Quantitative correlation of ethanol elimination rates in vivo with liver alcohol dehydrogenase activities in fed, fasted and food-restricted rats.
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Alcohol Oxidoreductases↗
Biomedical subjects
T K Li
Publications and source records attributed to T K Li.
Monoamine uptake inhibitors attenuate ethanol intake in alcohol-preferring (P) rats.
The P line of alcohol-preferring rats drink pharmacologically significant amounts of ethanol when given free choice between a 10 percent ethanol solution and water. Serotonin (5-HT) uptake inhibitors and desipramine, a norepinephrine (NE) uptake inhibitor, were found to significantly reduce their ethanol consumption for up to 24 hours after intraperitoneal injection. To determine if this effect of 5-HT uptake inhibitors could be altered by receptor antagonists, some of which are short acting, P rats were trained to drink ethanol by free choice during scheduled availability, with ethanol being presented one hour every four hours during the light cycle. The majority of the ethanol was consumed during the first hour of availability, and the ethanol intake was significantly reduced by the 5-HT uptake inhibitors, fluoxetine and fluvoxamine. Pretreatment with antagonists for 5-HT1, 5-HT2 and alpha- and beta-NE receptor systems failed to alter the fluvoxamine attenuation of ethanol intake. The mechanism by which 5-HT uptake inhibitors alter ethanol preference remains unclear.
Alcohol Drinking↗
Effects of scheduled access on ethanol intake by the alcohol-preferring (P) line of rats.
The effects of scheduling the availability of ethanol on its voluntary consumption by the selectively bred alcohol-preferring P rats were examined under three conditions: unrestricted 24 hr/day access (Condition A), access limited to a continuous 4 hr/day (Condition B), and access limited to 1 hr every 3 hr, 4 times/day (Condition C). Food and water were always available. Daily alcohol intakes (mean +/- SEM) with Conditions A, B and C were 6.9 +/- 0.2, 2.1 +/- 0.2 and 4.4 +/- 0.2 g/kg, respectively, while the intake per hour of availability increased from 0.3 +/- 0.03 under Condition A to 1.1 +/- 0.4 g/kg under condition C. The amount of ethanol consumed per drinking episode under Conditions A, B and C were 1.1 +/- 0.1, 2.1 +/- 0.2 and 1.1 +/- 0.03 g/kg, respectively. Mean blood alcohol concentrations (BACs), determined periodically during the dark cycle of Condition A and five minutes after drinking episodes under Conditions B and C, were 59 +/- 10, 61 +/- 7 and 62 +/- 7 mg%, respectively. When unlimited access was reinstated after Condition C, daily alcohol consumption returned to a level similar to that under the initial Condition A (7.2 +/- 0.5 g/kg). When the ethanol concentration was increased from 5 to 20% (v/v) under Condition C, the amount of ethanol consumed per episode at 5% was significantly less than at the 10, 15 and 20% concentrations, and the volume consumed was significantly lower at the 20% concentration than at the 5, 10 and 15% concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗
Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats.
Rats of the alcohol-preferring P line (n = 7) were trained to self-administer ethanol (20% v/v) and water via an intragastric IG catheter. Food was available ad lib. Ethanol intakes averaged approximately 5-6 g/kg body wt./day. Treatment with the serotonin (5-HT) uptake inhibitor fluoxetine (10 mg/kg/day; IG) for seven consecutive days produced a marked decrease in ethanol self-administration on the first day, which was sustained throughout the seven days of treatment to values as low as 1 g/kg/day. Concomitant with the decrease in ethanol intake, the self-infusion of water gradually increased during the period of fluoxetine treatment. Total caloric intake (ethanol plus food) was moderately reduced during fluoxetine treatment; the decrease in food consumption was consistent but not statistically significant. When fluoxetine treatment was terminated, ethanol self-administration quickly returned to the prefluoxetine levels, while water intake began to decrease. Since no ethanol was consumed orally, the IG ethanol was not self-administered for its taste or smell, but apparently for its postingestive pharmacological effects. The robust reduction of ethanol self-infusion that occurred with fluoxetine treatment suggests that the 5-HT systems are involved in the reinforcing effects of ethanol in the P line of rats.
Alcohol Drinking↗
Operant responding for oral ethanol in the alcohol-preferring P and alcohol-nonpreferring NP lines of rats.
Rats of the P (n = 4) and NP (n = 5) lines were housed in operant chambers with food available ad lib, but all liquid was obtained by responding on either of two levers according to a FR5 schedule. Presses on one lever produced water from an automated dipper, while the other lever gave access to a dipper containing ethanol in concentrations ranging from 2 to 30% (v/v). P rats worked to obtain the ethanol at all concentrations offered and preferred the ethanol over water. The highest ethanol intake averaged 7.7 +/- 0.5 g/kg body weight/day at the 15% concentration and at least 5.8 +/- 0.9 g/kg/day for the 20-30% range. The NP rats responded more for the 2 and 5% concentrations of ethanol than for water, but responded predominantly for water when the ethanol concentrations were 10% and higher. In a second experiment, NP rats drank water rather than 10% ethanol by free-choice, even though the ethanol was mixed with a preferred flavor and the water with a nonpreferred flavor. The findings indicate that ethanol is rewarding to P rats in concentrations up to 30% (v/v) but is not rewarding to NP rats when the concentration is 10% and above.
Alcohol Drinking↗
Long and short alcohol deprivation: effects on AA and P alcohol-preferring rats.
In contrast to all other strains of rats previously tested, the heavy-drinking AA rats were recently found not to increase their daily intake of alcohol after a week without ethanol. This result was now replicated with F52 generation male AAs using Wistars as controls. The same AAs, however, after being switched to a choice between 0.05% saccharin and water, showed a significant increase in saccharin drinking after being deprived of it for a week. Alcohol deprivation for 24 hr or less hardly affected the intake by Wistars during the first hour of renewed intake but sharply increased that by AAs. Still longer deprivation produced progressively smaller first-hour intakes in the AAs. Unlike the AAs, alcohol-preferring P rats showed an increase in alcohol drinking after a week of deprivation similar to that seen with normal rats. However, in common with the AAs, their first hour intake was increased significantly by only a few hours of alcohol deprivation.
Alcohol Drinking↗
Regional brain contents of serotonin, dopamine and their metabolites in the selectively bred high- and low-alcohol drinking lines of rats.
The contents of dopamine (DA), serotonin (5-HT) and their primary acid metabolites were assayed in ten brain regions of the selectively bred high-alcohol drinking (HAD) and low-alcohol drinking (LAD) lines of rats. Compared with the LAD line, the contents of 5-HT and/or 5-hydroxyindoleacetic acid were approximately 10-20% (p less than 0.05) lower in several brain regions of the HAD line (cerebral cortex, striatum, nucleus accumbens, septal nuclei, hippocampus and hypothalamus). The levels of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid were also 10-20% lower in the nucleus accumbens and anterior striatum (p less than 0.05) of the HAD animals. These data are in agreement with previous findings that comparatively lower levels in 5-HT and DA systems are associated with high-alcohol drinking in rodents and support the involvement of certain 5-HT and DA pathways in the mediation of alcohol drinking behavior.
3,4-Dihydroxyphenylacetic Acid↗
Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats.
Neurochemical and neuropharmacological studies were undertaken to assess the involvement of CNS serotonin (5-HT), dopamine (DA) and GABA systems in regulating the alcohol-drinking behavior of two lines of rats selectively bred for their high alcohol-seeking behavior, namely the alcohol-preferring P line and the high alcohol-drinking HAD line of rats. Neurochemical data indicate that high alcohol-seeking behavior (when compared with data from rats with low alcohol-seeking characteristics) is associated with: a) lower (10-20%; p less than 0.05) contents of 5-HT in certain limbic regions (e.g., nucleus accumbens, frontal cortex, hypothalamus and hippocampus); b) a lower (10-15%; p less than 0.05) content of DA in the nucleus accumbens; c) higher (20-35%; p less than 0.05) densities of 5-HT1A binding sites in some limbic regions (e.g., medial nucleus accumbens, medial prefrontal cortex and ventral hippocampus); and d) a greater (20-50%) density of GABA axon terminals in the nucleus accumbens. Furthermore, the acute administration of high doses of ethanol appears to increase the activity of the 5-HT and DA projections to the nucleus accumbens of the P line of rats (as indicated by the 20-30% elevated tissue levels of 5-HT and DA metabolites following IP ethanol administration); neuronal tolerance to alcohol appears to develop in both these monoamine pathways, as suggested by an attenuated effect on metabolite levels by a challenge dose of ethanol given to P rats that had been chronically drinking alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗
Effects of fluoxetine and desipramine on palatability-induced ethanol consumption in the alcohol-nonpreferring (NP) line of rats.
Three groups of NP rats (n = 5/group) received food, water and one of 3 Polycose solutions ad lib. One group received a solution containing 3% (w/v) Polycose, 0.125% (w/v) saccharin, 0.5% (w/v) NaCl (3% POL solution) to which ethanol was gradually added over three weeks until the concentration of 10% (v/v) ethanol (E) was reached (3% POL + E group). Alcohol ingestion by the 3% POL + E group reached an average of 9 g of ethanol/kg b. wt./day; the rats attained average blood alcohol concentrations of 61 +/- 8 mg%. One control group (3% POL) was given the same solution as above but without ethanol. The second control group (17% POL) had access to a 17.6% Polycose solution supplemented with 0.125% saccharin and 0.5% NaCl and was isocaloric to the 3% POL + E solution. Although the three groups differed significantly in the amounts of food and Polycose solutions consumed, their total caloric intakes were equivalent. The IP administration of the serotonin (5-HT) uptake inhibitor fluoxetine (5 and 10 mg/kg) significantly reduced drinking of the group receiving the 3% POL + E solution by 23% and 67%, respectively, but did not alter intakes of the Polycose solutions by the 3% or 17% POL control groups. The IP administration of the norepinephrine (NE) uptake inhibitor desipramine (5 and 10 mg/kg) significantly reduced intake of the Polycose solution by the 17% POL group by 52 and 83%, respectively, but only the 10 mg/kg dose attenuated drinking of the solutions by the 3% POL and 3% POL + E groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗
Persistence of tolerance in the P line of alcohol-preferring rats does not require performance while intoxicated.
Persistence of tolerance was measured seven days after a single ethanol injection (2.5 g/kg b. wt.) in the alcohol-preferring P line of rats with and without testing in a shock-motivated jump task during the initial ethanol exposure. P rats were trained to jump 50 cm to avoid shock and were assigned to one of three groups. On day 0, group E/J (n = 8) was injected with ethanol and tested on the jump task until recovery to criterion (37.5 cm), while group S/J (n = 21) was injected with saline and was tested yoked to an E/J rat. Rats in the E/NJ group (n = 19) received ethanol but were not tested on day 0. Seven days later, all rats received 2.5 g ethanol/kg and were tested to criterion. Recovery times on day 7 were significantly longer (p less than 0.05) for rats in the S/J group (169 +/- 7 min) than for the E/J (141 +/- 11 min) and E/NJ (145 +/- 6 min) rats. Blood ethanol concentrations at recovery for the E/NJ group were higher than the S/J group on day 7 and higher than the E/J group on day 0 (p less than 0.05). The results indicate that the persistence of tolerance manifested by the P rats is an inherited behavioral trait that requires only ethanol exposure.
Alcohol Drinking↗
Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens.
The effects of acute IP administration (0.5, 1.0 or 2.0 g/kg) and local perfusion (25, 50 or 100 mM) of ethanol on the extracellular concentrations of dopamine (DA), serotonin (5-HT) and their metabolites in the nucleus accumbens (ACC) of the rat were studied with in vivo microdialysis coupled with a small-bore HPLC electrochemical detection procedure. The IP administration of 1.0 and 2.0 g/kg ethanol significantly (p less than 0.05) increased the extracellular levels of DA and 5-HT in the ACC whereas the 0.5 g/kg dose caused no change. In general, the extracellular levels of the 3 monoamine metabolites were not altered by IP ethanol except for a slight increase in the levels of homovanillic acid following the 2.0 g/kg dose. Local perfusion of 50 and 100 mM ethanol (but not 25 mM) through the microdialysis probe markedly increased (170-200% of control) the extracellular levels of DA in the ACC. Only the 100 mM concentration of ethanol altered the extracellular levels of 5-HT (2-fold increase), 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid. Addition of 100 microM ICS 205-930 (a 5-HT3 antagonist) to the perfusate markedly reduced the 100 mM ethanol-stimulated release of DA and 5-HT. Overall, the data suggest that ethanol can stimulate the release of both DA and 5-HT in the ACC and that the action of ethanol within the ACC may be mediated in part by 5-HT3 receptors.
3,4-Dihydroxyphenylacetic Acid↗
Taste preferences in rat lines selected for low and high alcohol consumption.
Alcohol-avoiding (ANA), alcohol-preferring (AA), and control Wistar rats were tested sequentially for their initial preferences for single concentration solutions of quinine, saccharin, salt, and citric acid, and then for an ascending series of saccharin concentrations. A similar study was subsequently conducted with the alcohol-nonpreferring (NP) and alcohol-preferring (P) rat lines. Both lines developed for low alcohol consumption drank much less saccharin than their respective lines developed for high alcohol intake when tested with the single concentration and with the ascending series. The ANAs also generally drank less of the bitter, salty, and sour solutions than the AAs or Wistars but little difference was found between the NPs and Ps with the other tastes. The curve relating saccharin consumption to concentration reached a maximum at about the same concentrations for AAs, Wistars, NPs, and Ps but for the ANAs, was shifted to the left. The results support a close relationship between the genetic factors influencing alcohol and saccharin intake in both line pairs. This relationship is probably not caused by saccharin tasting like alcohol to a rat, because other results indicate that the NPs do not have more negative reactions initially to the taste of alcohol, but it might be related to similar mechanisms mediating the reinforcement from sweet tastes and from systemic alcohol.
Alcohol Drinking↗
Densities of dopamine D2 receptors are reduced in CNS regions of alcohol-preferring P rats.
The densities of dopamine D2 recognition sites labelled with [3H]sulpiride were determined in the caudate-putamen, nucleus accumbens (medial and lateral portions), olfactory tubercle, substantia nigra (pars reticulata and pars compacta), and ventral tegmental area (VTA) of alcohol-naive, selectively bred P (N = 7) and NP (N = 7) rats using quantitative autoradiography. The binding of [3H]sulpiride was 20-25% lower (P < 0.05) in the caudate-putamen, medial and lateral nucleus accumbens, and VTA of the P compared with the NP rats. No significant differences were observed between the P and NP rats in the olfactory tubercle or substantia nigra. [3H]Sulpiride binding, using standard membrane preparations, established with Scatchard analysis that the difference in the densities of D2 recognition sites in the caudate-putamen between the P and NP rats was due to lower Bmax values for the P line. The results indicate that the number of dopamine D2 receptor sites is lower in several central nervous system regions of the P rats compared to NP rats.
Alcohol Drinking↗
Effects of D1 and D2 dopamine receptor agents on ethanol consumption in the high-alcohol-drinking (HAD) line of rats.
Dopamine receptor agonists and antagonists were tested for effects on alcohol drinking in female HAD rats (n = 10) given limited access (4 h/day) to a 10% (v/v) ethanol solution. Food and water were available ad libitum. Subcutaneous drug injections were given 30-60 min before the ethanol access periods. The D2 agonist quinpirole (0.04-2.0 mg/kg) caused a dose-dependent decrease in alcohol drinking throughout the 4-h period. Spiperone, a D2 antagonist, had no effect during the initial part of the session, but by the fourth hour, the 10 micrograms/kg dose tended to increase alcohol intake and the 30 micrograms/kg dose reduced intake. The D1 antagonist SCH-23390 (3-30 micrograms/kg) dose-dependently decreased ethanol drinking during the first hour of access. The D1 agonist SKF-38393 (2-6 mg/kg) also decreased alcohol intake, but it was less effective than SCH-23390. The findings implicate both D1 and D2 receptors in the reinforcing effects of alcohol drinking by the HAD line of rats.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Comparison of alcohol-preferring (P) and nonpreferring (NP) rats on tests of anxiety and for the anxiolytic effects of ethanol.
Rats of the selectively bred alcohol-preferring P and alcohol-nonpreferring NP lines were evaluated using three different behavioral measures of anxiety. Compared with NP rats, P rats (1) showed greater footshock-induced suppression of operant responding in an approach-avoidance conflict test; (2) spent less time in the open arms of an elevated plus maze; and (3) took longer in a passive avoidance test to step down from a platform to a grid floor where footshock was received 24 hours earlier. These findings indicate a greater degree of anxiety in the P than in the NP line of rats in these situations. Pretreatment with intraperitoneal (IP) ethanol (0.5-1.0 g/kg) injections produced anticonflict or anxiolytic effects in P but not in NP rats. However, the anticonflict effects of ethanol were small relative to those produced by chlordiazepoxide (CDP, 7.5 mg/kg) in both lines. The results demonstrate that selective breeding for divergent oral ethanol preference has produced associated differences between the P and NP lines of rats in behavioral tests of anxiety and in the anxiolytic effects of ethanol.
Alcohol Drinking↗
Serotonergic neurons in the alcohol preferring rats.
Previously, we have shown that the serotonin (5-HT) content and fiber density in a number of terminal brain regions have been found to be decreased in the selectively bred, alcohol preferring (P) rats than in the alcohol nonpreferring (NP) rats. In this study, we further report that, compared with NP rats, there were fewer 5-HT-immunostained (5-HT-IM) neurons in the major ascending raphe nuclei of the P rats. Among the three major groups of 5-HT neurons responsible for the majority of ascending projections to forebrain, dorsal raphe (B7), median raphe (B8), and B9, there were fewer 5-HT-IM neurons in the median and dorsal raphe (not including nucleus oralis) of P rats, compared with NP rats (unpaired Student's test). No difference was observed in the B9 group. When the animals were treated with pargyline and L-tryptophan to enhance the 5-HT in the neurons, the number of 5-HT-IM neurons increased in both lines of rats. However, the difference in the number of 5-HT neurons between the rat lines remained. The intensity of 5-HT-IM was also found to be lower in the dorsal raphe neurons of the untreated P than in the untreated NP rats. The decreased 5-HT-IM was supported by high performance liquid chromatography measurement of 5-HT content, which also indicated that 5-HT content of the dorsal raphe was lower in the P than in the NP rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗
Comparison of innate EEG parameters in rat lines selected for ethanol preference.
Through bidirectional selective breeding, lines of rats that differ greatly in their voluntary alcohol drinking behavior have been developed--namely, the alcohol-preferring (P) and high-alcohol-drinking (HAD) lines and the alcohol-nonpreferring (NP) and low-alcohol-drinking (LAD) lines. The present experiments were designed to determine if an association exists between ethanol preference and features of the electroencephalogram (EEG) during various sleep-wake behaviors. Of the EEG parameters measured, only theta activity in the hippocampus revealed differences in the lines. However, these differences were not generally associated with ethanol preference. The peak frequency and distribution mean of hippocampal theta activity during REM sleep were significantly higher in NP rats than in P, HAD, and LAD rats. In addition, theta frequency during alert immobility tended to be higher in NP rats than in P, HAD, and LAD rats. A qualitative comparison of these data with published data from unselected rats further suggested that the NP rats are uniquely different with respect to theta frequency.
Alcohol Drinking↗
Ethanol self-infusion into the ventral tegmental area by alcohol-preferring rats.
The ventral tegmental area (VTA) and its projections have been implicated in the reinforcing effects of drugs of abuse. Selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) lines of rats were used to evaluate the reinforcing actions of ethanol in the VTA using intracranial self-administration (ICSA) operant procedures. P rats self-administered nanoliter quantities of 50-200 mg% ethanol in artificial CSF directly into the VTA whereas NP rats had low levels of responding at these ethanol concentrations. Responses on the active lever were 50-fold higher for the P compared with the NP rats for the self-infusion of 150 mg% ethanol. NP rats responded at the same level on the active and inactive levers at all ethanol concentrations and had low responses/session (3 to 15 total responses) at all concentrations. Further, operant responding on the active lever was reduced when artificial CSF alone was substituted for 100 mg% ethanol, and responding on the active lever was reinstated when ethanol was returned. For one group of rats, an illuminated house light served as a discriminative stimulus, which signalled the availability of ICSA, while a cue light was paired with the onset of ethanol infusion. Extinction in the presence of these stimuli required 6-7 sessions. However, only 2-3 extinction sessions were necessary for another group trained without stimulus cues, suggesting that cues paired with the ICSA of ethanol can acquire conditioned reinforcing properties. The findings indicate that ethanol can act as a reinforcer when administered directly into the VTA.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗