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V G Erwin

Publications and source records attributed to V G Erwin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Common quantitative trait loci for alcohol-related behaviors and central nervous system neurotensin measures: locomotor activation.

We have analyzed LSXSS recumbinant inbred for ethanol-induced activity using 2.0 g/kg ethanol and a new method we call ethanol activation slope. The ethanol activation slope provides a robust dose-response measure of ethanol activation, independent of both activity after saline and the inhibitory effects of ethanol on locomotor activity. These behavioral data were used in a quantitative trait locus analysis to map chromosomal loci involved in ethanol-induced locomotor activity. We tentatively identified seven loci that mediate the low-dose stimulatory effect of ethanol and six loci involved in locomotion after 2.0 g/kg ethanol. Only one of the loci are in common between the two behaviors. We also compared the behavioral quantitative trait locus to those previously identified that are involved in regulating central nervous system neurotensin levels and neurotensin receptor densities. Six chromosomal regions were identified that regulate at least one central nervous system neurotensin measure and an ethanol-induced locomotor behavior. The identification of loci controlling both central nervous system neurotensin levels or neurotensin receptor densities and ethanol-induced locomotor activity strengthens the proposal that neurotensin regulates, in part, ethanol-induced behaviors and central nervous system sensitivity to ethanol.

Alcoholism↗
PubMed1996

Quantitative trait loci for ethanol sensitivity in the LS x SS recombinant inbred strains: interval mapping.

We are mapping the genes (quantitative trait loci or QTLs) that are responsible for individual differences in ethanol sensitivity, measured as the duration of loss of righting, reflex (LORR) and blood ethanol concentrations upon recovery of the righting reflex (BEC). The Long-Sleep (LS) and Short-Sleep (SS) selected lines of mice manifest an 18-fold difference in LORR and serve as a rodent model for ethanol sensitivity. The LS x SS recombinant inbred (RI) series, developed from LS and SS lines, are an important resource for QTL mapping of ethanol-related responses. The current report summarizes the initial QTL analysis of LORR and BEC in the LS x SS strains and compares the results of correlational analysis with an interval-mapping approach. The data provide strong evidence for QTLs that influence ethanol sensitivity on mouse chromosomes 1 and 2 and possible QTLs on chromosomes 1, 3, 4, 5, 6, 7, 12, 13, 16, and 18. These results are compared to those from an F2 cross which confirms QTLs on chromosomes 1, 2, 4, and 18.

Alcohol Drinking↗
PubMed1996

Neurotensin levels and receptors in HAS and LAS rat brains: effects of ethanol.

Previous studies of neurotensin (NT) levels and NT receptor densities in specific brain regions of mice selectively bred for differences in sensitivity to ethanol have shown that NTergic processes may mediate some actions of ethanol. In the present study, we have determined the levels of NT and NT receptor densities in specific brain regions of HAS and LAS rats that have been selectively bred for differences in sensitivity to ethanol-induced loss of righting response. Regional differences in NT levels were observed in brains from both HAS and LAS rats and values in hypothalamus, ventral midbrain, and nucleus accumbens from female rats were 25 to 75% higher than levels in corresponding regions from male rats. However, there were no significant line differences in NT-ir levels in corresponding regions from HAS and LAS animals. High-affinity binding (NTH Bmax values), measured by Scatchard analyses, were higher in ventral midbrain from HAS males than from LAS males. NTH receptor densities were higher in HAS males than in HAS females; sex differences were not observed in the LAS line. There were no significant line or sex differences between HAS and LAS in low-affinity (NTL) Bmax values in any brain region. In HAS females, subhypnotic doses of ethanol produced a decrease in NT levels in nucleus accumbens, whereas, hypnotic doses caused an increase in NT levels. Likewise, hypnotic doses elicited increases in NT levels in hypothalamus of female HAS and LAS, but not in ventral midbrain or caudate putamen. These results are consistent with low dose activation of mesolimbic and nigrostriatal dopaminergic neurons in which NT is colocalized with dopamine and with high dose inhibition of these pathways.

Animals↗
PubMed1996

Alterations in locomotor activity after microinjections of GBR-12909, selective dopamine antagonists or neurotensin into the medial prefrontal cortex.

It has been postulated that increased dopamine (DA) activity in the medial prefrontal cortex (mPFC) exerts an inhibitory influence over DA release in the nucleus accumbens and, thus, also over locomotor activity. Experiments were designed to examine the role of mPFC DA and neurotensin (NT), a neuropeptide which interacts with DA, in spontaneous locomotor activity. LS/IBG mice were injected bilaterally with either GBR-12909, a selective DA uptake blocker, the DA D1 receptor antagonist R-(+)-SCH-23390, the DA D2 receptor antagonist epidepride, NT or a combination of drugs. GBR-12909 produced a U-shaped dose-response curve with a maximum inhibition of 47% of control. Postmortem tissue levels of DA, 5-hydroxytryptamine, norepinephrine and their major metabolites were determined after microinjections of GBR-12909. Tissue levels of these compounds were not significantly affected by GBR-12909. However, the ratios of homovanilic acid/DA and homovanilic acid + 3,4-dihyroxyphenylacetic acid/DA were significantly decreased, whereas the 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio was not affected by GBR-12909, suggesting a selective effect on DAergic processes. By itself, R-(+)-SCH-23390 had no effect on locomotor activity except at a very high dose which caused locomotor inhibition (49% of control). Epidepride caused a dose-dependent inhibition of locomotor activity with a maximum inhibition of 49% of control. When coinjected with an inhibitory dose of GBR-12909, both epidepride and R-(+)-SCH-23390 attenuated the GBR-12909 effect in a dose-dependent manner. A broad range of doses of NT was found to have no consistent effect on locomotor activity. However, when coinjected with an inhibitory dose of GBR-12909, NT attenuated the GBR-12909-induced inhibition in a dose-dependent manner. The results suggest that stimulation of DA receptors in the mPFC, both DA D1 and DA D2 receptors mediates locomotor inhibition. Furthermore, stimulation of NT receptors appears to antagonize the effects of DA.

Analysis of Variance↗
PubMed1996

Genetic selection and characterization of mouse lines for acute functional tolerance to ethanol.

Rapid adaptation to central nervous system inhibitory effects of ethanol is observed in animals and humans and this acute functional tolerance (AFT) is influenced by genotype in rodents. Studies have been conducted to identify neurochemical processes influencing AFT to ethanol, but little is known regarding genetic regulation of AFT or genetic influences on processes that mediate acquisition of AFT. Our study was designed to develop, by selective breeding, lines of mice that differ in acquisition of AFT to ethanol; such mouse lines will be valuable in identifying the neuroadaptive processes mediating AFT. AFT is defined as the difference in blood ethanol concentration (BEC) at regaining balance on a stationary dowel rod after two consecutive doses of ethanol, 1.75 followed by 2.0 g/kg. Starting with a genetically heterogeneous foundation stock (HS/lbg), seven generations of selective breeding has been completed for high (HAFT1), low (LAFT1), and control lines and four generations have been completed for the replicate HAFT2 and LAFT2 lines. The lines do not differ in initial sensitivity to ethanol; however, the means for AFT scores differ by 2.3- and 4.3-fold for females and males, respectively (106.5 vs. 46.5 mg ethanol/dl blood) for females and 106.2 vs. 24.8 mg/dl for males). Frequency distributions for HAFT1 and LAFT1 show only modest overlap in AFT scores. The lines differ in rates of acquisition of AFT, but not in rates of ethanol clearance. Heritabilities were 0.04 and 0.26 for HAFT1 and LAFT1 lines, respectively, indicating that the selection was asymmetrical. Evidence is provided indicating that practice during intoxication has little effect on acquisition of AFT in HAFT1 and LAFT1 lines.

Animals↗
PubMed1995

Behavioral responses to low doses of cocaine are affected by genetics and experimental history.

We recently conducted a set of two experiments to investigate the possible co-operation between genetics and exposure to novelty on the putative locomotor inhibiting effects of low doses of cocaine in male and female C57BL/6 and DBA/2 mice. Experiment one examined the effects of three low doses of cocaine (0.1, 0.5, and 1.0 mg/kg) on locomotion, exploration, stereotypy and wall-seeking in an automated activity monitor. Testing occurred on two consecutive days, with subjects receiving an IP injection of saline on day one, and one dose of cocaine on day 2 (S-C). Immediately following injection, subjects were placed into automated activity monitors, where four behaviors were recorded; total distance, nosepokes, stereotypy and margin time. Using this S-C injection regimen, we found significant decreases in measures of total distance and stereotypy when compared to saline in both male and female C57 mice. Experiment two was designed to determine if the observed decrease in locomotor activity was the result of low-dose cocaine or pre-exposure to the test procedure and apparatus. All conditions and procedures were identical to those in experiment one, with the exception of the injection regimen. In this experiment, we injected all subjects IP with 0.1 mg/kg cocaine on day one, followed by saline on day two (C-S). Additionally, a group of subjects receiving saline on both days (S-S) served as the control. In contrast to experiment one results, cocaine produced locomotor activation. Furthermore, significant sex and strain differences were found in both experiments. The results of our experiments suggest that the behavioral effects of low doses of cocaine are markedly influenced by both the genetic constitution of the experimental animal and by familiarity with the test apparatus.

Animals↗
PubMed1995

Cross-tolerance between ethanol and neurotensin in mice selectively bred for ethanol sensitivity.

Neurotensin (NT), a tridecapeptide that satisfies criteria as a neurotransmitter, mimics many actions of ethanol, and evidence indicates that some of the acute effects of ethanol are mediated in part by NT. Recent studies have shown that chronic ethanol treatment produced a downregulation of NT receptors in mesolimbic brain regions of long sleep (LS) mice and that reduced NT binding capacity was associated with acquisition and decay of tolerance to ethanol-induced locomotor inhibition and hypothermia in these mice. The present study was undertaken to determine whether cross-tolerance develops between NT and ethanol and whether chronic NT infusion produces NT receptor downregulation. Animals chronically treated with ethanol were tolerant to NT-mediated locomotor inhibition at a dose of 1.8 pmol NT, ICV, and were tolerant to NT-induced hypothermia at 1.8 and 6.0 pmol NT. Following repeated injections or continuous infusion of NT ICV, LS mice showed tolerance to both NT- and ethanol-induced hypothermia and locomotor inhibition. Indeed, ethanol doses that are hypnotic in control mice (2.8 g/kg) were not effective in abolishing locomotor activity following chronic NT administration. Results with chronic saline infusion ICV indicate that stress alters sensitivity to ethanol-induced hypothermia. Chronic infusion of NT ICV produced a region-specific downregulation of high-affinity NT receptors in the striatum. The results demonstrate that cross-tolerance develops between NT and ethanol, and further support a role for neurotensinergic systems in the actions of ethanol.

Alcoholic Intoxication↗
PubMed1995

Changes in mouse brain neurotensin receptor density following chronic infusion of neurotensin.

Many centrally acting drugs affect neurotensin (NT) systems by increasing levels of the peptide in specific brain regions. If these changes represent increases in extracellular NT levels, then changes in NT receptors would be expected. The focus of this study was to examine the effects of continuous exposure of NT receptors to agonist. Continuous infusion of NT (0.6 or 6 nmol/h) into the lateral ventricle via an osmotic minipump for 3 days caused a significant increase (over saline infusion) in total and low-affinity NT receptor density in the cerebellum of LS mice. High-affinity NT receptor density was increased in the frontal cortex. Seven days of NT infusion (6 nmol/h) caused no changes in NT receptor density.

Animals↗
PubMed1995

Pharmacogenetics of cocaine: a critical review.

The development of genetic models to help explain individual differences in sensitivity to and susceptibility to misuse certain CNS active substances, like ethanol and psychostimulants, spans a brief, thirty-plus years. The first animal models involved inbred strains and selected lines of mice and rats and predicted genetic-based differential sensitivity to ethanol and its misuse in humans found a few years later. With drugs like cocaine, tracking genetic differences in sensitivity and misuse liability in humans is difficult because of legal problems. Genetically-defined animals, however, have shown most if not all of cocaine-related behavioural, neurophysiological and toxicological effects to evince wide variation with most effects being influenced by several genes. Thus, we argue that animal and human studies of individual differences in drug sensitivity be studied from both quantitative and molecular genetic approaches. For the former, new techniques involving recombinant inbred strains of rodents, genetic correlational analysis and quantitative trait loci analysis are particularly useful, especially as genetic synteny between rodents and humans becomes better described. Also, because drug effects are highly labile to environmental conditions as well as genetic-based individual differences, multivariate, systems level studies should be developed to provide more complete descriptive and mechanistic views of a multifaceted problem.

Animals↗
PubMed1994

Effects of acute and chronic ethanol administration on neurotensinergic systems.

A summary of pharmacogenetic studies designed to test the hypothesis that NT receptors might mediate or regulate some of the actions of ethanol is presented. Indeed, there are significant genetic correlations between ethanol-induced locomotor activation and high-affinity NT receptor densities in the FC. The results suggest that further studies are needed to determine the role of NT receptors in the FC and MPFC in regulating locomotor activity. In other studies, chronic ethanol treatment, under conditions that produced tolerance to ethanol and caused NT receptor downregulation in the NA and VMB, caused tolerance to locomotor inhibitory effects of centrally administered NT and blunted the effects of intra-VTA NT on dopamine metabolism in the NA and CP. The results show a relationship between NT receptor densities and pharmacological effects of ethanol.

Alcoholism↗
PubMed1994

Characterization of dopamine transporter and locomotor effects of cocaine, GBR 12909, epidepride, and SCH 23390 in C57BL and DBA mice.

C57BL/6 and DBA/2 mice were used to examine genetic differences in locomotor activating effects of acute cocaine administration and to determine whether differences were mediated by dopaminergic systems. C57BL/6 mice were less activated than DBA/2 mice at 5 and 10 min after 10 and 15 mg/kg cocaine. HPLC analysis showed equivalent brain cocaine concentrations in the two strains at 5 and 10 min after 10, 15, or 20 mg/kg doses. The selective dopamine uptake inhibitor, GBR 12909, at 5 and 7.5 mg/kg, produced greater locomotor activation in DBA/2 mice than in C57BL/6 mice. However, binding studies with the selective dopamine uptake ligand [3H]GBR 12935, revealed no between-strain difference in Kd or Bmax in caudate putamen (CP) or nucleus accumbens (NA) membranes. Competition assays using unlabeled dopamine to compete for [3H]GBR 12935 binding in CP or NA membranes showed no between-strain difference by brain region. The specific D1 or D2 antagonists, SCH 23390 or epidepride, respectively, produced dose-dependent decreases in locomotor activity but there were no between-strain differences. However, epidepride, at a dose of 0.003 mg/kg, completely reversed cocaine-induced (15 mg/kg) activation in both strains. These findings show that C57BL/6 and DBA/2 mice differ in dopamine-related behaviors and suggest that dopaminergic processes may mediate genetic differences in cocaine sensitivity.

Animals↗
PubMed1993

Characterization of neurotensin-stimulated phosphoinositide hydrolysis in brain regions of long sleep and short sleep mice.

Previous studies have shown that long sleep (LS) and short sleep (SS) mice, which were selectively bred for differences in brain sensitivity to ethanol, differ in neurotensin (NT) receptor densities in specific brain regions. The present study was designed to determine whether these receptor differences mediate differences in the effects of NT on the phosphoinositide (PI) second messenger system in four brain regions from LS and SS mice. Baseline and NT- or carbachol-stimulated PI hydrolysis were Ca(2+)-dependent. Stimulation of PI hydrolysis by NT or carbachol was region specific; NT effect was approximately equal in ventral midbrain (VMB) and entorhinal cortex (EC) with slightly less stimulation in nucleus accumbens (NA) and no effect in the cerebellum (CE). Carbachol-enhanced PI hydrolysis was greatest in the VMB followed by EC and NA with no stimulation in the CE. There were no between line (LS vs. SS) differences in carbachol effects, but stimulation by NT was greater in EC and NA from LS than from SS mice. Ethanol enhanced NT-stimulated, but not carbachol-stimulated, PI metabolism in SS and LS NA brain slices. Results with levocabastine, an inhibitor of low-affinity NT receptor (NTL) binding, suggest that NT may stimulate PI hydrolysis via NTL, as well as high-affinity receptors.

Animals↗
PubMed1993

Genetic correlations among ethanol-related behaviors and neurotensin receptors in long sleep (LS) x short sleep (SS) recombinant inbred strains of mice.

Studies were designed to examine the hypothesis that genetic based differences in sensitivity to several behavioral effects of ethanol are mediated, in part, by shared genes and that some of ethanol's actions are mediated by brain neurotensinergic processes. In these studies we have used recombinant inbred (RI) strains of mice derived from Long Sleep (LS/Ibg) and Short Sleep (SS/Ibg) lines of mice. The LS and SS mice were selectively bred to differ in hypnotic sensitivity but also differ in hypothermia and locomotor effects of ethanol. Therefore LS x SS RI strains were used to answer the question whether there are shared genetic influences on these diverse ethanol actions. Moreover, since the LS and SS mice were found to differ in neurotensin (NT) receptor densities in various brain regions, the LS x SS RI strains were used to determine associations between NT receptor densities and ethanol actions. The results showed a significant genetic correlation (r = .38) between hypnotic sensitivity and low-dose locomotor effects of ethanol and indicated multigenetic influences, with estimates of seven, four and three genes being responsible for mediating differences in hypnotic, hypothermic, and locomotor effects of ethanol, respectively. The findings are consistent with one or more genes having pleiotropic effects on these ethanol actions.

Alcohol Drinking↗
PubMed1993

Chronic ethanol administration downregulates neurotensin receptors in long- and short-sleep mice.

Neurotensin (NT) has been shown to differentially alter many of the physiologic responses to ethanol administration in long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differences in hypnotic sensitivity to ethanol. These mice have been shown to differ in NT receptor densities in cortical and mesolimbic brain regions and it has been suggested that ethanol actions may be mediated, in part, by neurotensinergic processes. The present study was conducted to further examine this hypothesis by determining the effects of acute and chronic ethanol administration on NT receptor systems in these mice. Scatchard analysis of [3H]NT binding in brain membranes from mice chronically treated with ethanol yielded a one-site model, whereas binding in membranes from control mice were best described by a two-site model. Values for binding capacity (Bmax) were significantly reduced in several brain regions, and binding site density for total, levocabastine-sensitive, and levocabastine-insensitive binding sites were also reduced. The maximum effect was seen after 2 weeks of chronic ethanol consumption. Three weeks after withdrawal from ethanol, Kd and Bmax had returned to control values. Similarly, binding density in all regions for total, levocabastine-sensitive, and levocabastine-insensitive sites had returned to control values within 2 weeks. NT receptor characteristics measured 2 h post-3.0 g/kg ethanol revealed that ethanol caused a rapid downregulation of both subtypes of NT receptors. The finding that both acute and chronic ethanol significantly downregulate the neurotensin receptor systems further supports the hypothesis that ethanol's actions may be mediated in part by neurotensinergic systems.

Animals↗
PubMed1993

Strain and housing affect cocaine self-selection and open-field locomotor activity in mice.

We recently conducted an experiment to investigate the possible cooperation between genetic makeup and differential housing on cocaine self-administration in male and female C57BL/6J and DBA/2J mice. Cocaine self-selection was measured in a two-choice test with one choice being cocaine-HCl solution of 40 mg% in tap water and the other choice being plain tap water. Housing conditions began at weaning (21-23 days of age) and consisted of group housed (GH) with 2-3 mice per cage, and isolated housed (IH) with 1 mouse per cage. The results of this study revealed overall strain, sex and housing differences, with C57BL/6Js consuming more cocaine solution than DBA/2J subjects, females consuming more cocaine solution than males, and group housed consuming more than isolate housed subjects. In a second study, the effect of differential housing on open-field locomotor activity was investigated. Testing was conducted on two consecutive days, with subjects receiving an IP injection of saline on day 1, and 15 mg/kg cocaine HCl on day 2. Four behaviors were recorded, including: total distance, nosepokes, stereotypy, and margin time. Overall, the results revealed significant strain differences for stereotypy and nosepokes, and males were found to be more activated by cocaine than females. Additionally, DBA males tended to be differentially affected by housing condition, with IH showing suppressed locomotor activity as compared to GH subjects. Last, significant strain by housing interactions occurred in nosepokes and stereotypy time.

Animals↗
PubMed1993

Pharmacogenetics of cocaine: I. Locomotor activity and self-selection.

We investigated the effects of cocaine on multiple activity measures and cocaine self-selection in C57BL/6Ibg and DBA/2Ibg mice. Male mice were tested in an automated activity monitor at three doses of cocaine, 5, 15 and 30 mg kg-1. Activity measures included locomotion, rearings, stereotyped movements and wall-seeking. Testing was conducted on 2 days with saline injection, i.p. on day one and cocaine i.p. injected on day two. We also tested other mice of both strains for cocaine ingestion in a two-choice test, pairing tap water with 40 mg% cocaine HCl in tap water. Two separate groups of mice received 15 or 30 mg kg-1 of cocaine i.p., killed at 5 min and brain cocaine levels were determined by HPLC. Cocaine produced dose-related increases in locomotion in both strains, with a delay in initial activation noticed at 30 mg kg-1 in C57s but not in DBAs. In DBAs, cocaine suppressed rearings and increased stereotyped movements while having no consistent effect on either behaviour in C57s. At all doses, cocaine produced moderate increases in proximity to the wall in DBAs and 30 mg kg-1 produced pronounced wall-seeking in C57s. At 15 and 30 mg kg-1 DBAs tended to have higher levels of cocaine in whole brain than did C57s. Finally, C57s consumed significantly more cocaine than did the DBAs.

Animals↗
PubMed1993

Pharmacogenetics of cocaine: II. Mesocorticolimbic and striatal dopamine and cocaine receptors in C57BL and DBA mice.

Studies were conducted to determine whether genetic differences in behavioural effects of cocaine in C57BL/6 and DBA/2 mice might be mediated by strain differences in dopamine and serotonin transporters and dopamine D1 and D2 receptors in specific brain regions. Binding characteristics of [3H]CFT, a cocaine analogue, in the presence of either GBR12909, a dopamine uptake blocker or fluoxetine, a serotonin uptake blocker and binding of [3H]-paroxetine, a specific serotonin uptake receptor antagonist, were evaluated. We observed regional differences in [3H]CFT binding parameters in the presence of GBR12909 or fluoxetine, but no strain differences by brain region were observed. There were no differences in [3H]paroxetine binding characteristics between corresponding brain regions from C57BL and DBA/2 mice. The D1 antagonist, [3H]SCH23390 and the D2 ligands [3H]sulpiride or [125I]epidepride were used to determine dopamine receptor characteristics. Regional differences were found in [3H]SCH23390 and [3H]sulpiride, with higher affinities and lower densities in frontal cortex compared to striatum; with no differences in [3H]SCH23390 binding in corresponding tissues from C57BL and DBA/2 brains. There were strain-related differences in [3H]sulpiride and in [3H]epidepride binding in striatal membranes with higher densities in C57BL than in DBA/2. Our findings suggest striatal D2 receptor differences are possibly involved in genetic differences in cocaine-related behaviours.

Animals↗