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W J McBride

Publications and source records attributed to W J McBride.

At least 19 recordsLinked to original sources
PubMed2006

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach.

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Alcohol Drinking↗
PubMed2006

Protein expression changes in the nucleus accumbens and amygdala of inbred alcohol-preferring rats given either continuous or scheduled access to ethanol.

Chronic ethanol (EtOH) drinking produces neuronal alterations within the limbic system. To investigate changes in protein expression levels associated with EtOH drinking, inbred alcohol-preferring (iP) rats were given one of three EtOH access conditions in their home-cages: continuous ethanol (CE: 24h/day, 7days/week access to EtOH), multiple scheduled access (MSA: four 1-h sessions during the dark cycle/day, 5 days/week) to EtOH, or remained EtOH-naïve. Both MSA and CE groups consumed between 6 and 6.5g of EtOH/kg/day after the 3rd week of access. On the first day of EtOH access for the seventh week, access was terminated at the end of the fourth MSA session for MSA rats and the corresponding time point (2300h) for CE rats. Ten h later, the rats were decapitated, brains extracted, the nucleus accumbens (NAcc) and amygdala (AMYG) microdissected, and protein isolated for 2-dimensional gel electrophoretic analyses. In the NAcc, MSA altered expression levels for 12 of the 14 identified proteins, compared with controls, with six of these proteins altered by CE access, as well. In the AMYG, CE access changed expression levels for 22 of the 27 identified proteins, compared with controls, with 8 of these proteins altered by MSA, as well. The proteins could be grouped into functional categories of chaperones, cytoskeleton, intracellular communication, membrane transport, metabolism, energy production, or neurotransmission. Overall, it appears that EtOH drinking and the conditions under which EtOH is consumed, differentially affect protein expression levels between the NAcc and AMYG. This may reflect differences in neuroanatomical and/or functional characteristics associated with EtOH self-administration and possibly withdrawal, between these two brain structures.

Alcohol Drinking↗
PubMed2005

Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody.

A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.

Animals↗
PubMed2005

Gene expression in the hippocampus of inbred alcohol-preferring and -nonpreferring rats.

The hippocampus is sensitive to the effects of ethanol and appears to have a role in the development of alcohol tolerance. The objective of this study was to test the hypothesis that there are innate differences in gene expression in the hippocampus of inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats that may contribute to differences in sensitivity to ethanol and/or in the development of tolerance. Affymetrix microarrays were used to measure gene expression in the hippocampus of alcohol-naive male iP and iNP rats in two experiments (n=4 and 6 per strain in the two experiments). Combining data from the two experiments, there were 137 probesets representing 129 genes that significantly differed (P < or = 0.01); 62 probesets differed at P < or = 0.001. Among the 36% of the genes that were expressed more in the iP than iNP rat at this level of significance, many were involved in cell growth and adhesion, cellular stress reduction and anti-oxidation, protein trafficking, regulation of gene expression, synaptic function and metabolism. Among the 64% of the genes that had lower expression in the hippocampus of iP than iNP rats were genes involved in metabolic pathways, cellular signaling systems, protein trafficking, cell death and neurotransmission. Overall, the data indicate that there are significant innate differences in gene expression in the hippocampus between iP and iNP rats, some of which might contribute to the differences observed in the development of alcohol tolerance between the selectively bred P and NP lines.

Alcohol Drinking↗
PubMed2004

Ethanol drinking and deprivation alter dopaminergic and serotonergic function in the nucleus accumbens of alcohol-preferring rats.

The alcohol deprivation effect is a temporary increase in the intake of, or preference for, ethanol after a period of deprivation that may result from persistent changes in key limbic regions thought to regulate alcohol drinking, such as the nucleus accumbens. The present study tested the hypothesis that chronic alcohol drinking under continuous 24-h free-choice conditions alters dopamine and serotonin neurotransmission in the nucleus accumbens and that these alterations persist in the absence of alcohol. Using the no-net-flux microdialysis method, the steady-state extracellular concentration (point of no-net-flux) for dopamine was approximately 25% higher in the adult female alcohol-preferring P rats given prior access to 10% ethanol, even after 2 weeks of ethanol abstinence, compared with the P rats gives access only to water. However, the extracellular concentration of serotonin was approximately 35% lower in animals given 8 weeks of continuous access to ethanol compared with water controls and animals deprived of ethanol for 2 weeks. The effect of local perfusion with 100 microM sulpiride (D(2) receptor antagonist) and 35 microM 1-(m-chlorophenyl)-biguanide (5-hydroxytryptamine(3) receptor agonist) on dopamine overflow were reduced approximately 33% in both groups of ethanol-exposed P rats compared with water controls. Free-choice alcohol drinking by P rats alters dopamine and serotonin neurotransmission in the nucleus accumbens, and many of these effects persist for at least 2 weeks in the absence of ethanol, suggesting that these underlying persistent changes may be in part responsible for increased ethanol drinking observed in the alcohol-deprivation effect.

Alcohol Drinking↗
PubMed2004

Low-dose stimulatory effects of ethanol during adolescence in rat lines selectively bred for high alcohol intake.

BACKGROUND: The low-dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes. METHODS: Subjects were adolescent (31-40 days of age) rats from the alcohol-preferring (P) and -nonpreferring (NP) lines and from the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) replicate lines. On day 1, all subjects (n = 8-10/line/gender/dose) received intraperitoneal saline injections and were placed in the activity monitor for 30 min. On day 2, subjects received intraperitoneal saline or 0.25, 0.50, 0.75, 1.0, or 1.5 g EtOH/kg. RESULTS: The LMA of male and female P rats was increased with low doses (0.25-0.75 g/kg) and decreased at the highest dose (1.5 g/kg) of EtOH. Similar effects were observed with low doses of EtOH on the LMA of HAD-1 and HAD-2 rats. None of the EtOH doses stimulated LMA in the NP, LAD-1, or LAD-2 rats, although all of the low-alcohol-intake lines of rats showed decreased LMA at the highest dose of EtOH. Only the P rats among the high-alcohol-consuming lines of rats showed decreased LMA at the highest dose of EtOH. CONCLUSION: Selective breeding for high alcohol consumption seems to be associated with increased sensitivity to the low-dose stimulating effects of EtOH and reduced sensitivity to the high-dose motor-impairing effects of ethanol. The expression of these phenotypes emerges during adolescence by the age of onset of alcohol-drinking behavior.

Age Factors↗
PubMed2004

Long-lasting alterations of the mesolimbic dopamine system after periadolescent ethanol drinking by alcohol-preferring rats.

BACKGROUND: This study tested the hypothesis that ethanol consumption by alcohol-preferring (P) rats during the periadolescent period causes persistent alterations in the mesolimbic dopamine (DA) system. After ethanol drinking during periadolescence, P rats were examined for alterations in basal locomotor activity, changes in extracellular DA levels and extraction fraction in the nucleus accumbens (NAc) by using no-net-flux (NNF) microdialysis, and changes in the response of the mesolimbic DA system to ethanol. METHODS: Male P rat pups were given 24-hr free-choice access to 15% (v/v) ethanol from postnatal day (PD) 30 through PD 60. On PD 70, rats were assessed for locomotor activity. On PD 70 to 80, rats were implanted with bilateral guide cannulas aimed above the NAc. After at least 5 days, microdialysis probes were inserted bilaterally; on the following day, NNF microdialysis experiments were conducted. On the day after the NNF experiment, conventional microdialysis experiments were conducted to measure extracellular levels of DA in response to intraperitoneal injection of saline or ethanol 2.5 g/kg. RESULTS: Compared with the ethanol-naive group, ethanol drinking by P rats during periadolescence did not alter basal locomotor activity, nor did it alter the basal extracellular concentration of DA. There was, however, a significant increase in the extraction fraction of DA of ethanol-drinking animals relative to the controls (57.4 +/- 2.7% and 45.8 +/- 2.3%, respectively). Additionally, compared with controls, P rats with exposure to ethanol during the periadolescent period showed a prolonged increase in the extracellular levels of DA after a challenge dose of ethanol. CONCLUSIONS: The results of the microdialysis experiments suggest that periadolescent ethanol drinking by P rats increases basal DA neurotransmission (as indicated by higher DA clearance while maintaining the same extracellular DA concentrations) and prolongs the response of DA neurotransmission to ethanol.

Age Factors↗
PubMed2003

Amphetamine-modified acoustic startle responding and prepulse inhibition in adult and adolescent alcohol-preferring and -nonpreferring rats.

Selective breeding has been used to develop the alcohol-preferring (P) and -nonpreferring (NP) rats, with the P rat having lower CNS levels of dopamine (DA) and reduced DA innervation in the nucleus accumbens compared with the NP rat. The acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR are experimental behaviors altered by DA agonists. We examined whether functional differences in amphetamine (AMPH)-modified ASR and PPI exist between P and NP rats. AMPH [0.0 (saline), 1.0, 2.0, or 4.0 mg/kg] was injected 15 min prior to placement into a startle apparatus. After a 5-min habituation period, rats were given approximately twelve 95-, 105-, or 115-dB white-noise burst (ASR) and PPI trials. As adults, P rats were sensitive to AMPH potentiation of the ASR to a greater extent than NP rats. During adolescence, P and NP rats had similar levels of AMPH-potentiated ASR. As adults, NP rats displayed potentiated, rather than disrupted, PPI at the 1.0-mg/kg dose, whereas P rats displayed the expected disrupted PPI at the 4.0-mg/kg dose. As adolescents, NP rats did not display significant differences in PPI after AMPH, whereas P rats displayed dose-dependent disruption of PPI, which was significant at the 4.0-mg/kg dose. The limited effect of AMPH on increasing the ASR and the presence of AMPH-potentiated PPI at the lowest dose in the adult NP rat suggests reduced functioning of the interactions between DA circuits and the neurocircuitry mediating the ASR and PPI, compared with P rats. However, the neurocircuitry mediating PPI does not appear to be fully developed in the adolescent NP rat. The present findings also indicate that lower levels of DA content and immunoreactive fibers in the P rat may not reflect reduced DA neuronal activity, because the P rat displayed AMPH-potentiated ASR, and, at the highest dose, AMPH disruption of PPI during both adulthood and adolescence.

Acoustic Stimulation↗
PubMed2002

Central nervous system mechanisms in alcohol relapse.

BACKGROUND: Alcohol relapse is a major problem in the treatment of alcohol abuse and alcoholism. Understanding the long-term neuronal alterations that promote relapse of alcohol drinking is critical for the development of pharmacotherapies to treat alcoholism and alcohol abuse. The major objectives of this workshop were to present recent findings, by using rodent models, on behavioral and neurobiological factors that may underlie alcohol relapse and the results of clinical and pharmacological treatment strategies for preventing relapse. METHODS: Prolonged ethanol drinking and repeated periods of alcohol deprivation were studied in nonselected rats and in rats selectively bred for high alcohol preference (P rat). The expression of a robust alcohol deprivation effect (ADE) was used as a model for alcohol relapse in rodents. Operant techniques were used to examine responding for ethanol after deprivation in both rats and C57BL/6J mice. Environmental cues and stress were used to assess their effects on reinstatement of alcohol responding. Microdialysis and [14C]-2-deoxyglucose techniques were used to examine neuronal alterations associated with alcohol relapse. RESULTS: Prolonged free-choice ethanol drinking followed by deprivation produced an ADE in both stock and P rats. These rats demonstrated loss of control on reinstatement after chronic drinking and after prolonged deprivation. Acamprosate and naltrexone effectively reduced the ADE in stock rats. Stress reinstated operant responding for alcohol, and rats trained to associate a cue with ethanol presentation increased responding on the ethanol-associated lever in the absence of ethanol. After repeated deprivations, P rats shifted their preference toward drinking higher concentrations of ethanol, which increased the magnitude and duration of the ADE. Stock rats also shifted their preference toward solutions with higher ethanol concentrations and demonstrated a loss of control after prolonged ethanol drinking and deprivation. Long-lasting alterations in neuronal activity, serotonin-3 receptor function, and dopamine neurotransmission within the mesolimbic system were evident after chronic drinking that followed a prolonged deprivation period. CONCLUSIONS: The ADE is a useful model for studying alcohol relapse in both rats and mice. The potential validity of this model is supported by the findings that acamprosate and naltrexone are effective in preventing the ADE in rodents, and both compounds have gained recognition for their therapeutic effects in clinical populations. Genetics, stress, and environmental cues are all important factors that influence alcohol relapse. Long-term alterations in neuronal activity within the mesolimbic system, which possibly involve dopamine and serotonin, may underlie alcohol relapse.

Acamprosate↗
PubMed2001

Negative interaction of dopamine D2 receptor antagonists and GBR 12909 and GBR 12935 dopamine uptake inhibitors in the nucleus accumbens.

The objective of this study was to examine the interaction of dopamine D2 receptor antagonists and dopamine uptake inhibitors on the regulation of extracellular dopamine release in the nucleus accumbens of Wistar rats employing in vivo microdialysis and in vitro dopamine uptake studies. Application of the D2 receptor antagonists raclopride (100 microm) or sulpiride (100 microm) alone through the microdialysis probe in the nucleus accumbens for 60 min increased the extracellular levels of dopamine in the nucleus accumbens to 150% and 200% of basal, respectively. Perfusion of the nucleus accumbens for 60 min with the dopamine uptake inhibitors, 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909; 100 microm) or 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride (GBR 12935; 100 microm) alone, increased the extracellular levels of dopamine in the nucleus accumbens to 400% and 350% of basal, respectively. Co-perfusion of 100 microM GBR 12909 or GBR 12935 with either 100 microM sulpiride or raclopride produced a significant reduction in the GBR 12909 or GBR 12935 induced increase in the extracellular levels of dopamine to basal levels. In vitro, GBR 12909 (1-9 nM) dose-dependently inhibited active uptake of [3H]dopamine in homogenates of the nucleus accumbens. Addition of 100 microm sulpiride had little effect on GBR 12909 inhibition of [3H] dopamine uptake, suggesting that dopamine D2 receptor antagonists are not blocking the actions of the GBR-type dopamine uptake inhibitors at the dopamine transporter. Overall, the data suggest that complex interactions occur in vivo between D2 antagonists and GBR-type dopamine uptake inhibitors, which negate their effects on elevating the extracellular levels of dopamine in the nucleus accumbens.

Animals↗
PubMed2001

An epidemic of dengue 3 in far north Queensland, 1997-1999.

OBJECTIVES: To describe an epidemic of dengue type 3 that occurred in far north Queensland in 1997-1999 and its influence on the further development of dengue prevention and control strategies. DESIGN: Epidemiological and laboratory investigation of cases, entomological surveys and phylogenetic analysis of dengue virus isolates. MAIN OUTCOME MEASURES: Numbers and characteristics of confirmed cases; Breteau Index (BI; number of containers breeding Aedes aegypti per 100 premises); effect of control measures on mosquito populations; genetic homology of epidemic virus with other dengue virus isolates. RESULTS: The epidemic lasted 70 weeks and comprised 498 confirmed cases in three towns (Cairns, Port Douglas and Mossman); 101 patients (20%) were admitted to hospital. Median interval between symptom onset and notification was seven days (range, 0-53 days), and cumulative duration of viraemia of public health significance was 2,072 days. BIs in affected areas were high, particularly in Mossman (45) and Port Douglas (31). Control measures significantly reduced mosquito populations (assessed as number of ovitraps containing Ae. aegypti eggs and mean number of eggs per trap [P< 0.05 for both]). However, transmission persisted in several foci, in part due to undetected waterfilled containers breeding Ae. aegypti. The epidemic virus belonged to serotype 3; phylogenetic analysis suggested it was imported from Thailand. CONCLUSIONS: The epidemic had greater morbidity than other recent Queensland epidemics of dengue and was harder to control, necessitating substantial revision of the Dengue Fever Management Plan for North Queensland. The epidemic's severity supports the hypothesis that dengue viruses from South East Asia are more virulent than others.

Aedes↗
PubMed2001

Effects of ethanol on the dorsal raphe nucleus and its projections to the caudate putamen.

The objective of this study was to examine the effects of intraperitoneal injection of ethanol on the activity of the dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) system and its projections to the rostral caudate putamen (CPu) and determine whether rapid tolerance to the effects of ethanol develops in this system. Adult, male, Wistar rats were used in these experiments. In experiment 1, a microdialysis procedure was used to determine (a) the effects of acute intraperitoneal administration of ethanol (1.75 and 2.5 g/kg) on the extracellular levels of 5-HT in the rostral CPu and (b) whether rapid tolerance develops to these effects. In experiment 2, firing rates of 5-HT neurons were determined in the DRN after intraperitoneal administration of 2.5 g/kg of ethanol. The results of the microdialysis experiments indicated that the 2.5-g/kg dose significantly (P < .005) increased the extracellular levels of 5-HT to 150%-160% of baseline. Compared with findings for rats pretreated with saline 24 h earlier, prior treatment 24 h earlier with 2.5 g/kg of ethanol had no effect on the extracellular levels of 5-HT produced by a challenge dose of 2.5 g/kg of ethanol. Contrary to the effects in the CPu, intraperitoneal administration of 2.5 g/kg of ethanol significantly (P<.005) decreased the firing rates of 5-HT neurons in the DRN to approximately 50% of control. Overall, the results suggest to us that there is a dissociation between the effects of acute administration of ethanol on 5-HT cell body neuronal activity and 5-HT synaptic activity. The higher extracellular levels of 5-HT in the CPu may be due to increased release of 5-HT from a direct or an indirect action of ethanol, a result of inhibiting 5-HT reuptake, or related to both of these mechanisms. In addition, the findings suggest to us that rapid tolerance did not develop to the effects of ethanol on the 5-HT system within the CPu.

Animals↗
PubMed2001

Regional central nervous system densities of delta-opioid receptors in alcohol-preferring P, alcohol-nonpreferring NP, and unselected Wistar rats.

The densities of delta-opioid receptors in the central nervous system of alcohol-naive, adult, male, alcohol-preferring P, alcohol-nonpreferring NP, and Wistar rats were examined with the use of quantitative autoradiography. Slides with coronal 20-microm sections through the regions of interest were incubated in 5 nM [3H]-[D-Pen(2),D-Pen(5)]enkephalin (DPDPE) to label delta(1)-opioid receptor sites. Nonspecific binding was determined in the presence of 10 microM naloxone. Significant differences between the P and the NP rat lines were found in numerous cortical regions, the basolateral amygdala, and the posterior hippocampus, with 10%-20% lower [3H]-DPDPE binding found in the P line. In most regions examined, binding levels in the Wistar rats were intermediate between those of the P and the NP rats. Significantly lower [3H]-DPDPE binding levels in the P rat may indicate fewer delta(1)-opioid receptors or decreased binding affinity. The lower binding in certain limbic regions, such as the basolateral amygdala and posterior hippocampus, as well as cortical differences in the P rat may be associated with the divergent alcohol drinking behaviors found between the P and the NP lines.

Alcohol Drinking↗
PubMed2001

D1-D2 dopamine receptor interaction within the nucleus accumbens mediates long-loop negative feedback to the ventral tegmental area (VTA).

The objective of the present study was to examine the effects of perfusion of dopamine (DA) D1- and D2-like receptor agonists in the nucleus accumbens (ACB) on the long-loop negative feedback regulation of mesolimbic somatodendritic DA release in the ventral tegmental area (VTA) of Wistar rats employing ipsilateral dual probe in vivo microdialysis. Perfusion of the ACB for 60 min with the D1-like receptor agonist SKF 38393 (SKF, 1-100 microM) dose-dependently reduced the extracellular levels of DA in the ACB, whereas the extracellular levels of DA in the VTA were not changed. Similarly, application of the D2-like receptor agonist quinpirole (Quin, 1-100 microM) through the microdialysis probe in the ACB reduced the extracellular levels of DA in the ACB in a concentration-dependent manner, whereas extracellular levels of DA in the VTA were not altered. Co-application of SKF (100 microM) and Quin (100 microM) produced concomitant reductions in the extracellular levels of DA in the ACB and VTA. The reduction in extracellular levels of DA in the ACB and VTA produced by co-infusion of SKF and Quin was reversed in the presence of either 100 microM SCH 23390 (D1-like antagonist) or 100 microM sulpiride (D2-like antagonist). Overall, the results suggest that (a) activation of dopamine D1- or D2-like receptors can independently regulate local terminal DA release in the ACB, whereas stimulation of both subtypes is required for activation of the negative feedback pathway to the VTA.

Animals↗
PubMed2001

Alcohol reinforcement and voluntary ethanol consumption.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The organizer/chair was Ting-Kai Li and the co-chair was Rainer Spanagel. The presentations were (1) Genetic differences in alcohol drinking and reinforcement: The sP and sNP Rats, by Giancarlo Colombo; (2) Ventral tegmental area-Neuroanatomical substrate for alcohol reinforcement, by William J. McBride; (3) Metabolic mapping of alcohol reinforcement, by Linda J. Porrino; (4) Role of opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress, by Tsutomu Suzuki; and (5) Repeated deprivations enhance the reinforcing properties of ethanol in alcohol preferring (P) rats, by Zachary A. Rodd-Henricks.

Alcohol Drinking↗
PubMed2001

Local cerebral glucose utilization rates in alcohol-naïve high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: The present study compared baseline local cerebral glucose utilization (LCGU) values within reward-relevant brain regions in alcohol-naïve, adult male high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats from replicate lines 1 and 2. METHODS: 2-[14C]Deoxyglucose ([14C]2-DG) was injected (125 microCi/kg) intravenously during the rats' dark cycle. Timed arterial blood samples were collected over 45 min and assayed for glucose as well as [14C]2-DG content. Rats were then decapitated; their brains quickly removed and frozen in isopentane at -50 degrees C. Coronal sections from each brain were apposed to film and exposed for 2 days. Image densities were analyzed using quantitative autoradiography. RESULTS: Data were collected from several key limbic (nucleus accumbens, ventral tegmental area, olfactory tubercle, amygdala, hippocampus, ventral pallidum, and septum), basal ganglia, cortical (medial prefrontal, frontal, parietal, temporal, occipital, entorhinal, pyriform, and cingulate), and subcortical (thalamus, habenula, and superior colliculus) structures. Because there were no significant differences between the replicates within each drinking line, data from the two replicates were combined to determine drinking line differences. When both replicate lines were combined, there were trends toward higher (approximately 15%) LCGU rates in HAD (n = 15) versus LAD (n = 16) rats within the parietal and occipital cortices, but neither of these line differences reached statistical significance (p < 0.01). CONCLUSIONS: The findings suggested that, within the HAD and LAD replicate rat lines, the selection for alcohol preference did not lead to differences in functional brain activity, as measured with the 2-DG method.

Alcohol Drinking↗
PubMed2001

Quantitative autoradiography of mu-opioid receptors in the CNS of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: The binding of [3H]DAMGO to mu-opioid sites was measured in the CNS of selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats to test the hypothesis that high alcohol preference is associated with higher densities of mu-opioid receptors. METHODS: Adult, alcohol-naïve male HAD and LAD rats from replicate line 1 were decapitated and their brains frozen in isopentane. Brain sections were incubated with 5 nM [3H]DAMGO, and nonspecific binding was determined in the presence of unlabeled DAMGO. Films were exposed for 60 days, then analyzed using quantitative autoradiography. RESULTS: The densities of [3H]DAMGO binding sites were measured within subregions of neocortex, limbic system, basal ganglia, diencephalon, and brainstem. LAD rats had significantly higher [3H]DAMGO binding (10-30%) than HAD rats within the anterior dorsal hippocampus (CA2), posterior hippocampus (dorsal CA1, and ventral CA1, CA3, and dentate gyrus), thalamus (medial dorsal, lateral, medial dorsal, central, ventral lateral, ventral medial, and ventral medial geniculate nuclei), habenula, and amygdala. No significant interline differences were found in the prefrontal, cingulate, frontal, parietal, temporal, occipital or entorhinal cortices, olfactory tubercle, nucleus accumbens, lateral septum, ventral tegmental area, hypothalamus, caudate-putamen, substantia nigra, claustrum, central gray, or superior colliculus. CONCLUSIONS: The present findings with the HAD and LAD lines do not support the hypothesis that high alcohol preference is associated with higher densities of CNS mu-opioid receptors. Instead, the present results, in combination with previously published findings, suggest that the mu-opioid system may play a complex role in regulating high-alcohol-drinking behavior.

Alcohol Drinking↗