Biomedical subjects

T K Li

Publications and source records attributed to T K Li.

353 records · Page 20Linked to original sources

PubMedDate not supplied

Mesolimbic dopamine system in alcohol-preferring rats.

The mesolimbic dopamine system of the brain, in particular the nucleus accumbens (Acb), is long known to be involved in reward behavior. When compared with the alcohol-nonpreferring NP rats, the alcohol-preferring P rats exhibit lower dopamine (DA) levels in the Acb as well as in other forebrain areas (20). In the present study, the DA innervation density, as determined by tyrosine hydroxylase (TH) immunostaining, was found lower in the selective cingulum cortex and the shell of the Acb of the P compared with that of NP rats. These structures cluster in the medial aspect of the mesolimbic system. There were no differences in other major DA mesolimbic brain regions. The subpopulation of DA neurons in the ventral tegmental area (VTA) projecting to the Acb was found to be smaller in the P than in the NP rats, as shown by horseradish peroxidase tracing and TH immunocytochemistry double staining. However, the total number of the DA neurons in the VTA, the major mesolimbic DA center, was found to be similar in the P and NP rats. These results indicate a selective reduction of catecholaminergic innervation in the dopaminergic medial mesolimbic system in the P rats and suggest that the P and NP rat lines should be a useful model for the investigation of DA involvement in alcohol drinking as well as other reinforced behaviors.

Alcohol Drinking↗

PubMedDate not supplied

Apomorphine and 7-OH DPAT reduce ethanol intake of P and HAD rats.

Adult male rats of the alcohol-preferring (P) line (N = 10) and high alcohol drinking (HAD) line (N = 12) were used to study the effects of IP administration of 0.125-0.50 mg/kg 7-OH DPAT (a putative D agonist) and 0.25-1.0 mg/kg apomorphine (a dopamine agonist with 50-fold higher affinities for the D1 and D2 receptors than for the D3 receptor) on the concurrent intakes of 10% (v/v) ethanol and 0.0125% (g/v) saccharin during a daily 4-h scheduled access period. Control intakes by the P rats for the 4-h period were 17.9 +/- 0.5 and 7.2 +/- 0.4 ml for the ethanol and saccharin solutions, respectively. For the HAD line, ethanol consumption was 18.7 +/- 0.2 ml and saccharin intake was 8.7 +/- 1.6 ml for the 4-h period. In terms of grams ethanol/kg body wt, the 4-h intakes were 2.2 +/- 0.2 for the P line and 3.0 +/- 0.3 for the HAD rats. Both P and HAD rats consumed approximately 40% of their total ethanol intake in the first 15 min of access while consuming only about 15% of their total saccharin intake during this 15-min period. The putative D3 agonist 7-OH DPAT produced a decrease in ethanol intake in the first h to 45-55% of control levels for the P rat (p < 0.01) and to 25-70% of control values in the HAD line (p < 0.001). Apomorphine caused a dose-dependent decrease in ethanol intake in the first hour to 15-70% of control values in the P rat (p < 0.001) and to 25-60% of control levels in the HAD line (p < 0.001). Saccharin and 4-h food intakes for both lines were not altered by either 7-OH DPAT or apomorphine. Overall, these results suggest that D2 and D3 dopamine receptors may play a role in mediating alcohol drinking behavior of the selectively bred HAD and P lines of rats.

Alcohol Drinking↗

PubMedDate not supplied

Effects of ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests.

Neonatal alcohol exposure during the first 1-2 weeks of age is known to produce subsequent behavioral hyperactivity in rats. However, little is known about the effects of alcohol exposure during adolescence on subsequent adult behavior. In the present study, male and female P rats had free access to 10% alcohol during adolescence (3-8 weeks of age). After 8 days of abstinence, their behavior was evaluated in the cross-maze and in the inescapable slip funnel tests during the 10th week of age. Two-way ANOVAs revealed significant effects of alcohol drinking on several variables. Compared to alcohol-naive rats, the alcohol-exposed group started exploration earlier (3.5 +/- 0.3 vs. 5.4 +/- 0.7 s, p = 0.03) and made fewer defecations. In the slip funnel test, the alcohol group spent more time immobile (130 +/- 7 vs. 107 +/- 5 s, p = 0.01) and less time attempting to escape out of the funnel (11 +/- 2 vs. 28 +/- 5 s, p = 0.002) than the control group. Overall, the results suggest that the effects of alcohol drinking by P rats during adolescence on subsequent behavior are to reduce novelty-induced anxiety (cross-maze test) and lower response to stress induced by an inescapable situation (slip-funnel test).

Aging↗

PubMedDate not supplied

Long-term effects of alcohol drinking on cerebral glucose utilization in alcohol-preferring rats.

The 2-[14C]deoxyglucose (2-DG) quantitative autoradiography technique was used to determine rates of local cerebral glucose utilization (LCGU) in discrete brain regions in alcohol-chronic (A-C), alcohol-deprived (A-D) and alcohol-naïve (A-N) adult, male alcohol-preferring (P) rats. The hypothesis to be tested is that neuronal alterations occur as a result of chronic alcohol drinking and some of these alterations persist for long periods in the absence of alcohol. Following 6 weeks of daily 4-h scheduled access sessions to 15% (v/v) ethanol and water, group A-D received only water during the sessions over the next 2 weeks, whereas groups A-C and A-N continued to receive ethanol-water and water-water, respectively. On the 14th day of the deprivation interval, LCGU rates were measured 1 h prior to the scheduled access period. Mean ethanol intake for the A-D and A-C groups was 1.5+/-0.1 g ethanol/kg body weight per 4 h. LCGU rates were significantly decreased in 49 of 57 regions or subregions examined in the A-C group compared to the A-N group, including subregions of the cerebral cortex, hippocampus and structures in the mesocorticolimbic and nigrostriatal systems. Following alcohol deprivation, LCGU values in the A-D group were partially or completely returned to A-N levels in many, but not all, regions. In several limbic regions (e.g., ventral tegmental area, olfactory tubercle, medial prefrontal cortex, ventral pallidum and lateral septum), no recovery of LCGU rates was observed after 2 weeks of alcohol deprivation. This study demonstrates that chronic alcohol consumption produces significant reductions in functional neuronal activity in P rats, some of which persist in the absence of ethanol. The extent to which LCGU rates returned to normal levels following 2 weeks of alcohol deprivation varied among brain regions, suggesting that there are imbalanced interactions among and within several CNS sites, which do not reflect either the alcohol-naïve or chronic alcohol-exposed state. Such neuronal imbalances may underlie relapse of alcohol drinking following prolonged abstinence.

Alcohol Drinking↗

PubMedDate not supplied

Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats.

The levels of serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA) are decreased in the hippocampus, nucleus accumbens, and cortex of selectively bred alcohol-preferring (P) rats, compared with the alcohol-nonpreferring (NP) rats. In this study, we have confirmed these findings by immunocytochemistry and quantitative image analysis which indicates that there is a reduction of 5-HT immunostained fibers in several brain areas of alcohol-naive P rats. Three major areas possibly related to alcohol drinking, hippocampus, accumbens, and cortex, were examined. Pathways to these areas were also examined. The 5-HT fiber bundles had the same pattern in P and NP rats. However, in the terminal regions of the ventral hippocampus, the amount of 5-HT fibers was reduced in P rats as compared with NP rats. The 5-HT fibers in the hilus and CA4 of the dentate gyrus were also significantly decreased in the P rats. No differences in fiber density were seen in the anterior nucleus accumbens, but a significant decrease was seen in the middle medial and posterior accumbens of P rats. In the cortical regions examined, decreases in 5-HT fibers were observed in the posterior cingulum and anterior frontal cortex, but not in the insular frontal cortex of P rats. These observations indicate that there are quantitative decreases in 5-HT innervations or that the 5-HT in some 5-HT fibers is reduced to a level undetectable by immunocytochemistry in the brains of P rats when compared with that of NP rats.

Animals↗

PubMedDate not supplied

Regional CNS densities of monoamine receptors in alcohol-naive alcohol-preferring P and -nonpreferring NP rats.

The densities of subtypes of serotonin (5-HT) and dopamine (DA) receptors were determined in the CNS of alcohol-naive alcohol-preferring P and -nonpreferring NP lines of rats. Autoradiography studies were undertaken to measure the densities of 5-HT1B sites labelled with 100 pM [125I](-)-iodocyanopindolol, 5-HT3 sites labelled with 2 nM [3H]LY 278584, and D1 sites labelled with 1 nM[3H]SCH 23390. Membrane binding, using tissue combined from the olfactory bulb, olfactory tubercle, and nucleus accumbens, was carried out to determine Kd and B max values for the binding of 0.25-8.0 nM[3H]7-OH DPAT to D3 sites. Among the 48 regions measured for differences in 5-HT1B recognition sites, statistically significant differences (p < 0.05) were found only in the cingulate and retrosplenial cortices, in the lateral and medial septum, and in the lateral nucleus of the amygdala, with lower values being found in the P than the NP line. There were no significant differences in the regional CNS densities of D1 or 5-HT3 sites between the P and NP lines. There were also no differences between the rat lines in the Kd or Bmax values for [3H]7-OH DPAT binding to D3 sites. The lower densities of 5-HT1B sites in the CNS of the P compared to the NP rats may be a result of reduced numbers of 5-HT1B presynaptic autoreceptors as well as postsynaptic receptors in the P line. The observation that there are no differences in the amount of radioligand binding to D1, 5-HT3, and D3 sites between the P and NP lines suggests that the disparate alcohol drinking behaviors of these two lines is not associated with an innate alteration in the densities of these receptor subtypes.

Animals↗

PubMedDate not supplied

Regional CNS densities of serotonin and dopamine receptors in high alcohol-drinking (HAD) and low alcohol-drinking (LAD) rats.

The densities of subtypes of serotonin (5-HT) and dopamine (DA) receptors were determined in the CNS of male alcohol-naive HAD and LAD lines of rats. Autoradiographic studies were undertaken to measure the densities of (a) 5-HT1A sites labelled with 2 nM [3H]8-OH DPAT, (b) 5-HT2A sites labelled with 2 nM [3H] ketanserin, (c) D1 sites labelled with 1 nM [3H]SCH23390, and (d) D2 sites labelled with 20 nM [3H]sulpiride. Membrane binding, using tissue combined from the olfactory bulb, olfactory tubercle, and nucleus accumbens, was carried out to determine Kd and Bmax values for the binding of 0.25-8.0 nM [3H]7-OH DPAT to D3 sites. Among the 14 regions measured for densities of 5-HT1A sites, no interline differences were found in the cerebral cortical regions or in the septal nuclei; however, within the hippocampus, 15-20% lower binding of [3H]8-OH DPAT was observed in the posterior dorsal CA3 and dentate gyrus of the HAD line. There were no interline differences in any of the 10 regions examined for [3H]ketanserin binding to 5-HT2A sites, or in the densities of D1 and D2 sites in the mesolimbic and nigrostriatal DA systems, except for a 35% higher density of D2 sites in the substantia nigra pars compacta of the HAD line. There were no interline differences in the Kd or Bmax values for [3H]7-OH DPAT binding to D3 sites. Overall, these results indicate that no marked interline differences are evident in the densities of 5-HT1A, 5-HT2A, D1, D2, and D3 receptors within the mesolimbic system that could be associated with the disparate alcohol drinking behaviors of the HAD and LAD rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMedDate not supplied

Alcohol preference and voluntary alcohol intakes of inbred rat strains and the National Institutes of Health heterogeneous stock of rats.

The alcohol preference ratios and the daily free-choice ethanol intakes (10% ethanol versus water) of the newly constituted National Institutes of Health (NIH) heterogeneous stock (N/Nih) rats, and of the eight inbred strains from which N/Nih derived, were measured. Among the eight inbred strains, ACI/N, WKY/N, F344/N, BUF/N, BN/Ssn, WN/N, M520/N, and MR/N, the ACI exhibited the lowest preference and intakes and the MR and the M520 the highest. The mean values for the N/Nih animals were intermediate among those of the inbred strains. The range of intake for the N/Nih rats was 0.06-9.5 g/kg of body weight/day, indicating that they should serve as an appropriate foundation in selection studies for alcohol-drinking preference.

Alcohol Drinking↗

PubMedDate not supplied

Effect of fasting on the activity and turnover of rat liver alcohol dehydrogenase.

Alcohol dehydrogenase activity in rat liver decreased with fasting to about 60% of the fed level, but the specific activities of the enzyme purified from livers of fed and 12- or 48-hr fasted animals were similar, 3.2-3.4 U/mg protein. Therefore, the decrease in enzyme activity with fasting should have resulted from a decrease in the amount of enzyme protein. Accordingly, the turnover of alcohol dehydrogenase was examined in fed and fasted rats. The fractional rate of enzyme synthesis (ks) in fed rats was determined by radioisotopic methods to be 0.13 day-1 and it increased to 0.18 day-1 after a 12- or 48-hr fast. The absolute rate of synthesis (V) and the fractional rate of degradation (kd) were calculated from these ks values and the total enzyme content in livers from animals that were fasted for 8 to 72 hr. After 48-72 hr of fasting, V decreased 16% and kd increased about 20% with respect to the fed values. Together, these changes accounted for the lowered enzyme activity in the fasted state. The rapid decrease in enzyme activity with fasting, t1/2 congruent to 16 hr, was found to be due to a rapid increase in kd from 0.14-0.16 day-1 in fed animals to 0.61 day-1 during the first 8 hr after the initiation of fast. Thereafter, kd decreased steadily to reach 0.18 day-1 after 48-72 hr of fasting.

Alcohol Dehydrogenase↗

PubMedDate not supplied

Alcohol and aldehyde dehydrogenase isoenzymes in North American Indians.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isoenzyme phenotypes were determined in autopsy liver samples from 50 North American Indians from New Mexico. Forty-six of the 50 livers had sufficient ADH activity to allow phenotyping at the ADH2 and ADH3 loci. All 46 livers possessed the "typical" ADH2 1-1 phenotype. The frequency of the ADH3(2) allele was 0.59 and is the highest thus far reported in any racial population. All 50 livers possessed the ALDH I isoenzyme which exhibits the greatest anodic mobility on starch gel electrophoresis at pH 7.6. The results show that ADH and ALDH phenotypes among American Indians living in New Mexico are very similar to those of Caucasian populations and quite different from those of Orientals.

Adolescent↗

PubMedDate not supplied

Effects of ethanol on monoamine and amino acid release from cerebral cortical slices of the alcohol-preferring P line of rats.

The effects of 250 mg/100 ml ethanol on the efflux of 3,4-dihydroxyphenylacetic acid (DOPAC) and the 35 mM K+-stimulated, Ca2+-dependent release of norepinephrine (NE), dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate, and aspartate from cerebral cortical slices of the alcohol-preferring P line of rats and stock Wistar rats were studied. The K+-stimulated, Ca2+-dependent release of GABA for the P rats was 35% lower, while the release of glutamate was almost twice that of the stock animals. The release of the other compounds was similar for the two groups. Addition of 250 mg/100 ml ethanol to the superfusion media did not alter the release of NE, DA, and 5-HT nor the efflux of DOPAC from cortical slices of either group of rats. However, the K+-stimulated, Ca2+-dependent release of GABA, glutamate, and aspartate was significantly enhanced by ethanol for both the P and stock group of rats. These in vitro data do not support a direct action of ethanol on DA, NE, and 5-HT release or on DOPAC efflux, but suggest a direct action on the transmitter release process for GABA, glutamate, and aspartate in the cerebral cortex.

Alcohol Drinking↗