and reliability of the smoke and nicotine dose delivered to human subjects. The quantified smoke delivery system was found to deliver doses of nicotine with a substantially greater degree of precision than procedures typically used in previous laboratory studies of smoking behavior.

Caffeine effects: interaction of drug and wheelrunning experience.

Male Sprague-Dawley rats were tested for wheelrunning following repeated injections of caffeine or distilled water after varying amounts of experience with caffeine and wheelrunning. Rats experienced with caffeine in combination with wheelrunning ran significantly more than rats experienced only with caffeine or wheelrunning alone. Results suggest that caffeine's stimulant effects are greater when subjects are experienced with wheelrunning while under the influence of the drug.