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Biomedical subjects

J M Murphy

Publications and source records attributed to J M Murphy.

At least 19 recordsLinked to original sources
PubMed1998

The novel benzodiazepine inverse agonist RO19-4603 antagonizes ethanol motivated behaviors: neuropharmacological studies.

The novel imidazothienodiazepine inverse agonist RO19-4603 has been reported to attenuate EtOH intake in home cage drinking tests for at least 24 h post-drug administration after systemic administration. In the present study, selectively bred alcohol-preferring (P) rats were trained under a concurrent (FR4-FR4) operant schedule to press one lever for EtOH (10% v/v) and another lever for saccharin (0.05% or 0.75% g/v), then dose-response and timecourse effects of RO19-4603 were evaluated. Systemic RO19-4603 injections (0.0045-0.3 mg/kg; i.p.) profoundly reduced EtOH responding by as much as 97% of vehicle control on day 1. No effects were seen on saccharin responding except with the highest dose level (0.3 mg/kg). In a second experiment, microinjections of RO19-4603 (2-100 ng) directly into the nucleus accumbens (NA) suppressed EtOH responding on day 1 by as much as 53% of control: Control injections dorsal to the NA or ventral tegmental area did not significantly alter EtOH or saccharin responding. On day 2, rats in both experiments received no RO19-4603 treatments; however, all 7 of the i.p. doses, and all 3 of the intra-NA infusions continued to significantly suppress EtOH responding by 43-85% of vehicle control levels. In addition, i.p. injections of RO19-4603 produced a dose-dependent decrease in the slope of the cumulative record for EtOH responding, while concomitantly producing a dose-dependent increase in the slope for saccharin responding. RO19-4603's actions appear to be mediated via recognition sites at GABAA-BDZ receptors which regulate EtOH reinforcement, and not via mechanisms regulating ingestive behaviors. Based on recent in situ hybridization studies in our laboratory, we hypothesize that occupation of alpha4 containing GABAA diazepam insensitive (DI) receptors in the NA, may mediate in part, the RO19-4603 suppression of EtOH responding in EtOH-seeking P rats.

Alcohol Deterrents↗
PubMed1998

Benzodiazepine receptor antagonists modulate the actions of ethanol in alcohol-preferring and -nonpreferring rats.

The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one, 0.05-2 mg/kg) and the beta-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-beta-carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavioral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice test between ethanol (10% v/v) and a saccharin (0.0125% g/v) solution, both antagonists dose-dependently reduced intake of ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of the 4 h limited access. Saccharin drinking was suppressed only with the highest doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxiolytic effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the plus maze test in alcohol-preferring rats, but potentiated the ethanol-induced suppression in alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) attenuated the ethanol (0.5 and 1.5 g/kg)-induced suppression in the open field in alcohol-nonpreferring rats; however, CGS 8216 potentiated the depressant effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These findings provide evidence that benzodiazepine receptor antagonists may differentially modulate the behavioral actions of ethanol in alcohol-preferring and-nonpreferring rats. It is possible that the qualitative pharmacodynamic differences seen in the present study may be related to selective breeding for alcohol preference. The findings indicate the potential for development of receptor specific ligands devoid of toxic effects which may be useful in the treatment of alcohol abuse and alcoholism.

Alcohol Drinking↗
PubMed1998

The dental practitioner's role in protecting children from abuse. 1. The child protection system.

The last British Dental Journal article on child protection was in 1986. Since then there have been major changes in both legislation and approaches to child protection. A local authority child protection specialist and a consultant in paediatric dentistry outline the development of child protection and the dental practitioner's role in the inter-agency child protection system in this, the first of three inter-related articles.

Child↗
PubMed1998

The relationship of school breakfast to psychosocial and academic functioning: cross-sectional and longitudinal observations in an inner-city school sample.

OBJECTIVE: To determine if a relationship exists between participation in a school breakfast program and measures of psychosocial and academic functioning in school-aged children. METHODS: Information on participation in a school breakfast program, school record data, and in-depth interviews with parents and children were collected in 1 public school in Philadelphia, Pa, and 2 public schools in Baltimore, Md, prior to the implementation of a universally free (UF) breakfast program and again after the program had been in place for 4 months. One hundred thirty-three low-income students had complete data before and after the UF breakfast program on school breakfast participation and school-recorded measures, and 85 of these students had complete psychosocial interview data before and after the UF breakfast program. Teacher ratings of behavior before and after the UF breakfast program were available for 76 of these students. RESULTS: Schoolwide data showed that prior to the UF breakfast program, 240 (15%) of the 1627 students in the 3 schools were eating a school-supplied breakfast each day. Of the 133 students in the interview sample, 24 (18%) of the students ate a school-supplied breakfast often, 26 (20%) ate a school-supplied breakfast sometimes, and 83 (62%) ate a school-supplied breakfast rarely or never. Prior to the UF breakfast program, students who ate a school-supplied breakfast often or sometimes had significantly higher math scores and significantly lower scores on child-, parent-, and teacher-reported symptom questionnaires than children who ate a school-supplied breakfast rarely or never. At the end of the school term 4 months after the implementation of the UF breakfast program, school-supplied breakfast participation had nearly doubled and 429 (27%) of the 1612 children in the 3 schools were participating in the school breakfast program each day. In the interview sample, almost half of the children had increased their participation. Students who increased their participation in the school breakfast program had significantly greater increases in their math grades and significantly greater decreases in the rates of school absence and tardiness than children whose participation remained the same or decreased. Child and teacher ratings of psychosocial problems also decreased to a significantly greater degree for children with increased participation in the school breakfast program. CONCLUSION: Both cross-sectional and longitudinal data from this study provide strong evidence that higher rates of participation in school breakfast programs are associated in the short-term with improved student functioning on a broad range of psychosocial and academic measures.

Achievement↗
PubMed1998

Rats self-administer carbachol directly into the nucleus accumbens.

The potential reinforcing effect of the muscarinic cholinergic agonist carbachol within the nucleus accumbens (ACB) was examined in female Wistar rats by using the technique of intracranial self-administration. Rats dose dependently self-administered solutions of 0.0-6.6 mM (in a volume of 100 nL per injection) directly into the ACB. Rats self-administered the 3.3 and 6.6 mM doses significantly more than the group given only vehicle. The caudate putamen did not support reliable self-administration of the 6.6-mM dose. Rats exhibited preference for the lever that produced infusions of 3.3 and 6.6 mM carbachol into the ACB over the lever that had no consequence. The self-infusion of the 6.6-mM dose into the ACB was inhibited by the coadministration of the muscarinic antagonist scopolamine (0.25 mM), but not by the nicotinic antagonist mecamylamine (6.6 mM). The present results suggest that direct activation of muscarinic receptors within the ACB supports self-administration and could result from reinforcement or from elicitation of a novel stimulus.

Animals↗
PubMed1998

Regional differences within the rat ventral tegmental area for muscimol self-infusions.

The present study examined the effects of activating GABA(A) receptors in the anterior and posterior regions of the ventral tegmental area (VTA) on operant reinforcement behavior, using the technique of intracranial self-administration. Rats were given the opportunity to self-administer vehicle alone (artificial CSF) and vehicle containing 25, 50, and 100 microM muscimol, a GABA(A) agonist, into the anterior or posterior VTA during four sessions (3 h/session) in standard two-lever operant chambers. Rats received five times greater infusions of 50 and 100 microM muscimol than vehicle into the posterior VTA; both doses significantly increased responding above vehicle levels on the active and inactive (control) levers equally. When the response requirement for muscimol infusions was increased from a fixed-ratio 1 (FR1) to FR3 in a single-lever chamber, the total session responses increased approximately twofold. Muscimol was not self-infused when cannula placements were in the anterior VTA. The self-infusion of muscimol into the posterior VTA was attenuated by coadministration of picrotoxin. Overall, the results suggest that the activation of GABA(A) receptors in the posterior VTA produces goal-directed behavior.

Animals↗
PubMed1998

Serotonin3 receptor antagonism of alcohol intake: effects of drinking conditions.

The effects of 5-HT3 receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01-3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1-3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT3 antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT3 antagonists on ethanol intake.

Alcohol Drinking↗
PubMed1998

Relationship between hunger and psychosocial functioning in low-income American children.

OBJECTIVE: Using large-scale surveys from nine states, the Community Childhood Hunger Identification Project (CCHIP) estimates that 8% of American children under the age of 12 years experience hunger each year. CCHIP operationalizes child hunger as multiple experiences of parent-reported food insufficiency due to constrained resources. The current study examined the relationship between food insufficiency and school-age, low-income children's psychosocial functioning. The study also assessed the interinformant (parent versus child) reliability and time-to-time reliability of the CCHIP measure. METHOD: Two hundred four school-age children and their parents from four inner-city public schools were interviewed using parent, teacher, and clinician report measures of psychosocial functioning. Ninety-six children and their parents were reinterviewed 4 months later. RESULTS: Hungry and at-risk for hunger children were twice as likely as not-hungry children to be classified as having impaired functioning by parent and child report. Teachers reported higher levels of hyperactivity, absenteeism, and tardiness among hungry/at-risk children than not-hungry children. Parent and child reports of hunger were significantly related to each other, and time-to-time reliability of the CCHIP measure was acceptable. CONCLUSIONS: Results of this study suggest that intermittent experiences of food insufficiency and hunger as measured by CCHIP are associated with poor behavioral and academic functioning in low-income children. The current study also supports the validity and reliability of the CCHIP measure for assessing hunger in children.

Adolescent↗
PubMed1998

Hunger in children in the United States: potential behavioral and emotional correlates.

OBJECTIVE: Results from a recent series of surveys from 9 states and the District of Columbia by the Community Childhood Hunger Identification Project (CCHIP) provide an estimate that 4 million American children experience prolonged periodic food insufficiency and hunger each year, 8% of the children under the age of 12 in this country. The same studies show that an additional 10 million children are at risk for hunger. The current study examined the relationship between hunger as defined by the CCHIP measure (food insufficiency attributable to constrained resources) and variables reflecting the psychosocial functioning of low-income, school-aged children. METHODS: The study group included 328 parents and children from a CCHIP study of families with at least 1 child under the age of 12 years living in the city of Pittsburgh and the surrounding Allegheny County. A two-stage area probability sampling design with standard cluster techniques was used. All parents whose child was between the ages of 6 and 12 years at the time of interview were asked to complete a Pediatric Symptom Checklist, a brief parent-report questionnaire that assesses children's emotional and behavioral symptoms. Hunger status was defined by parent responses to the standard 8 food-insufficiency questions from the CCHIP survey that are used to classify households and children as "hungry," "at-risk for hunger," or "not hungry." RESULTS: In an area probability sample of low-income families, those defined as hungry on the CCHIP measure were significantly more likely to have clinical levels of psychosocial dysfunction on the Pediatric Symptom Checklist than children defined as at-risk for hunger or not hungry. Analysis of individual items and factor scores on the Pediatric Symptom Checklist showed that virtually all behavioral, emotional, and academic problems were more prevalent in hungry children, but that aggression and anxiety had the strongest degree of association with experiences of hunger. CONCLUSION: Children from families that report multiple experiences of food insufficiency and hunger are more likely to show behavioral, emotional, and academic problems on a standardized measure of psychosocial dysfunction than children from the same low-income communities whose families do not report experiences of hunger. Although causality cannot be determined from a cross-sectional design, the strength of these findings suggests the importance of greater awareness on the part of health care providers and public health officials of the role of food insufficiency and hunger in the lives of poor children.

Affective Symptoms↗
PubMed1998

The family APGAR and psychosocial problems in children: a report from ASPN and PROS.

BACKGROUND: Our study examined whether the lack of social support as measured by the Family APGAR was related to parents' and physicians' identification of child psychosocial problems and sociodemographic and symptom characteristics of the children screened. METHODS: The parents of 9626 children, ages 4 to 15 years, seen for outpatient medical visits participated in this national study. Parents completed the Family APGAR and the Pediatric Symptom Checklist (PSC), a measure of psychosocial dysfunction. Physicians rated the presence of a new or recurrent psychosocial problem in the child. RESULTS: Children from families with a lack of social support were 4.3 times as likely to receive scores indicating impairment on the PSC and 2.2 times as likely to be identified as having psychosocial problems by physician report. Families with low social support were significantly more likely to report low parental educational achievement, single parent status, and a history of mental health services for the child. Fifty percent of children from families with low social support were identified as having a psychosocial problem by either the PSC or physician rating, or both; however, only 21% of the children identified with psychosocial impairment by these two measures had scores indicating poor family functioning on the Family APGAR. CONCLUSIONS: A lack of family social support is associated with child psychosocial dysfunction as assessed by two different measures. However, the Family APGAR was not a sensitive measure of child psychosocial problems, and thus it supplements, but does not replace, information concerning the child's overall psychosocial functioning.

Adolescent↗
PubMed1998

High-affinity benzodiazepine antagonists reduce responding maintained by ethanol presentation in ethanol-preferring rats.

In the present study, we examined two high-affinity and selective benzodiazepine (BDZ) receptor antagonists (ZK 93426, CGS 8216) in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. The in vivo actions of CGS 8216 (1-30 mg/kg) and ZK 93426 (5-75 mg/kg) were examined after intraperitoneal or oral administration. Flumazenil (10-40 mg/kg) was used as a reference BDZ antagonist. EtOH (10% v/v) and saccharin (0.05 g/v) solutions were concurrently available for 30 min each day under a two-lever fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. A 40 mg/kg intraperitoneal injection of flumazenil given on the first injection day (day 1) nonsignificantly reduced control levels of responding maintained by EtOH by 36%. No effects were observed 24 hr after drug administration (day 2). Oral administration of flumazenil was without effect. On day 1, intraperitoneal administration of CGS 8216 (1-20 mg/kg) and ZK 93426 (1-50 mg/kg) reduced control levels of responding maintained by EtOH by 44% to 73%; on day 2, EtOH maintained responding continued to be suppressed with the highest doses (> or = 20 mg/kg) suppressing control levels of responding by as much as 62%. Oral administration of higher doses of CGS 8216 (5-30 mg/kg) and ZK 93426 (10-75 mg/kg) reduced responding maintained by EtOH by as much as 54% to 84% of controls; however, no effects were seen on day 2. Only the highest intraperitoneal dose of ZK 93426 (50 mg/kg) suppressed responding maintained by saccharin. These findings demonstrate that some BDZ antagonists decrease responding maintained by EtOH. The findings suggest that certain BDZ antagonists may have potential as pharmacotherapies to prevent or decrease EtOH abuse in humans.

Animals↗
PubMed1998

The alcohol deprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions.

The alcohol-deprivation effect (ADE) was examined under 4-hr operant and 24-hr free-choice alcohol access in the alcohol-preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR-5/FR-1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long-lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.

Alcohol Drinking↗
PubMed1997

Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward.

The objectives of this study were to examine the involvement of D1 and D2 receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1 and D2 agonists was used to determine whether activating D1 and/or D2 receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mM (25, 50, and 100 pmol/100 nl of infusion), neither the D1 agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2 agonist (-)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mM each, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mM R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1 antagonist, or 0.50 mM S(-)-sulpiride, a D2 antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mM) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Comparison of rats selectively bred for high and low ethanol intake in a forced-swim-test model of depression: effects of desipramine.

This investigation examined if there is a relationship between selective breeding for high or low alcohol intake and immobility in a force-swim-test (i.e., "behavioral despair") model of depression. Time spent immobile in a water-filled cylinder was measured in the alcohol-preferring (P and nonpreferring (NP) lines of rats, and in the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines. Each rat was tested for 2 10-min trials administered 24 h apart, and pretreatment with saline or desipramine (10.0 or 20.0 mg desipramine/kg b.wt. i.p.) also was evaluated. Drug was administered immediately after Trial 1 and again 1 h before Trial 2. When tested without pretreatment in Trial 1 or with saline pretreatment in Trial 2, NP rats spent significantly more time immobile than did P rats, but no comparable line differences were found when HAD and LAD rats were tested. Desipramine pretreatment reduced the time spent immobile in rats of the 2 alcohol-nonpreferring lines (i.e., the NP and LAD rats), but had no significant effect in rats of the 2 alcohol-preferring lines (the P and HAD rats). These findings do not support the hypothesis that there is a functional relationship between high alcohol drinking and susceptibility to "behavioral despair" as measured by the forced-swim test. The results with desipramine suggest that selection for high alcohol intake may be associated with insensitivity to desipramine.

Alcohol Drinking↗
PubMed1997

Alcohol intake of P rats is regulated by muscarinic receptors in the pedunculopontine nucleus and VTA.

Experiments were conducted to determine whether muscarinic receptors within the pedunculopontine nucleus (PPN) and ventral tegmental area (VTA) are involved in regulating ethanol drinking behavior in the alcohol-preferring P line of rats. Female P rats were given limited access (2 h/day) to 10% (v/v) ethanol and 0.0125% (g/100 ml) saccharin solutions. Food was available ad libitum. Cholinergic agents were microinjected unilaterally into the PPN or VTA immediately prior to ethanol access. Intra-PPN carbachol (1-4 microg/0.5 microl), which can inhibit cholinergic neuronal activity within the PPN, decreased ethanol (70% decrease at the highest dose; p < 0.05) and saccharin (90% decrease at the highest dose; p < 0.05) intake in a dose-dependent manner within the first 30 min. Intra-PPN scopolamine (5-15 microg/0.5 microl), which can stimulate cholinergic neuronal activity within the PPN, decreased ethanol intake in a dose-dependent manner within the first 30 min (65% decrease at the highest dose; p < 0.05) without reducing saccharin intake. Intra-VTA methylscopolamine (1-10 microg/0.5 microl), a muscarinic antagonist, significantly (p < 0.05) reduced ethanol (60% decrease at the highest dose) and saccharin (50% decrease at the highest dose) intakes during the 2-h access period. Intra-VTA carbachol, a cholinergic agonist (1 and 2 microg/0.5 microl) decreased ethanol consumption in a dose-dependent manner within the first 60 min (50% decrease at the highest dose) without reducing saccharin intake. Overall, these results support an involvement of the cholinergic PPN-VTA system in regulating alcohol drinking and general consummatory behaviors of the P line of rats.

Alcohol Drinking↗