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T K Li

Publications and source records attributed to T K Li.

At least 55 records · Page 3Linked to original sources
PubMed2000

Effects of 5-HT(3) receptor antagonists on daily alcohol intake under acquisition, maintenance, and relapse conditions in alcohol-preferring (P) rats.

Previous research indicated that 5-HT(3) antagonists can reduce ethanol drinking in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT(3) antagonists MDL 72222 (MDL) or ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisition, maintenance, and following a period of deprivation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL (1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 10 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT(3) antagonist. To examine the effects of a 5-HT(3) antagonist on relapse of ethanol drinking, another group of P rats was allowed access to ethanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to ethanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 mg/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60-80%) and during maintenance drinking (35-70%) in P rats pretreated with saline during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of either MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with 1 mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) or ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observed on the first day of reinstatement. Overall, the results suggest that 5-HT(3) receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treatment with 5-HT(3) antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat.

Alcohol Drinking↗
PubMed2000

Identification of quantitative trait loci influencing alcohol consumption in the high alcohol drinking and low alcohol drinking rat lines.

Selective breeding has been employed to develop high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rat lines from the heterogeneous N/Nih rat. Within-family selection and a rotational breeding design were used to discourage inbreeding (Li et al, 1993). To identify quantitative trait loci (QTLs) contributing to alcohol consumption, reciprocal HAD and LAD matings in conjunction with F1 intercrosses were used to create 459 F2 progeny. Using selective genotyping of 151 F2 progeny with extreme alcohol consumption scores and a novel least squares method developed by Haley et al (1994), five chromosomal regions (1, 5, 10, 12, and 16) were identified with lod scores greater than 2.0. Genotyping of the entire sample of 459 F2 progeny produced maximum lod scores of 3.5 on chromosome 5, 2.4 on chromosome 10, 4.7 on chromosome 12 and 2.9 on chromosome 16. The evidence of linkage to chromosome 1 diminished substantially to a maximum lod score of 0.5 when all F2 progeny were genotyped. This study is the first genome-wide study for QTLs underlying alcohol consumption that has employed noninbred lines. Further localization of these QTLs will likely provide insight and candidate genes for the study of human alcoholism.

Alcohol Drinking↗
PubMed2000

Clinical perspectives for the study of craving and relapse in animal models.

Several major clinical models of alcoholism in which craving plays a role are summarized and key questions are raised regarding the course of craving in the emergence of alcoholism, how it varies in different stages of the disorder (e.g. active alcoholic, withdrawal, protracted abstinence) and what craving may contribute to major signs and symptoms of alcoholism. Turning to animal models, a plea is made for development of a standardized definition of human craving that can be represented and operationalized in animal models. Until there is scientific consensus on such a definition, four ways are elucidated in which animal model research can contribute to advances in our knowledge of human craving and the role it plays in addictive behavior: (1) engaging both basic and clinical researchers to identify parallel constructs of craving and predictors of craving for adoption in comparative human and animal model studies; (2) conducting exploratory research on craving in animal models using relapse to drinking as the dependent measure; (3) identifying mechanisms that underlie clinical signs and symptoms of alcoholism in animal models; and (4) identifying genetic models in basic research that account for variations in response to alcohol that may also occur in humans. This latter point is made in a discussion of the genetic contribution to voluntary alcohol consumption, the alcohol deprivation effect, tolerance and dependence, as illustrated by differences between alcohol-preferring (P) rats and -nonpreferring (NP) rats. The review concludes with four questions and issues that need to be among those that guide future research on craving.

Alcohol-Related Disorders↗
PubMed2000

Involvement of nicotinic receptors in alcohol self-administration.

BACKGROUND: Alcohol and nicotine, in the form of tobacco, are commonly co-abused. Nicotinic receptors also have been implicated in alcohol action. We designed the present study to examine the possible involvement of nicotinic receptors in alcohol self-administration. METHODS AND RESULTS: Pretreatment with lower doses (0.1-0.4 mg/kg) of nicotine, administered acutely or chronically, did not affect alcohol consumption, whereas a higher dose (0.8 mg/kg) initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment. We observed the same pattern of nicotine effects on alcohol self-administration using an operant procedure. A dose of 0.8 mg/kg of nicotine initially suppressed operant responding for alcohol. Such suppression of alcohol self-administration was more pronounced during the first 20 min of the 60 min operant session. Responding for alcohol in the nicotine treated group, however, was significantly increased above the saline treated group by the 5th day of treatment. Mecamylamine, a noncompetitive nicotinic receptor antagonist, reduced alcohol consumption, whereas dihydro-beta-erythroidine (DHbetaE), a competitive nicotinic receptor antagonist, did not modify alcohol consumption. CONCLUSIONS: The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self-administration. The failure of DHbetaE to reduce alcohol consumption, however, suggests that ethanol-nicotine interaction is mediated by other nicotinic receptor subtypes rather than alpha4beta2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism.

Alcohol Drinking↗
PubMed2000

Mechanism of action of camptothecin.

Camptothecin (CPT) class of compounds has been demonstrated to be effective against a broad spectrum of tumors. Their molecular target has been firmly established to be human DNA topoisomerase I (topo I). CPT inhibits topo I by blocking the rejoining step of the cleavage/religation reaction of topo-I, resulting in accumulation of a covalent reaction intermediate, the cleavable complex. The primary mechanism of cell killing by CPT is S-phase-specific killing through potentially lethal collisions between advancing replication forks and topo-I cleavable complexes. Collisions with the transcription machinery have also been shown to trigger the formation of long-lived covalent topo-I DNA complexes, which contribute to CPT cytotoxicity. Two novel repair responses to topo-I-mediated DNA damage involving covalent modifications of topo-I have been discovered. The first involves activation of the ubiquitin/26S proteasome pathway, leading to degradation of topo-I (CPT-induced topo-I downregulation). The second involves SUMO conjugation to topo-I. The potentials roles of these new mechanisms for repair of topo-I-mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed.

Animals↗
PubMed2000

Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking.

OBJECTIVE: There is now compelling evidence for genetic influence on susceptibility to alcoholism. This article presents results from studies qualifying alcoholism as a pharmacogenetic disorder of the brain. METHOD: Studies from the author's research group and other investigators, of human subjects and experimental animal models, are reviewed. Included are experiments on the pharmacogenetics (elimination and metabolism) and pharmacodynamics (initial response, tolerance and dependence) of ethanol. RESULTS: Studies in humans have reliably shown that the genes for the principal enzymes of alcohol metabolism influence drinking behavior and alcoholism risk. Notably, the functional genetic variants of alcohol dehydrogenase that exhibit high alcohol oxidizing activity, and the genetic variant of aldehyde dehydrogenase that exhibits low acetaldehyde oxidizing activity, protect against heavy drinking and alcoholism. Extensive studies of inbred and selectively bred experimental rodent models with alcohol drinking preference, tolerance development and alcohol withdrawal susceptibility have shown strong genetic influence on these responses to ethanol. Neuroanatomical, neurochemical and genetic studies have shown the involvement of serotonin, dopamine, glutamate, gamma-aminobutyric acid and opioid pathways in these actions of ethanol. Genetic studies, including association and genome-wide survey studies in both humans and rodents, implicate serotonin 1b receptor, dopamine D2 receptor, tryptophan hydroxylase and neuropeptide Y as candidate targets of genetic susceptibility in these pharmacodynamic actions of ethanol. CONCLUSIONS: There are genetic predisposing factors for alcoholism. Nonspecific susceptibility factors include personality traits characterized by behavioral inhibition (e.g., novelty-seeking and impulsivity). These genetically influenced traits interact with other, also genetically influenced, traits involved in the metabolism and pharmacodynamic effects of alcohol, and this interaction forms the basis for nominating alcoholism as a pharmacogenetic disease. Clearly, there are also many environmental factors that influence drinking behavior. Individuals have different sets of susceptibility genes and experience different kinds of environmental provocation. These factors underlie the heterogeneity and complexity of the clinical phenotype of alcoholism.

Alcohol Dehydrogenase↗
PubMed2000

Alcohol deprivation effect is prolonged in the alcohol preferring (P) rat after repeated deprivations.

BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the ratio of ethanol/total fluid intake and the voluntary intake of ethanol solutions over baseline drinking conditions when ethanol access is reinstated after a period of alcohol deprivation. The ADE has been posited to be an animal model for alcohol craving. The current study examined the effects of initial deprivation length and number of deprivation exposures on the ADE in alcohol-preferring (P) rats. METHODS: Adult female P rats received 24-hr free-choice access to 10% (v/v) ethanol and water for 6 weeks. Rats were then randomly assigned to five groups deprived of ethanol for 0 (control), 2, 4, 6, or 8 weeks (W). All deprived groups were then given 24-hr access to ethanol for 2 weeks before being deprived of ethanol for another 2 weeks. RESULTS: After the initial ethanol deprivation period, the deprived groups displayed a similar 2-fold ADE (e.g., 4-W group; 4.6 +/- 0.5 for baseline vs. 10.5 +/- 0.3 g/kg/day for the 1st reinstatement day) during the initial 24-hr period. Ethanol consumption began to return to control levels 48 (7.1 +/- 0.4 g/kg/day) and 72 (6.4 +/- 0.4 g/kg/day) hrs later. In addition, each deprived group showed increases in the ratio of ethanol/total fluid intake upon reinstatement, and there was a tendency for sustained higher ethanol intake ratios during the first 3 postexposure days for the 4-, 6-, and 8-W groups, but only during the first 2 reinstatement days for the 2-W group. The second deprivation did not increase the magnitude of the ADE over that observed in the first deprivation during the initial 24-hr period of re-exposure, but it did prolong the duration of the ADE into the 2nd and 3rd reinstatement day for the 2-, 4-, and 6-W groups and into the 5th reinstatement day for the 8-W group. CONCLUSIONS: Equivalent robust ADEs can be seen in P rats with deprivation periods of 2-8 W, which suggests that the ADE has a rapid onset and is not affected by the durations of deprivation that were tested. The duration of the ADE was prolonged in P rats exposed to a second deprivation period, suggesting that factors associated with the ADE phenomenon could be strengthened by repeated deprivations.

Alcohol Drinking↗
PubMed2000

Analysis of heritability of hormonal responses to alcohol in twins: beta-endorphin as a potential biomarker of genetic risk for alcoholism.

BACKGROUND: Hormonal responses to alcohol have been reported to differ in subjects with and without a family history of alcoholism which suggests that alcohol-induced hormonal changes might be used to identify individuals who are at elevated genetic risk for developing alcoholism. However, before a biological response can be used as a marker of genetic risk for disease, it must first be demonstrated that the response is, in fact, heritable. The present study was designed to determine whether hormonal responses to alcohol are heritable. METHODS: The adrenocorticotropic hormone (ACTH), beta-endorphin (beta-E), cortisol (CORT), and prolactin (PRL) responses to alcohol were examined in male and female identical (monozygotic or MZ) and fraternal (dizygotic or DZ) twin pairs. Male subjects consumed 0.35 g ethanol/kg body weight (BW) and females consumed 0.325 g ethanol/kg BW in each of two alcohol drinking sessions administered 1 hr apart (total dose of 0.7 g/kg BW in males and 0.65 g/kg BW in females). Plasma hormone content was analyzed in samples collected before (resting conditions) and at 15, 60, 75, 120, 180, and 240 min after onset of drinking. Hormonal responses to alcohol were examined with twin analyses using the TWINAN90 program. A separate analysis was performed for each of the four hormones. A subset of subjects from each zygosity was seen on two separate occasions to establish retest reliability. Heritability of hormonal responses to alcohol was estimated using the intraclass correlation approach before and after removing the contribution of covariates that have the potential of influencing the plasma levels of these hormones. RESULTS: Resting plasma levels of all four hormones were within the expected range, and the beta-E, ACTH, and PRL responses to the alcohol challenge evidenced good test-retest reliability. Of the four hormones examined, the only one that showed significant heritability after alcohol drinking was beta-E. Heritability estimates were not altered for any of the four hormones after removal of the variance contributed by covariates, such as gender and age. CONCLUSIONS: Taken together with other recent findings, the results suggest that the beta-E response to alcohol may represent a new biomarker that can be used to identify individuals who are at elevated genetic risk for developing alcoholism.

Adult↗
PubMed2000

Involvement of dopamine D2 autoreceptors in the ventral tegmental area on alcohol and saccharin intake of the alcohol-preferring P rat.

BACKGROUND: The ventral tegmental area (VTA) dopamine (DA) system is considered to be involved in mediating the actions of ethanol (EtOH). The objective of the present study was to examine the role of VTA DA D2 receptors in regulating EtOH intake of alcohol-preferring P rats. METHODS: EtOH (10% v/v) and saccharin (SACC, 0.0125% g/v) intake during 2 hr of limited access was assessed after microinjections of the D2 agonist quinpirole and the D2 antagonist sulpiride into the anterior VTA (AVTA) of female P rats. Both EtOH-SACC alternate-day-access conditions and daily availability of EtOH and SACC solutions to separate groups of subjects were used. A second D2 agonist, quinelorane, and coadministration of 2.0 microg sulpiride with 2.0 microg quinpirole were tested in animals given limited access to EtOH. Finally, the effects of quinpirole injected 2 mm dorsal to the VTA and within the posterior VTA (PVTA) were assessed under EtOH-SACC alternate-day-access conditions. RESULTS: Microinjections of 2.0-6.0 microg quinpirole into the AVTA dose dependently decreased EtOH intake 40-80% during the first 30 min of the limited access sessions but did not alter SACC intake. Injections of 2.0-4.0 microg quinelorane into the AVTA also reduced EtOH intake in the first 30 min. Administration of 0.5-2.0 microg sulpiride into the AVTA had no effect on either EtOH or SACC intakes but did attenuate the effects of quinpirole on reducing EtOH intake. Injections of 2.0-4.0 quinpirole 2 mm dorsal to the VTA did not alter EtOH or SACC intakes. Posterior VTA injections of quinpirole decreased EtOH and SACC intakes approximately 25-30% and 60-70%, respectively, in the first 30 min. None of the treatments altered intakes during the 30-120 min period. CONCLUSIONS: The data suggest that DA neuronal activity within the AVTA may be important for maintaining EtOH drinking in P rats, whereas DA neuronal activity within the PVTA may be involved in regulating general drinking and/or motivational behaviors. Overall, the results confirm the involvement of mesolimbic DA in EtOH self-administration and suggest that there is functional heterogeneity within the VTA regulating drinking behavior of the P rat.

Alcohol Drinking↗
PubMed2000

Norepinephrine uptake sites in the locus coeruleus of rat lines selectively bred for high and low alcohol preference: a quantitative autoradiographic binding study using [3H]-tomoxetine.

BACKGROUND: The locus coeruleus (LC) is the largest norepinephrinergic cell group in the central nervous system and contains a high density of norepinephrine (NE) uptake sites. Alcohol-preferring (AP) rats and high-alcohol-drinking (HAD) rats are selectively bred for high alcohol preference, whereas alcohol-nonpreferring (NP) rats and low-alcohol-drinking (LAD) rats are bred for low alcohol preference. However, it is unknown whether NE uptake sites in the LC are associated with alcohol preference in AP and HAD rats when compared with their respective control rats, NP and LAD rats. This study was designed to examine this question. METHODS: Animals were decapitated and brains were removed, frozen with dry ice powder, and stored in a deep freezer. The LC tissue blocks were cut into 14 micro cryostat sections, collected on glass slides, and incubated with 0.6 nM [3H]-tomoxetine in 50 mM Tris-HCl buffer system. For nonspecific binding, 1 microM desipramine was added to the radioactive ligand. Sections were rinsed, quickly dried, and processed for quantitative autoradiography. In addition, galanin content in the LC was also studied. RESULTS: The LC possessed a high density of [3H]-tomoxetine binding sites. There were fewer tomoxetine binding sites (fmol/mg protein) in the AP rats (433.0 +/- 8.1) than in the NP rats (495.6 +/- 3.7). HAD rats (386.5 +/- 13.2) also possessed fewer tomoxetine binding sites than LAD rats (458.7 +/- 10.1). Galanin content in the LC was similar between AP and NP rats and between HAD and LAD rats. CONCLUSIONS: Because both AP rats and HAD rats were selectively bred for alcohol preference, the finding of consistently low levels of [3H]-tomoxetine binding in the LC of these two lines of rats with high alcohol preference suggests that down-regulation of NE transporters in the LC of AP and HAD rats may be associated with alcohol-seeking behavior. A possible involvement of the coerulear NE uptake sites in depression is also discussed. Galanin in the LC may not relate to alcohol preference.

Alcohol Drinking↗
PubMed2000

The expression of an alcohol deprivation effect in the high-alcohol-drinking replicate rat lines is dependent on repeated deprivations.

BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the ratio of alcohol/total fluid intake and voluntary intake of ethanol (EtOH) solutions over baseline drinking conditions when EtOH access is reinstated after a period of alcohol deprivation. The ADE has been posited to be an animal model for alcohol craving. In the current study, we examined the effects of initial deprivation length and number of deprivation exposures on the ADE in the replicate lines of the high-alcohol-drinking (HAD) rats. METHODS: Adult male HAD-1 and HAD-2 rats received 24 hr free-choice access to 10% (v/v) EtOH and water for 6 weeks. Rats were then assigned to groups deprived of EtOH for 0 (control), or 2 to 8 weeks. All deprived groups were then given 24 hr access to EtOH for 2 weeks before being deprived of EtOH for another 2 weeks. This cycle of 2 weeks of access and 2 weeks of deprivation was carried out for a total of four deprivations. RESULTS: After the initial EtOH deprivation period, EtOH consumption in HAD-1 and HAD-2 rats returned to baseline levels but failed to exhibit either an early onset ADE (initial 2 hr) or prolonged ADE (24 hr). An ADE was observed in two of the four deprived groups for the HAD-1 rats (2 week and 6 week groups) and in all deprived groups for the HAD-2 rats after a second deprivation, and in all deprived groups of both lines after a third deprivation. In the HAD-2 line, but not in the HAD-1 line, the duration of the ADE was prolonged into the second reinstatement day after the fourth deprivation. CONCLUSIONS: The expression of an ADE was observed only after repeated deprivation periods in the HAD lines. The duration of the ADE was prolonged in the HAD-2 line, but not in the HAD-1 line, with repeated deprivations, which suggests a dissociation between selection for alcohol preference and the effects of repeated deprivations on the duration of the ADE.

Alcohol Drinking↗
PubMed2000

Reverse microdialysis of a dopamine uptake inhibitor in the nucleus accumbens of alcohol-preferring rats: effects on dialysate dopamine levels and ethanol intake.

BACKGROUND: The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol-preferring rats. METHODS: Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 microl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 microM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF. RESULTS: GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 microM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 microM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal; p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 microM was significantly greater for EtOH-experienced rats than for EtOH-naïve rats [F(7,59) = 14.85, p < 0.0001, analysis of variance, Student-Newman-Keuls post hoc test]. CONCLUSIONS: The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol-preferring animals.

Alcohol Drinking↗
PubMed2000

Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping.

BACKGROUND: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. METHODS: Additional genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. RESULTS: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). CONCLUSIONS: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.

Alcoholism↗
PubMed2000

Effects of allopregnanolone on the EEG of alcohol-preferring and alcohol-nonpreferring rats.

BACKGROUND: Alcohol preferring (P) and alcohol-nonpreferring (NP) rats have been shown to have differing behavioral and electrophysiological responses to drugs that are positive modulators of the gamma-aminobutyric acid type A (GABA-A) receptor complex, such as ethanol and benzodiazepines. The neuroactive steroid allopregnanolone is also a positive modulator of GABA-A receptors; therefore, we hypothesized that P and NP rats would respond differently to intraperitoneally administered allopregnanolone. METHODS: Male P and NP rats were implanted with screw electrodes that overlay the frontal and parietal cortices and with a depth electrode aimed at the amygdala. Allopregnanolone (0.0-10.0 mg/kg ip) was administered 10 min before recording the EEG. RESULTS: Allopregnanolone increased high-frequency power (8-32 Hz) in the cortex and amygdala of both P rats and NP rats. In addition, allopregnanolone increased the predominant frequency of the cortical EEG in the 8 to 16 Hz bandwidth, decreased the predominant frequency in the 32 to 50 Hz bandwidth, and increased EEG variability (16-50 Hz). The effects of allopregnanolone were qualitatively similar in P and NP rats. However, P rats were more sensitive to low doses of allopregnanolone in cortex, whereas NP rats responded to lower doses of allopregnanolone in the amygdala. CONCLUSIONS: These data indicate that P and NP rats differ in their sensitivity to the EEG effects of allopregnanolone in the cortex and amygdala, which suggests that differences in GABAergic systems between P and NP rats may contribute to some of the differences observed in their behavioral repertoire.

Alcohol Drinking↗
PubMed2000

Neurophysiological findings and drinking levels in high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: Specific neurophysiological profiles, such as reduced P300 amplitude or altered spectral power in the EEG, have been associated with a risk for alcoholism in several clinical populations. In certain rodent models, high versus low alcohol consumption is associated with similar neurophysiological differences. For example, alcohol-preferring (P) rats have increased spectral power and decreased P300 amplitudes compared with alcohol-nonpreferring (NP) rats. In the present study, the neurophysiological profiles of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were assessed (1) to determine if their electrophysiological profiles are similar to P and NP rats and (2) to examine the relationship of these neurophysiological indices to ethanol drinking. METHODS: Ethanol-naive HAD and LAD rats were implanted with cortical and amygdalar recording electrodes. Baseline EEG and event-related potentials (ERPs) then were assessed. Subsequently, all rats were trained to self-administer ethanol by using a sucrose-substitution procedure. RESULTS: Baseline EEG and ERP (i.e., pre-ethanol exposure) were assessed based on line (HAD versus LAD) and actual ethanol consumption (high drinkers versus low drinkers). At baseline, ethanol-naive HAD rats displayed significantly greater power in the cortical EEG and decreased amygdala N1 ERP amplitude compared with ethanol-naive LAD rats. Similar EEG and ERP profiles have been observed when P and NP rats are compared. No differences in P300 between lines were observed, but high-drinking rats, independent of line, had significantly decreased P300 amplitude in the amygdala compared with low-drinking rats. CONCLUSIONS: These data suggest there are some similarities in EEG and ERP profiles of P and HAD rats compared with NP and LAD rats. Furthermore, the data suggest that decreased P300 amplitude in the amygdala is associated with increased limited access ethanol drinking.

Alcohol Drinking↗