Biomedical subjects

L Lumeng

Publications and source records attributed to L Lumeng.

At least 37 records · Page 2Linked to original sources

PubMed2000

Ethanol locomotor sensitization, but not tolerance correlates with selection for alcohol preference in high- and low-alcohol preferring mice.

RATIONALE: Some theories have advanced a role for both locomotor sensitization and tolerance in the reinforcing properties of drugs. The present studies used selected lines of mice to assess genetic correlations among ethanol drinking, ethanol locomotor sensitization, and tolerance to the depressant effects of ethanol. OBJECTIVES: Ethanol-naive high- and low-alcohol preferring (HAP and LAP) selected lines of mice were tested for locomotor sensitization to ethanol and acquisition of acute functional tolerance to ethanol using the static dowel test. METHODS: For the locomotor sensitization study, mice received four i.p. injections of one of five doses of ethanol (0-3.5 g/kg) at 48-h intervals. On the sensitization test day, 48 h after the last drug administration day, all mice received a 2.0-g/kg ethanol injection. Other mice from the same lines were subjected to a two-injection (3.75 g/kg total), acute functional tolerance procedure assessing disruption of balance on a static dowel. RESULTS: Lines differed neither in the acute locomotor activating nor depressant effects of ethanol. Additionally, neither line's response to the depressant effect of 3.5 g/kg ethanol changed with repeated injection. However, locomotor sensitization was seen in HAP but not LAP mice that had received 2.75 g/kg or 3.5 g/kg ethanol during repeated administration. Both HAP and LAP mice acquired equivalent acute functional tolerance, as measured by an increase in blood ethanol concentration between the first and second recovery measures. CONCLUSIONS: Overall, these findings imply that high ethanol consumption in mice appears to be genetically related to ethanol locomotor sensitization. Additionally, ethanol locomotor sensitization does not appear to be related to tolerance to the depressant effects of ethanol. These findings support a role for sensitization in high alcohol-seeking behavior in mice.

Alcohol Drinking↗

PubMed2000

An assessment of novelty-seeking behavior in alcohol-preferring and nonpreferring rats.

This study examined novelty-seeking behavior in rat populations selectively bred for high and low alcohol-drinking behavior. In Experiment 1, and "odor-enhanced" novel environment produced greater behavioral activation in P compared to NP rats. In Experiment 2, the activity of high alcohol-drinking P and HAD rats was enhanced to a greater extent following the presentation of novel odors in a familiar arena, compared to the NP and LAD rats. The results suggest that, when measuring locomotor activity, alcohol-preferring rats are more reactive to novelty than their nonpreferring counterparts. Experiments 3 and 4, however, did not support the hypothesis that novelty seeking is associated with genetic vulnerability to high alcohol-drinking behavior. When measuring nose-poking behavior in response to novel odors and preference for a novel vs. a familiar chamber, behavior of the preferring lines did not differ from that of the nonpreferring lines, although P rats were more active in the place-preference paradigm. The overall results indicate that the relationship between novelty and alcohol drinking is only modestly associated, and is observed under specific conditions. Moreover, this study underscores the importance of using multiple measures when assessing complex behaviors such as novelty seeking.

Alcohol Drinking↗

PubMed2000

Effects of ethanol on startle responding in alcohol-preferring and -non-preferring rats.

The objectives of the present study were to determine (a) if differences exist between the selectively bred alcohol-preferring (P) and -non-preferring (NP) lines of rats in the acoustic startle response (ASR) and prepulse inhibition (PPI), and (b) the effects of ethanol on these measures. Alcohol-naïve adult female P and NP rats received a single i.p. injection of saline or ethanol (0.25, 0.5, 1. 0, or 1.5 g/kg) and were placed in the startle apparatus 10 min later. After a 5-min acclimation period, rats received five alternating trials of a startle stimulus alone (SSA) (115-dB white noise) or a PPI trial (90-dB white noise preceding a 115-dB white noise). Analysis of the ASR revealed that P rats exhibited higher startle amplitudes than did NP rats with saline injections. The 0. 5-g/kg ethanol dose reduced the startle amplitude in P, but not NP, rats. The 1.0- and 1.5-g/kg ethanol doses nearly abolished the ASR in the NP line, whereas only the highest ethanol dose had this effect in the P line. Vehicle-treated P and NP rats exhibited comparable PPI levels, but only P rats showed a significant disruption (30%) at the 0.50-g/kg ethanol dose. Neither P nor NP rats were affected by ethanol treatment at the 0.25-g/kg dose. Overall, the results suggest that: (a) the difference in baseline ASR may indicate line differences in the neurocircuitry mediating this response, possibly reflecting higher innate levels of emotional reactivity in the P line; (b) the P line may be more sensitive than the NP line to the effects of ethanol in reducing emotional reactivity; and (c) low-dose ethanol may have a greater disruptive effect on sensorimotor gating mechanisms in the P than NP rat.

Alcohol Drinking↗

PubMed2000

Acoustic startle and fear-potentiated startle in alcohol-preferring (P) and -nonpreferring (NP) lines of rats.

The objective of the present study was to determine whether alcohol-preferring P and -nonpreferring NP rats differ in their acoustic startle response and in fear-potentiated startle. In Experiment 1, male P and NP rats were tested on the startle response to acoustic stimuli ranging from 90-115 dB. Experiments 2 and 3 examined fear-potentiated startle and extinction of the response. In Experiment 2, rats received two light foot shock training sessions separated by 3-4 h. Testing consisted of ten acoustic startle (115 dB) and fear-potentiated startle (light preceding the acoustic startle) presentations administered every 24 h for 9 consecutive days. To test potentiated startle learning under reduced training conditions, a single training session was administered in Experiment 3, and a single within-session extinction test of 50 startle and 50 potentiated startle trials occurred the following day. Results of Experiment 1 indicated that P and NP rats did not differ in startle at any of the acoustic intensities tested. Following fear-potentiated startle conditioning in Experiment 2, however, both acoustic startle and potentiated startle responding were consistently greater in P than NP rats over most of the first 6 test days with P rats having approximately a 100% greater acoustic startle and 50-100% greater potentiated startle response. Moreover, following a single training session in Experiment 3, only P rats showed significant fear-conditioned startle. Additionally, P rats exhibited a 50-100% elevated acoustic startle response over that observed in NP rats. Taken together, the data indicate that, although experimentally naive male P and NP rats show similar acoustic startle responses, P rats become more responsive to both startle-alone and potentiated startle stimuli following fear conditioning. The change in general startle reactivity of the P rat following aversive conditioning, along with facilitated light foot shock learning, suggests that stress exposure may be an important variable in examining associations between anxiety and alcohol drinking behavior.

Acoustic Stimulation↗

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

Alcoholic liver disease.

Important mechanisms responsible for alcohol-induced liver injury include mitochondrial damage and loss of ATP, formation of acetaldehyde-and other aldehyde-protein adducts, release of reactive oxygen species (ROS) from mitochondrial electron transfer chain, CYP2E1 , and activated Kupffer cells (KCs); weakening of antioxidant defense systems; and increased intestinal permeability with endotoxemia. Endotoxin interacts with ethanol and/or acetaldehyde, and such interaction leads to a complex cascade of autocrine and paracrine pathways that involve the release of cytokines (proinflammatory, anti-inflammatory, and mutagenic), chemokines, and eicosanoids. These pathways are mediated by activation of KCs, induction of proliferation, and other phenotype changes in hepatic stellate cells (HSCs) leading to transformation to myofibroblasts (the latter is responsible for fibrogenesis, chemotaxis, and contractility, therefore contributing to portal hypertension, angiogenic response, and release of additional cytokines), and stimulation of sinusoidal cells (SECs) to release adhesive molecules and cytokines. Recent data implicate a likely role of apoptosis as a mechanism of hepatocyte cell death in alcoholic liver disease.

Journal Article↗

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

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

Effects of MDL 72222, a serotonin3 antagonist, on operant responding for ethanol by alcohol-preferring P rats.

BACKGROUND: Previous studies indicated that, under continuous access conditions, the 5-HT3 antagonist MDL 72222 (MDL) effectively reduced ethanol drinking of alcohol-preferring P rats. However, MDL was without effect when similar doses were tested under scheduled access conditions, unless the ethanol access period was randomly presented. This study examined the effects of MDL on operant responding for ethanol and water by adult male alcohol-preferring P rats. METHODS: During the dark cycle, subjects in the first experiment were trained to respond concurrently for 15% ethanol and water on a fixed-ratio 5 (FR-5) and FR-1 schedule of reinforcement, respectively. Approximately 30 min before the 4-hr operant session, rats were injected subcutaneously (sc) with saline or MDL (1, 3, or 5 mg/kg). A second experiment tested the effects of 1 mg/kg MDL on operant responding for 15% ethanol in 1-hr sessions when operant access was given at a fixed time each day (fixed scheduled access, FSA group) or at variable time periods throughout the dark cycle (variable scheduled access, VSA group). RESULTS: In the first experiment, only the 5 mg/kg dose of MDL decreased responding for ethanol (approximately 20%) during the first 30 min of the 4-hr session. This dose also reduced total 4-hr responding for ethanol and water. In the second experiment, the 1 mg/kg dose of MDL had no effect on operant responding by the FSA group, but significantly reduced ethanol responding by the VSA group. CONCLUSIONS: These results suggest that 5-HT3 receptors may be involved in mediating the reinforcing effects of ethanol, and that temporal-environmental cues associated with the presentation of ethanol may be one factor involved in reducing the effectiveness of 5-HT3 antagonists to attenuate ethanol intake.

Alcohol Drinking↗

PubMed1999

Electrophysiological response to neuropeptide Y (NPY): in alcohol-naive preferring and non-preferring rats.

Electroencephalograms (EEGs) and event-related potentials (ERPs) to auditory stimuli were recorded following intracerebroventricular administration of neuropeptide Y (saline, NPY: 1.0, 3.0 nmol) in two lines of rats that have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Previous studies have demonstrated that NPY has a distinct electrophysiological profile that is similar to that of ethanol. In outbred Wistar rats, both NPY and ethanol produced highly significant decreases in the amplitude and increases in the latency of the N1 component of the ERP to all three auditory stimuli. Because the N1 has been associated with attention, these data suggest that both NPY and alcohol may diminish attentional processes. In the present study, NPY-induced decreases in N1 amplitude were also found, but only to the frequently presented tone. This suggests that both P and NP rats may have attenuated responses to NPY's effects on attention/arousal. Like outbred Wistars, P and NP rats were also found to have significant NPY-induced increases in N1 latency in the cortex and hippocampus. However, in the amygdala, while P rats evidenced increases in N1 latency and decreases in N1 amplitudes, NP rats displayed the opposite effects. Spectral analysis revealed that NPY also produced differential EEG responses in P and NP rats. In previous studies in outbred Wistar rats NPY has been found to produce slowing of delta (1-2 Hz) frequencies at the 1-nmol dose and reductions in power, particularly in the higher frequencies in the amygdala, at the 3-nmol dose. This electrophysiological profile is not unlike what is seen following alcohol and benzodiazepines and is associated with anxiolysis. P rats were found to have this general pattern of EEG responses to NPY but attenuated suggesting that they may have reduced responses to electrophysiological measures of the anxiolytic effects of NPY. In contrast, NP rats had NPY-induced EEG effects in amygdala and frontal cortex that were opposite to those seen in P rats. These opposing responses to NPY tended to produce a "normalization" of the power differences that existed between the two rat lines at baseline. Taken together with previous findings that P rats have decreased NPY concentrations in limbic and frontal cortical sites, these data suggest that differences in the regulation of NPY neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.

Alcohol Drinking↗

PubMed1999

Neurontensin studies in alcohol naive, preferring and non-preferring rats.

Neurotensin is a tridecapeptide, present in the central nervous system and the gastrointestinal tract in man and animals. Previous studies in mice selectively bred for differences in hypnotic sensitivity to ethanol have provided data to suggest that neurotensinergic systems may mediate differences in ethanol's actions in these animals. The present study sought to determine if brain neurotensin levels differed between two lines of rats which have been selectively bred for alcohol preferring or non-preferring behaviors. In addition, electroencephalographic and event-related potential responses to intracerebroventricular saline and neurotensin (10 or 30 microg) were evaluated between the rat lines. Similar to human subjects at high genetic risk for alcoholism, preferring rats were found to have more electroencephalographic fast frequency activity and lowered amplitude of the P3 component of the event-related potential in cortical sites under the saline condition. Overall, electrophysiological response to neurotensin, in the two rats lines, was substantially similar to what has been reported previously in outbred Wistar rats, and consisted of dose-related decreases in overall electroencephalographic spectral power concomitant with increases in amplitude and decreases in the latency of the N1 component of the event-related potential. However, differences in neurotensin responses between the preferring and non-preferring rat lines were also found. The differences in electroencephalographic high-frequency activity and in P3 amplitude seen between the rat lines under control conditions were eliminated by administration of neurotensin. In addition, preferring rats appeared to be more sensitive to neurotensin-induced increases in N1 amplitude. Brain neurotensin concentrations were also found to differ between the lines. Significantly lower concentrations of neurotensin were found in the frontal cortex of preferring rats when compared to non-preferring rats or outbred Wistars. Taken together, these studies suggest that differences in the regulation of neurotensin neurons may contribute to the expression of behavioral preference for ethanol consumption in selective rat lines. Additionally, drugs targeting the neurotensinergic system may plausibly be of utility in the treatment of alcoholism.

Acoustic Stimulation↗

PubMed1999

Selective breeding for high and low alcohol preference in mice.

High and low alcohol preference (HAP and LAP, respectively) mice were created by 10 generations of bidirectional selection for differences in two-bottle choice alcohol consumption. The progenitors used for selection were HS/lbg mice, which are a genetically defined, outbred stock. During selection, mice had 24-h, daily access to 10% alcohol (v/v) and water ad libitum for 30 days and were selected based on the alcohol (g/kg) consumed per day over the entire period. Food was available ad libitum. At S10, line means for alcohol consumption differed greatly, with consumption of over 12 g/kg per day in the HAP mice and less than 2 g/kg per day in the LAP mice. Realized heritability for bidirectional selection was approximately 0.2. Female mice consumed more alcohol than male mice. There were no differences between lines in alcohol elimination rate, nor were there line differences in intake of salt or quinine solutions. However, consumption of saccharin solutions was greater in HAP mice than LAP mice, consistent with previous findings of a genetic correlation between sweet preference and alcohol drinking. Because the mouse genome is relatively well characterized, these selected lines should prove a useful tool for assessment of the genetic basis of, and phenotypes that correlate with, alcohol drinking.

Alcohol Drinking↗

PubMed1999

Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: Most transplant centers in the United States immunize patients awaiting liver transplantation against hepatitis B to prevent acquisition of hepatitis B through transplantation (de novo hepatitis B). A recent study showed that only 16% of patients with cirrhosis awaiting liver transplantation responded to single-dose recombinant vaccine. METHODS: We studied the immunogenicity of double-dose recombinant vaccine in patients with cirrhosis awaiting liver transplantation. RESULTS: Over a 4-year period (January 1994 to December 1997), 140 patients with cirrhosis without past or current hepatitis B infection were given double-dose recombinant vaccine (40 microg of Engerix B; SmithKline Beecham, Philadelphia, PA) at 0, 1 to 2, and 2 to 4 months. Hepatitis B surface antibody (HBsAb) was measured 1 to 3 months after completing vaccination. The response rate was 37%. However, HBsAb titers became undetectable in 35% of the responders during the post-transplant follow-up period. One hundred and thirty-seven patients underwent 144 liver transplantation procedures during the study period, and 3 patients developed de novo hepatitis B (2.2%). Livers transplanted from hepatitis B core antibody (HBcAb)-positive donors was the source of de novo hepatitis B in all cases. Two of the 3 patients who developed de novo hepatitis B were immunized before transplantation and one of them was a responder. CONCLUSION: Although the response rate to double-dose recombinant vaccines is higher than the previously reported response to single-dose vaccine, it still is less than optimal.

Adult↗

PubMed1999

Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the dreaded complications of cirrhosis. Although there are no randomized controlled studies showing improved survival with screening, patients with cirrhosis are screened for HCC. Little is known about the practice of HCC screening in the United States. Our aim was to describe the practice of HCC screening in patients with cirrhosis in the United States. METHODS: In March 1998, we mailed a standard questionnaire to 1021 physician members of the American Association of Study for Liver Diseases and the same questionnaire was re-sent to nonrespondents 4 weeks later. RESULTS: We received a response from 554 members (54%). After excluding those not involved in active adult patient care, 473 responses were eligible for analysis. Eighty-four percent of the respondents routinely screened patients with cirrhosis for HCC (screening respondents). Nearly half of the screening respondents limited the HCC screening to patients with high-risk etiologies such as hepatitis B or C or hemochromatosis. Although alpha-fetoprotein (99.7%) and ultrasound (93%) were the two most frequently used screening methods, a sizable proportion of the screening respondents (25%) used abdominal computed tomography for routine screening. On multivariate analysis, the following variables predicted screening for HCC by the respondents: seeing more than one new cirrhotic per week (odds ratio [OR]: 5.4, 95% confidence interval [CI]: 2.5-11.7); practicing for < 10 yr (OR: 4.0, 95% CI: 1.2-13.4); an opinion that screening is cost-effective (OR: 6.4, 95% CI: 1.6-25); an opinion that screening prolongs survival (OR: 5.7, 95% CI: 1.8-17.9); and an opinion that not screening poses malpractice liability (OR: 9.3, 95% CI: 4.2-20.8). CONCLUSIONS: The majority of respondents routinely screen patients with cirrhosis for HCC. Approximately half of the screening respondents limit their screening to only patients with high-risk etiologies. On multivariate analysis, several variables predicted screening for HCC by the respondents.

Adult↗