Increased alcohol drinking in isolate-housed alcohol-preferring rats.

Alcoholism is a complex disorder influenced by interactions between genetic and environmental risk factors. This study examined the influence of isolate housing on ethanol intake in alcohol-preferring (P) and non-alcohol-preferring (NP) rats. Rats were isolate-housed or pair-housed for 8 weeks when between 45 and 96 days old. Ethanol drinking was assessed using a 24-hr preference test (10% ethanol vs. water) and 20-min limited access tests. A behavioral test battery was used to assess anxiety-like, depressive-like, acoustic startle, and motor behavior. Isolate housing increased home cage drinking in both lines and increased limited access drinking selectively in P rats. Isolation also reduced swim test immobility and prepulse inhibition in P rats and increased locomotor stereotypies in NP rats. Taken together, these data demonstrate that LinexEnvironment interactions influence the effects of isolation. Furthermore, isolation selectively increased ethanol intake in high drinking P rats. This effect was not correlated with changes in other behaviors. Selective enhancement of limited access ethanol drinking in P rats may represent a model whereby genetic liability to excessive drinking is enhanced by specific environmental exposures.

Two-choice reaction time performance in Sprague-Dawley rats exposed to alcohol during adolescence or adulthood.

Adolescent alcohol abusers display subtle attention impairments. This study used a two-choice reaction time task to examine the effects of ethanol on sustained attention following adult or adolescent exposure. Sprague-Dawley rats were exposed to ethanol vapor for 14 days starting on postnatal day 30 (adolescence) or 60-64 (adulthood) and were then trained to perform the two-choice reaction time task. Ethanol exposure resulted in blood ethanol levels averaging 215 mg/dl. Behavior following adult ethanol exposure was characterized by increased accuracy and omissions during the two-choice reaction time task, reduced fixed ratio lever pressing, and reductions in the highest fixed ratio completed on a progressive ratio schedule. Adolescent ethanol exposure transiently increased two-choice reaction time accuracy and slightly reduced fixed ratio lever presses. Improved accuracy was unexpected, but might be related to ethanol-induced increases in central nervous system arousal and/or mild behavioral perseveration. Increased omissions, reduced lever pressing, and reductions in the highest fixed ratios completed most likely reflect decreased 'motivation to work' and index generalized anhedonia. This study is the first to demonstrate that rats exposed to ethanol during adulthood are more sensitive to the effects of ethanol on sustained attention than rats exposed to ethanol during adolescence and to ethanol-induced anhedonia, as indexed by two-choice reaction time performance.

Neurobehavioral profiles during the acute phase of ethanol withdrawal in adolescent and adult Sprague-Dawley rats.

RATIONALE: Adolescent and adult rats show differential sensitivity to many of the effects of ethanol. OBJECTIVES: The current studies were designed to further explore differences in the development of ethanol dependence by examining anxiety-like behavior, acoustic startle, prepulse inhibition, and EEG activity during the acute phase of ethanol withdrawal. METHODS: Male Sprague-Dawley rats were exposed to ethanol vapor (12h/day for 14 days) during adolescence or adulthood. Neurobehavioral assessments were performed before exposure began and then during the acute phase of ethanol withdrawal (i.e., 7-10h after the termination of daily ethanol exposure). RESULTS: Behavior in the light-dark box did not reveal indices of pronounced anxiety-like behavior in ethanol exposed rats from either age group during withdrawal. Acoustic startle magnitude was significantly reduced and prepulse inhibition significantly enhanced in ethanol exposed rats during withdrawal, but these changes were independent of age. Frontal cortical EEG activity was not altered during ethanol withdrawal, but high frequency power in the parietal power EEG (i.e., 16-32 and 32-50 Hz) was selectively increased in ethanol exposed adolescents. CONCLUSIONS: The overall indices of ethanol withdrawal observed in these studies were mild, but these data do support the hypothesis that ethanol withdrawal symptoms can differentially develop in adolescent and adult rats. However, sensitivity to ethanol during adolescence can be increased or decreased depending on the symptom being assessed. As a result, it is unclear if more rapid development of ethanol dependence in adolescents is a factor, which facilitates the development of alcoholism.

The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats.

NPY is one of the most abundantly expressed peptides within the CNS, and has been previously demonstrated to be altered in several animal models of depression, as well as to be differentially regulated by acute and repeated stress. The effect of social deprivation, through isolation housing, on brain NPY concentrations in adult rats has not been previously investigated. The effects of 12 weeks of social isolation, in adult rats, on anxiety-related behaviors and central concentrations of NPY in: hypothalamus, amygdala, caudate-putamen, hippocampus, and frontal cortex were evaluated. Single housed animals spent significantly more time on the open arms of the elevated plus maze and in the central area of the open field as compared to pair housed controls. These data are most likely indicative of enhanced exploration and novelty seeking. Concentrations of neuropeptide Y were increased in the caudate-putamen of the single housed subjects. NPY levels in caudate/putamen and hypothalamus were also significantly correlated with time spent in the open arms of the elevated plus maze. These data suggest that chronic social isolation, in these adult Wistar rats, did not increase anxiety but produced enhanced exploration in tests of anxiety, an effect that was associated with NPY concentrations in the striatum and hypothalamus.

Enhanced prepulse inhibition following adolescent ethanol exposure in Sprague-Dawley rats.

OBJECTIVES: Recent studies have demonstrated that ethanol exposure differentially affects adolescents and adults. The current studies were designed to compare the effects of 2-week exposure to ethanol during adolescence or adulthood on the acoustic startle response (ASR) and prepulse inhibition (PPI) METHODS: Male Sprague-Dawley rats were exposed to ethanol vapor 12 hr/d (on from 6 pm to 6 am) for 14 days during adolescence or adulthood. Six days after the cessation of ethanol vapor exposure, the ASR and PPI were assessed. RESULTS: During ethanol treatment, overall blood alcohol levels averaged 230 to 250 mg/dl in the adolescent and adult treatment groups. Assessment of the ASR revealed that latency to startle was more rapid in adolescents than in adults, but ASR latency was not altered by ethanol exposure. In addition, ASR magnitude was lower in adolescents and was decreased in ethanol-exposed rats on startle trials. Ethanol exposure significantly enhanced PPI, but only after adolescent exposure CONCLUSIONS: These data further demonstrate a differential sensitivity of adolescents and adults to the effects of ethanol exposure. Specifically, a 2-week period of ethanol exposure during adolescence selectively enhanced PPI, a neurobehavioral index of sensorimotor gating. However, ASR magnitude was decreased by ethanol exposure regardless of age. On the basis of previous studies, the effects of ethanol exposure on PPI data could indicate that adolescent rats exposed to ethanol are more likely to exhibit behavioral inflexibility and that ethanol exposure acts as a more potent physical stressor in adolescent rats.

Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models.

This article presents an overview of the proceedings from a symposium entitled "Is adolescence special? Possible age-related vulnerabilities to chronic alcohol or nicotine exposure," organized by Susan Barron and Linda Spear and held at the 2004 Research Society on Alcoholism Meeting in Vancouver, British Columbia. This symposium, co-sponsored by the Fetal Alcohol Syndrome Study Group and the Neurobehavioral Teratology Society, focused on our current knowledge regarding the long-term consequences of ethanol and/or nicotine exposure during adolescence with the emphasis on data from rodent models. The support from these two societies represents the understanding by these research groups that adolescence represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in which many risky behaviors including alcohol consumption and smoking typically begin. The speakers included (1) Aaron White, who presented data on the effects of adolescent ethanol exposure on subsequent motor or cognitive response to an ethanol challenge in adulthood; (2) Richard Bell, who presented data suggesting that genetic differences could play a role in adolescent vulnerability to ethanol; (3) Craig Slawecki, who presented data looking at the effects of chronic exposure to alcohol or nicotine on neurophysiologic and behavioral end points; and (4) Ed Levin, who presented data on acute and long-term consequences of adolescent nicotine exposure. Finally, Linda Spear provided some summary points and recommendations regarding unresolved issues and future directions.

Antagonism of neuropeptide YY1 receptors does not inhibit ethanol's effects on cortical EEG and ERPs in Wistar rats.

OBJECTIVE: Ethanol and neuropeptide Y (NPY) can have additive neurobehavioral effects. In the present study, the NPY Y1 receptor antagonist BIBP3226 was administered alone or in combination with a moderate dose of ethanol to determine whether it interacted with the neurobehavioral effects of ethanol. METHOD: Male Wistar rats were implanted with cortical recording electrodes and a lateral ventricular cannula. The effects of 1 nmol BIBP3226, 0.75 g/kg ethanol and the combination (BIBP3226 + EtOH) on neurophysiological activity and locomotion were then assessed. RESULTS: Ethanol significantly increased 1-2 Hz parietal cortical power and this effect was partially antagonized by BIBP3226. Peak frequencies in the parietal cortical 6-8 Hz and 8-16 Hz bands were also altered by ethanol, but these effects were not reversed by BIBP3226. BIBP3226 or ethanol, when administered alone, did not alter motor activity or cortical event-related potentials (ERPs) but administration of BIBP3226 + EtOH reduced motor activity, reduced parietal cortical N1 ERP amplitude and increased frontal cortical N1 ERP latency. CONCLUSIONS: In the present study, the most prominent effect of antagonizing central NPY Y1 receptors was a facilitation of the effects of ethanol. In particular, the effects of combined administration of BIBP3226 and ethanol are indicative of enhanced sedation and possibly cognitive impairment.

Increased CRF-like and NPY-like immunoreactivity in adult rats exposed to nicotine during adolescence: relation to anxiety-like and depressive-like behavior.

OBJECTIVE: Recently, animal models have been developed that demonstrate that adolescent nicotine exposure produces neurobehavioral changes which persist into adulthood. This study further examined the impact of adolescent nicotine exposure on anxiety-like and depressive-like behavior, as well as on levels of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) in this model. METHODS: Male adolescent rats (35-40 days old) were administered nicotine using Nicoderm CQ patches (Smith-Kline Beecham). Behavior in the elevated plus maze (EPM) and forced swim test (FST) was assessed 2-3 weeks after exposure ended. Brain levels of CRF and NPY were then assessed 5-6 weeks after behavioral tests were completed. In addition, blood and brain levels of nicotine resulting from nicotine treatment were examined. RESULTS: After 5 days of exposure to 5 mg/kg/day nicotine, blood levels of nicotine averaged 66+/-5 ng/ml and brain nicotine levels averaged 52+/-4 ng/g. Rats exposed to nicotine displayed an anxiety-like profile in the EPM (i.e., decreased time spent in the open arms) and an antidepressant-like profile in the FST (i.e., less time spent immobile). Rats exposed to nicotine also had increased hypothalamic and frontal cortical CRF, increased hypothalamic and hippocampal NPY, and a decreased ratio of NPY to CRF in the amygdala. CONCLUSIONS: This study demonstrates that adolescent nicotine exposure produces lasting increases in anxiety-like behavior and may reduce depressive-like behavior. These behavioral changes also occurred in concert with alterations in CRF and NPY systems. Thus, lasting neurobehavioral changes associated with adolescent nicotine exposure may be related to allostatic changes in stress peptide systems.

Assessment of sustained attention in ad libitum fed Wistar rats: effects of MK-801.

RATIONALE: Rodent models designed to assess cognitive function, such as sustained attention tasks, use food and/or fluid restriction in order to motivate responding. However, evidence indicates that dietary restriction can have profound effects on brain function and on the neurobehavioral effects of drugs. OBJECTIVE: The primary objective of this study was to demonstrate the feasibility of using ad libitum fed rats to assess sustained attention in an operant 2-choice reaction time (2-CRT) task. Because N-methyl-D-aspartate (NMDA) receptor function is critical for sustaining attention in animal models, the effects of the NMDA antagonist MK-801 on 2-CRT performance were also assessed. METHODS: Male Wistar rats (n = 20) rats were trained to perform an operant 2-CRT task. A 10% sucrose solution was used as the reinforcer. After performance levels stabilized, the effects of MK-801 (0.01-0.12 mg/kg, IP) were assessed. RESULTS: Stable levels of performance on the final version of the 2-CRT task was established after 2-3 months of training. Consistent with prior reports, correct trials varied as a function of stimulus light duration (1000 ms: 67 +/- 3%, 500 ms: 59 +/- 3%, 100 ms: 51 +/- 3%, 50 ms: 43 +/- 2%). Administration of 0.06 mg/kg MK-801 significantly increased choice accuracy. Administration of 0.12 mg/kg MK-801 significantly slowed reaction times and resulted in pronounced motor incoordination. CONCLUSIONS: This study demonstrates that ad libitum fed rats can be trained to perform a 2-CRT task. However, the levels of choice accuracy are lower than typically observed under conditions of dietary restriction. The increase in choice accuracy following MK-801 is consistent with the effects of psychomotor stimulants and may suggest sustained attention was slightly enhanced by MK-801.

Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure.

Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) have opposing effects on stress-associated and consummatory behaviors in rodents. Recent studies also suggest that both peptides influence ethanol intake. In the present study, the effects of administration of CRF and NPY into the lateral ventricle on ethanol intake in naive and ethanol-vapor-exposed Wistar rats were examined. A limited access paradigm was used to measure intake of a 10% (v/v) ethanol solution in Wistar rats trained to drink using a sucrose fading procedure. Ethanol vapor exposure for 8 weeks significantly elevated ethanol intake in this limited access paradigm relative to pre-exposure levels. The effects of icv administration of CRF (1 microg), NPY (10 microg) or NPY/CRF combined (10 and 1 microg, respectively) on ethanol intake were then assessed. In non-vapor-exposed subjects, icv infusion of NPY had no effect on ethanol intake, while a significant suppression of drinking was seen following icv administration of CRF. Administration of NPY in combination with CRF had no effect on ethanol intake in non-ethanol-vapor-exposed rats. In vapor-exposed subjects, both NPY and CRF reduced ethanol intake, but when given in combination, no difference from vehicle was detected. Locomotor activity was measured during drinking sessions and was unaffected by peptide administration. These studies underscore the importance of a history of exposure to chronic ethanol vapor in the regulation of ethanol intake by NPY. Furthermore, the results presented here suggest that a balance between the stress-related peptides NPY and CRF may be involved in the regulation of ethanol intake.

Effect of ethanol on brain neuropeptides in adolescent and adult rats.

OBJECTIVE: Alcohol misuse early in life is associated with an increased risk of alcoholism. It is possible that this increased risk in adolescent drinkers is in part related to the susceptibility of the adolescent brain to ethanol. This study assessed the effects of ethanol exposure on several neuropeptides to begin to elucidate potential substrates that could mediate the differential effects of ethanol on adolescent and adult rats. METHOD: Male Sprague Dawley rats were exposed to ethanol vapor or air during adolescence (30 days old, n = 9, controls = 8) or adulthood (80-90 days old, n = 9, controls = 8) for 10 days. Blood alcohol concentrations averaging 250 mg/dl were maintained during this period. After 7 weeks of cessation from ethanol vapor, brain tissue was collected from the frontal cortex, caudate, hippocampus, amygdala and hypothalamus to assess the immunoreactivity levels of neuropeptide Y (NPY-LI), corticotropin-releasing hormone, substance P (SP-LI) and neurokinins (NK-LI). RESULTS: Ethanol exposure decreased overall hippocampal NPY-LI and increased SP-LI and NK-LI in the caudate, but these effects were more prominent in adult rats. Rats in the adult treatment groups (both ethanol exposed and controls) also had significantly lower levels of frontal cortical NK-LI, frontal cortical SP-LI and hypothalamic SP-LI relative to rats in the adolescent treatment groups. CONCLUSIONS: These data indicate that brief exposure to alcohol has long-term effects on levels of NPY-LI, SP-LI and NK-LI. As these effects were primarily the result of changes in rats exposed to ethanol during adulthood, however, they are unlikely to contribute to the increased susceptibility of adolescents to the effects of chronic ethanol exposure.

Effects of neuropeptide Y on appetitive and consummatory behaviors associated with alcohol drinking in wistar rats with a history of ethanol exposure.

BACKGROUND: Neuropeptide Y (NPY) reduces ethanol intake under free access conditions in Wistar rats with a history of prolonged ethanol vapor exposure. The current study was designed to determine whether NPY differentially alters ethanol-associated appetitive behavior (i.e., lever pressing) or ethanol consumption in Wistar rats with a history of ethanol vapor exposure. METHODS: Wistar rats were first trained to self-administer 10% ethanol in a paradigm that provided 25 min of free access to 10% ethanol after completing a 20-lever press response requirement (i.e., an RR20 schedule). After stable level lever pressing was established, operant sessions were suspended during a 9-week period of ethanol vapor exposure. Self-administration sessions were then reinstituted, and a fixed time (FT) schedule of 10% ethanol access was used to assess the effects of ethanol exposure and NPY on lever pressing and drinking behavior. Under the FT schedule, the maximum number of lever presses emitted within 10 min was assessed before providing access to 10% ethanol. RESULTS: Ethanol vapor exposure did not alter patterns of lever pressing under the RR20 schedule, but lever presses emitted under the FT schedule were reduced after ethanol vapor exposure. Ethanol intake was significantly increased after ethanol vapor exposure. NPY significantly reduced ethanol intake but did not significantly reduce lever pressing under the FT schedule. CONCLUSIONS: Taken together, these data suggest that chronic ethanol exposure increases ethanol intake without clearly enhancing its reinforcing value. Furthermore, NPY has a greater impact on the consummatory factors mediating ethanol intake than appetitive factors mediating ethanol seeking.

Electrophysiological effects of allopregnanolone in rats with a history of ethanol exposure.

BACKGROUND: Sensitivity to the anticonvulsant effects of allopregnanolone (ALLO) is enhanced during the early phase of ethanol (EtOH) withdrawal. However, it is unclear whether this enhanced sensitivity generalizes to ALLO's neurobehavioral effects during protracted abstinence. The purpose of this study was to examine the neurophysiological effects of ALLO in rats with a history of chronic EtOH exposure after a protracted period of abstinence. METHODS: Male Wistar rats were exposed to EtOH vapor for 14 hr/day for 5 weeks. Blood EtOH levels were maintained between 200 and 250 mg/dl. The effects of ALLO (0.0-10 mg/kg, intraperitoneally) on motor activity, the electroencephalogram (EEG), and auditory event-related potentials then were assessed after 6 to 8 weeks of abstinence from EtOH. RESULTS: ALLO's effects on the EEG were consistent with previous studies and were unaffected by EtOH exposure. ALLO increased high-frequency EEG power and shifted peak EEG frequencies in a benzodiazepine- and barbiturate-like manner in both the cortex and the hippocampus. The effects of ALLO on event-related potentials were attenuated in rats with a history of EtOH exposure. Low doses of ALLO (1 and 5 mg/kg) reduced cortical P1 amplitude in response to the standard tone but only in the control group. ALLO also increased N1 amplitude in the hippocampus of the control group while having no significant effect in EtOH-exposed rats. Low doses of ALLO (1 and 5 mg/kg) were found to increase motor activity. CONCLUSIONS: These data indicate that a history of EtOH exposure attenuates some of the neurophysiological effects of ALLO in a manner consistent with cross-tolerance. Taken together, these data suggest that increased sensitivity to ALLO's neurobehavioral effects is limited to the early phases of EtOH withdrawal and may not extend to more protracted periods of abstinence.

Comparison of anxiety-like behavior in adolescent and adult Sprague-Dawley rats.

The conditions under which age differences in anxiety are observed in rodents are unclear. These studies explored the influence of test condition on anxiety-like behavior in adolescent and adult rats using the light-dark box. Behavior was assessed under different illumination levels (30 or 60 lux) and after brief stress (restraint or bright light). Anxiety-like behavior did not differ in the 30-lux test but was increased in adolescents in the 60-lux test. Restraint increased anxiety-like behavior in adolescents, resulting in elevated anxiety-like behavior relative to adults. Bright light decreased anxiety-like behavior, possibly because of negative contrast or novelty-induced anxiolysis. These studies demonstrate that adolescents display increased anxiety-like behavior when test conditions are more aversive and following exposure to stress.

Effect of social isolation on ethanol consumption and substance P/neurokinin expression in Wistar rats.

Environmental factors, such as adverse life experiences and family/peer influences have a substantial influence on the development of disorders related to alcohol use. In animals, maternal or peer separation/isolation has been used as an environmental intervention that has been shown to alter neurodevelopment and influence drinking behaviors in rodents and primates. In this study, the effects of adult peer isolation on subsequent ethanol intake were investigated in Wistar rats. Because central tachykinin levels have been reported to differ between rats selected for enhanced ethanol preference, neuropeptide [neurokinin A (NKA), substance P (SP)] concentrations were also estimated. Lower levels of ethanol intake, in a two-bottle free-choice model, were observed on the first day of forced ethanol drinking in the single-housed animals. However, overall ethanol consumption was unaffected by peer isolation. Peer isolation significantly lowered SP and NKA levels in the hypothalamus, but this effect was not related to ethanol consumption or body weight. These data indicate that endogenous SP and neurokinin levels are reduced by isolation housing, but this was not associated with alterations in drinking levels using a two-bottle choice procedure.

Long-term neurobehavioral effects of alcohol or nicotine exposure in adolescent animal models.

Adolescent alcohol and nicotine abuse is common, but its neurodevelopmental consequences remain unclear. This laboratory utilized adolescent rodent models to assess the hypothesis that adolescents are highly susceptible to the effects of alcohol and nicotine. Rats were exposed to ethanol for 10-14 days using an intermittent vapor inhalation paradigm. Rats were continuously exposed to nicotine for 5 days using Nicoderm CQ transdermal patches. Alcohol or nicotine exposure altered neurobehavioral function when assessed after 3-7 weeks of abstinence. Alcohol-induced changes include increased electroencephalographic (EEG) frequency, decreased amplitude of the cortical N1 and hippocampal P3 event-related potential (ERP) components, enhanced anxiety-like behavior, and enhanced depressive-like behavior. Nicotine-induced changes include decreased slow-wave cortical EEG power, increased cortical N1 ERP amplitude, decreased motor activity, and increased anxiety-like behavior. These findings support the hypothesis that adolescents are uniquely susceptible to the effects of chronic alcohol and nicotine exposure.

Comparison of the onset of hypoactivity and anxiety-like behavior during alcohol withdrawal in adolescent and adult rats.

BACKGROUND: Early life alcohol use is associated with increased alcoholism risk. It has been suggested that alterations in the sensitivity of adolescents to the acute effects of ethanol may contribute to this risk by promoting excessive intake. However, an enhanced propensity for developing ethanol dependence or withdrawal-related behavior could also contribute to increased risk. The objective of these studies was to compare the appearance of ethanol withdrawal-related behaviors in adolescent and adult rats. METHODS: Male Sprague-Dawley rats were exposed to ethanol vapor (12 hr/day) for 12 or 14 days during adolescence or adulthood. In the first study, locomotor activity was assessed after 2, 4, 7, 10, and 14 days of ethanol exposure. In the second study, open field behavior was assessed after 5 or 12 days of ethanol exposure. In follow-up studies, changes in sucrose preference during ethanol withdrawal and motor activity during food restriction were assessed in adolescent rats. Withdrawal assessments were made 7 to 9 hr after daily exposure ended. RESULTS: Hypoactivity emerged rapidly in adolescent rats during ethanol withdrawal in activity tests, but comparable reductions were not found in adult rats. However, hypoactivity developed in both adolescents and adults in the novel open field. Enhanced anxiety-like behavior in the open field was not observed in either age group during withdrawal. Finally, sucrose preference was unchanged during ethanol withdrawal, and food restriction increased motor activity in adolescent rats. CONCLUSIONS: These data confirm that symptoms of withdrawal may be differentially expressed in adolescent and adult rats. However, discrepancies in hypoactivity between studies suggest that assessment in a novel versus familiar environment may influence the expression of withdrawal-related behaviors.

Neurophysiologic consequences of neonatal ethanol exposure in the rat.

Many of the neurotoxic and neurobehavioral consequences of neonatal ethanol exposure in the rat have been characterized. However, in few studies has adult neurophysiologic function been assessed in rats exposed to ethanol during this key developmental period. In the current study, the effects of neonatal ethanol exposure on adult electroencephalographic (EEG) activity and auditory event-related potentials (ERPs) were examined in the rat. Male Sprague-Dawley rats were exposed to ethanol at 6.0 g/kg/day between postnatal days 4 through 9 by using an artificial-rearing procedure. Two control groups were used: a suckle control (SC) group and a gastrostomized control (GC) group. After reaching adulthood (i.e., at 3.5-4 months old), recording electrodes were implanted into the brain of each rat, so that EEG activity and auditory ERPs from the cortex and hippocampus could be assessed. Rats exposed to ethanol during the neonatal period were hyperactive as adults. Assessment of the EEG activity revealed that ethanol exposure increased peak frequency in the frontal cortical and parietal cortical 16-32 Hz frequency bands. Assessment of ERPs revealed that parietal cortical N1 amplitude was reduced in ethanol-exposed rats. Furthermore, parietal cortical N1 latency was increased in the GC group. These findings demonstrate that enhanced motor activity in rats exposed to ethanol during neonatal development occurs in combination with EEG indices of enhanced cortical and hippocampal arousal. Furthermore, a deficiency in cortical N1 amplitude indicates adult rats may have attention deficits. Overall, these results indicate that neonatal ethanol exposure has enduring neurobehavioral consequences, which persist into adulthood. This neurobehavioral profile in the rat is consistent with clinical observations of attention deficits and hyperactivity in children exposed to ethanol during prenatal development.

Neurokinin type-3 receptor stimulation impairs ethanol-associated appetitive behavior in Wistar rats.

OBJECTIVES: Stimulating central neurokinin type-3 (NK-3) receptors decreases ethanol intake in rats. Although paraventricular nucleus of the hypothalamus (PVN) has a high density of NK-3 receptors, their influence on ethanol reinforcement has not been examined. This study's purpose was to assess the effects of intra-PVN infusion of senktide, a NK-3 receptor agonist, on ethanol self-administration. In a follow-up study, senktide's effects on ethanol self-administration after intracerebroventricular (ICV) infusion were examined. METHODS: Male Wistar rats were trained to self-administer 10% ethanol (10E) in the "Sipper Tube" model described by Samson and colleagues, Guide cannula were then aimed bilaterally at the PVN or unilaterally at the lateral cerebral ventricle. Intra-PVN (5-100 ng/side) or ICV (30-500 ng/rat) effects of senktide on 10E self-administration were also examined as a preliminary test of senktide's selectivity. RESULTS: Intra-PVN and ICV infusion of senktide reduced the average number of consecutive lever presses and increased the time taken to complete the lever press requirement when 10E served as the reinforcer. Increased duration of the lever-pressing component was observed when senktide was administered prior to 2S self-administration sessions. Neither PVN nor ICV senktide administration significantly altered 10E or 2S consumption. CONCLUSIONS: These data suggest that stimulation of central neurokinin typ-3 receptors in the Wistar rat reduces appetitive behavior while having little or no impact on consummatory behavior. Ethanol "seeking" appeared more sensitive to disruption by senktide than sucrose "seeking." However, further studies assessing the senktide's effects on sucrose-maintained behavior are needed to verify this hypothesis. Lastly, it is hypothesized that lack of effect of senktide on intake is in part related to the use of outbred Wistar rats in these studies instead of selectively bred rats.

Increased anxiety-like behavior in adult rats exposed to nicotine as adolescents.

OBJECTIVE: Twenty percent of adolescents between 12 and 18 years old are regular smokers. Recently developed animal models demonstrate that adolescent nicotine exposure produces behavioral and electrophysiological changes, which persist into adulthood. The purpose of this study was to further define the behavioral effects of nicotine exposure during adolescence. METHODS: Male 31-36-day-old adolescent rats were administered 5.0 mg/kg/day nicotine using transdermal Nicoderm CQ patches (SmithKline Beecham). During nicotine exposure, motor activity was assessed. Behavior in both standard open field and modified open field was examined 2-3 weeks after exposure ended. RESULTS: Nicotine exposure significantly enhanced motor activity in nicotine-exposed rats compared with controls, demonstrating the acute stimulatory effects of transdermal nicotine. Two to three weeks after nicotine exposure ended, significantly lower levels of exploratory activity were observed relative to controls in the standard open field. Rats exposed to nicotine during adolescence also retreated to the perimeter of the open field more quickly than control rats. In a modified open field, nicotine exposure reduced approaches to food, contact with food and food intake. CONCLUSIONS: Taken together, these data suggest that adolescent nicotine exposure may induce an anxiogenic profile, which persists beyond acute nicotine withdrawal. Given the hypothesized role of stress and anxiety in the maintenance of smoking, it could be speculated that anxiety associated with smoking abstinence may play an important role in continued adolescent tobacco use.