published_or_final_version / Pharmacology / Master / Master of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

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The maternal consumption of alcohol during pregnancy produces a wide range of abnormalities in the offspring. The major objectives of this thesis were to investigate (1) the correspondence between prenatal ethanol-induced alterations in behavior and in hypothalamicpituitary- adrenal (HPA) activity, (2) the ability of early postnatal handling as an environmental manipulation to attenuate at least some of the adverse behavioral and physiological consequences of prenatal ethanol exposure, and (3) possible mechanisms mediating the HP A hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol and the possible influence of postnatal handling on those mechanisms. Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum fed control (C) treatment groups were tested as young adults (-35-120 d of age) or mid-aged adults (13-14 months of age). The first study investigated the effects of prenatal ethanol exposure (E) and postnatal handling (H) on behavior and HPA activity during a conditioned taste aversion (CTA) task. We tested the hypothesis that E animals which underwent postnatal handling would show improved conditioned aversion learning and reduced HPA activity compared to E animals that did not experience handling (nonhandled, NH). We found that prenatal ethanol exposure and postnatal handling independently resulted in an increased rate of consumption of a saccharin solution over five preexposure days. In addition, we found that handling differentially affected posttoxicosis consumption of the conditioned solution as well as corticosterone (CORT) levels in E, PF and C animals. H-E animals showed increased posttoxicosis intake compared to H-PF and H-C animals during reexposure under non-deprived conditions; CORT levels were lower in PF and C than E males compared to their N H counterparts during reexposure under food- and waterdeprived conditions. Thus, E animals were less able to utilize environmental cues in the present study, displaying a more rapid reduction in neophobia compared to PF and C animals and, following postnatal handling, showing a decreased acquisition of conditioned aversion and an increased CORT response during reexposure to the conditioned solution. The second study examined spatial learning and memory in young adult (2 months) and mid-aged (13-14 months of age) H and N H E and control animals utilizing a Morris water maze. We investigated the hypothesis that postnatal handling would improve spatial navigation in E animals compared to E animals that did not experience handling and/or attenuate differences among E and control animals, and that this effect might be age-dependent. We also examined whether performance deficits in mid-aged animals would correspond to increases in CORT levels on the last day of testing. Young E males showed impairments in spatial navigation compared to young PF and C animals, taking longer to find the hidden platform over the course of testing and displaying an alteration in search pattern when the platform was removed. Interestingly, differences in young E, PF and C animals in escape latency and in distance traveled prior to finding the platform were apparent in H but not in N H animals. There were no differences in performance on the Morris water maze in mid-aged E, PF and C animals, but CORT levels were elevated in mid-aged E compared to C animals, supporting previous data indicating that E animals demonstrate HPA hyperresponsiveness to stressors. Lastly, although mid-aged animals had longer escape latencies and an altered search pattern compared to young animals, handling did not appear to attenuate impairments associated with aging. The third study investigated the hypothesis that postnatal handling might attenuate stress-induced ACTH and/or CORT differences among E, PF and C animals. Furthermore, the ability pf postnatal handling to modulate HPA feedback deficits in E animals was examined during exposure to a restraint stressor following dexamethasone (DEX) administration. Both E females and males showed increased ACTH and CORT compared to PF and/or C animals following saline administration. Administration of DEX to block HPA activity significantly suppressed both plasma ACTH and CORT in all animals. However, E females exhibited increased and/or prolonged elevations in ACTH and CORT compared to PF and C animals following DEX blockade. These data suggest that the insult of prenatal ethanol exposure affects both male and female offspring, but that there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyperresponsiveness. Postnatal handling reduced ACTH levels in both females and males following saline administration. Following DEX administration, H males had lower CORT than NH males. Postnatal handling resulted in a more rapid decrease in stress-associated CORT elevations in C females, and attenuated differences in CORT between PF and C females. However, postnatal handling did not attenuate deficits in negative feedback inhibition in E females; E females in both the H and N H treatments showed elevated CORT compared to their C counterparts, and H-E females also showed elevated CORT compared to H-PF females. Thus, postnatal handling did not attenuate the typical HPA hyperresponsiveness to stressors observed in E animals (saline condition), nor did it eliminate deficits in HPA feedback inhibition in E females (DEX condition). The fourth study examined whether the mechanisms resulting in HPA hyperresponsiveness in E animals are similar to those underlying the effects of postnatal handling. Differences in HPA responsiveness between H and NH animals appear to be dependent upon basal CORT activity and not stress-induced elevations in CORT. Therefore, we tested the hypothesis that differences in HPA activity among E and control animals would not occur following adrenalectomy (ADX) but could be reestablished following replacement with basal levels of exogenous CORT. In the absence of a CORT feedback signal or in the presence of a constant, basal CORT feedback signal, E, PF and C animals did not significantly differ in their abilities to regulate ACTH secretion, indicating that during the trough of the circadian rhythm, E, PF and C animals are equally capable of regulating HPA activity utilizing either CORT-independent feedback or feedback mediated through basal CORT activity. Thus, the effects of prenatal ethanol exposure on HPA function do not appear to be dependent upon the feedback signal provided by basal CORT levels. In conclusion, handling did not attenuate the effects of prenatal ethanol exposure examined in the present experiments. This may be because the effects of postnatal handling and prenatal ethanol exposure on HPA function are mediated through different mechanisms as well as the finding that handling is, at least partly, mediated through mother-pup interactions. Therefore, postnatal handling might exert differential effects on litters in which pup behavior has already been altered by prenatal treatments, underscoring the enduring effects of prenatal ethanol exposure.

Alcohol abuse/dependence frequently co-occurs with antisocial personality disorder (ASPD) and conduct disorder (CD). Furthermore, crime studies have generally found that alcohol is involved in over 50% of violent crimes, and experimental studies support the notion that acute alcohol consumption indirectly increases the likelihood of aggressive and disinhibited behaviors in the laboratory. However, the mechanisms underlying alcohol's association with such behaviors remain unclear. The goals of this thesis were therefore to further elucidate potential mechanisms underlying (a) alcohol-induced aggressive, disinhibited behaviors and (b) the high comorbidity between delinquent, aggressive behaviors (characterizing CD/ASPD) and alcohol misuse/abuse/dependence. Thus, four studies were conducted, focusing on individual differences in the physiological response to alcohol intoxication. Specifically examined was the elevated heart rate (HR) response to alcohol, which is thought to reflect an increased sensitivity to alcohol-induced reward. / Results of Study I indicated that high HR Responders to alcohol self-reported increased multiple year delinquency (physical aggression, theft, and destruction of property), as well as more alcohol consumption and an increased positive subjective feeling following intoxication, as compared to low HR Responders. Furthermore, a high HR response was related to increased extraversion, disinhibition, boredom susceptibility, and total sensation seeking. Study II revealed that Aggressive Sons of Male Alcoholics (Agg-SOMAs) had the highest intoxicated HR response, and reported the most alcohol consumption, as compared to Non-Agg-SOMAs, or Agg - or Non-Agg - Non-SOMAs. Studies III and IV revealed that intoxicated high HR responders exhibited the most physical aggression (assessed by the Taylor Aggression Paradigm), as well as the most behavioral disinhibition (assessed by the Go/No-Go task) as compared to sober high HR Responders, or sober/intoxicated low HR responders. / In summary, individuals with a high HR response to alcohol appear to have an increased propensity for multiple addictive, disinhibited and aggressive behaviors. This determines a phenotype of both potential heuristic and clinical importance. These findings are discussed within the context of a hypothetical model of (a) the high comorbidity between alcohol use/misuse and aggression/ASPD, and (b) the increased likelihood of alcohol-induced aggressive, disinhibited behaviors.

The influence of a primarily Public form of self-awareness and of Private and Public Self-Consciousness on drunken physical aggression and complex reaction-time were examined. Two forms of the balanced-placebo design were employed. Results indicated that each form of self-focus played a significant role in the determination of various aspects of drunken comportment. Consumption of alcohol did not eliminate self-aware behavior on the measures employed. Public Self-Consciousness acted to increase drunken impairment. A modified form of the balanced-placebo design proved superior to the standard version for use with moderately high doses (1.32 ml/kg) of alcohol on a measure of subjective intoxication. The implications for the literature on self-focus and drunken comportment are discussed.

Using a rat model, the effects of a single dose or six to twelve months of daily oral administration of ethanol on the immune system were determined. The rats were challenged with sheep red blood cells after the various dosing periods to elicit an immune response. Immune system responsiveness was determined by means of white blood cell counts and differentials, antibody titers, and T-cell numbers. No deleterious effects of the ethanol on the immune response were seen, while the female alcohol-fed rats showed a significant increase in T-Cell numbers, white blood cell counts, and lymphocytes over the sham group.

The effects of moderate, long-term intake of ethanol on the hypothalamic response to cold stress were examined. The long-term experimental animals were given .25 ml of 28% ethanol or .25 ml of water orally once a day, five days a week for fourteen months. A stainless steel electrode was then surgically implanted into the paraventricular nucleus, after which the animal was subjected to cold stress (-150 C, 10 min.). Recordings were taken in the forms of frequency and activity. The data clearly indicate that: (1) alcohol fed rats exhibited a suppressed response to cold stress compared to sham-fed rats; (2) this suppression of activity occurred at the level of the hypothalamus, and (3) mortality was significantly lower in alcohol-fed males than it was in sham fed males. This study clearly points out the need for further work in the area of the beneficial effects of moderate doses of alcohol.

This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes.

The maternal consumption of alcohol during pregnancy produces a wide range of abnormalities in the offspring. The major objectives of this thesis were to investigate (1) the correspondence between prenatal ethanol-induced alterations in behavior and in hypothalamicpituitary- adrenal (HPA) activity, (2) the ability of early postnatal handling as an environmental manipulation to attenuate at least some of the adverse behavioral and physiological consequences of prenatal ethanol exposure, and (3) possible mechanisms mediating the HP A hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol and the possible influence of postnatal handling on those mechanisms. Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum fed control (C) treatment groups were tested as young adults (-35-120 d of age) or mid-aged adults (13-14 months of age). The first study investigated the effects of prenatal ethanol exposure (E) and postnatal handling (H) on behavior and HPA activity during a conditioned taste aversion (CTA) task. We tested the hypothesis that E animals which underwent postnatal handling would show improved conditioned aversion learning and reduced HPA activity compared to E animals that did not experience handling (nonhandled, NH). We found that prenatal ethanol exposure and postnatal handling independently resulted in an increased rate of consumption of a saccharin solution over five preexposure days. In addition, we found that handling differentially affected posttoxicosis consumption of the conditioned solution as well as corticosterone (CORT) levels in E, PF and C animals. H-E animals showed increased posttoxicosis intake compared to H-PF and H-C animals during reexposure under non-deprived conditions; CORT levels were lower in PF and C than E males compared to their N H counterparts during reexposure under food- and waterdeprived conditions. Thus, E animals were less able to utilize environmental cues in the present study, displaying a more rapid reduction in neophobia compared to PF and C animals and, following postnatal handling, showing a decreased acquisition of conditioned aversion and an increased CORT response during reexposure to the conditioned solution. The second study examined spatial learning and memory in young adult (2 months) and mid-aged (13-14 months of age) H and N H E and control animals utilizing a Morris water maze. We investigated the hypothesis that postnatal handling would improve spatial navigation in E animals compared to E animals that did not experience handling and/or attenuate differences among E and control animals, and that this effect might be age-dependent. We also examined whether performance deficits in mid-aged animals would correspond to increases in CORT levels on the last day of testing. Young E males showed impairments in spatial navigation compared to young PF and C animals, taking longer to find the hidden platform over the course of testing and displaying an alteration in search pattern when the platform was removed. Interestingly, differences in young E, PF and C animals in escape latency and in distance traveled prior to finding the platform were apparent in H but not in N H animals. There were no differences in performance on the Morris water maze in mid-aged E, PF and C animals, but CORT levels were elevated in mid-aged E compared to C animals, supporting previous data indicating that E animals demonstrate HPA hyperresponsiveness to stressors. Lastly, although mid-aged animals had longer escape latencies and an altered search pattern compared to young animals, handling did not appear to attenuate impairments associated with aging. The third study investigated the hypothesis that postnatal handling might attenuate stress-induced ACTH and/or CORT differences among E, PF and C animals. Furthermore, the ability pf postnatal handling to modulate HPA feedback deficits in E animals was examined during exposure to a restraint stressor following dexamethasone (DEX) administration. Both E females and males showed increased ACTH and CORT compared to PF and/or C animals following saline administration. Administration of DEX to block HPA activity significantly suppressed both plasma ACTH and CORT in all animals. However, E females exhibited increased and/or prolonged elevations in ACTH and CORT compared to PF and C animals following DEX blockade. These data suggest that the insult of prenatal ethanol exposure affects both male and female offspring, but that there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyperresponsiveness. Postnatal handling reduced ACTH levels in both females and males following saline administration. Following DEX administration, H males had lower CORT than NH males. Postnatal handling resulted in a more rapid decrease in stress-associated CORT elevations in C females, and attenuated differences in CORT between PF and C females. However, postnatal handling did not attenuate deficits in negative feedback inhibition in E females; E females in both the H and N H treatments showed elevated CORT compared to their C counterparts, and H-E females also showed elevated CORT compared to H-PF females. Thus, postnatal handling did not attenuate the typical HPA hyperresponsiveness to stressors observed in E animals (saline condition), nor did it eliminate deficits in HPA feedback inhibition in E females (DEX condition). The fourth study examined whether the mechanisms resulting in HPA hyperresponsiveness in E animals are similar to those underlying the effects of postnatal handling. Differences in HPA responsiveness between H and NH animals appear to be dependent upon basal CORT activity and not stress-induced elevations in CORT. Therefore, we tested the hypothesis that differences in HPA activity among E and control animals would not occur following adrenalectomy (ADX) but could be reestablished following replacement with basal levels of exogenous CORT. In the absence of a CORT feedback signal or in the presence of a constant, basal CORT feedback signal, E, PF and C animals did not significantly differ in their abilities to regulate ACTH secretion, indicating that during the trough of the circadian rhythm, E, PF and C animals are equally capable of regulating HPA activity utilizing either CORT-independent feedback or feedback mediated through basal CORT activity. Thus, the effects of prenatal ethanol exposure on HPA function do not appear to be dependent upon the feedback signal provided by basal CORT levels. In conclusion, handling did not attenuate the effects of prenatal ethanol exposure examined in the present experiments. This may be because the effects of postnatal handling and prenatal ethanol exposure on HPA function are mediated through different mechanisms as well as the finding that handling is, at least partly, mediated through mother-pup interactions. Therefore, postnatal handling might exert differential effects on litters in which pup behavior has already been altered by prenatal treatments, underscoring the enduring effects of prenatal ethanol exposure. / Arts, Faculty of / Psychology, Department of / Graduate