Biomedical subjects

F Scott Hall

Publications and source records attributed to F Scott Hall.

9 recordsLinked to original sources

PubMed2006

dextro- and levo-morphine attenuate opioid delta and kappa receptor agonist produced analgesia in mu-opioid receptor knockout mice.

We have demonstrated that the antianalgesia induced by dextro-morphine and levo-morphine is not mediated by the stimulation of mu-opioid receptors in male CD-1 mice. We now report that the dextro-morphine and levo-morphine attenuated antinociception produced by delta-opioid receptor agonist deltorphin II and kappa-opioid receptor agonist U50,488H given spinally in the male mu-opioid receptor knockout mice. The tail-flick response was used for the antinociceptive test. Intrathecal injection of levo-morphine (3 nmol) markedly inhibited the tail-flick response in wild type, partially in heterozygous, but not in homozygous mu-opioid receptor knockout mice. Intrathecal pretreatment with dextro-morphine (33 fmol) or levo-morphine (0.3 nmol) for 45 min also attenuated levo-morphine-produced antinociception in wide type mice. Intrathecal pretreatment with dextro-morphine (33 fmol) or levo-morphine (0.3 nmol) for 45 min attenuated the tail-flick inhibition produced by deltorphin II (12.8 nmol) and U50,488H (123.3 nmol) in wide type, heterozygous and homozygous mu-opioid receptor knockout mice. The findings provide additional evidence that mu-opioid receptors are not involved in the antianalgesia induced by dextro-morphine and levo-morphine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2006

Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice.

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

Acoustic Stimulation↗

PubMed2006

Behavioral methods in cannabinoid research.

In the absence of any specific behavioral assay for cannabinoids or endocannabinoids, a cannabinoid-induced profile in a series of four in vivo assays in mice is most commonly used to assess a specific cannabinoid activity at the behavioral level. Thus, when a given compound produces motor depression in an open field, catalepsy on an elevated ring, analgesia on a hot plate, as well as hypothermia, cannabinoid CB1 receptor activation is assumed, although exceptions are possible. The full cannabinoid profile, however, includes for example ataxia in dogs and discrimination learning in rats. In view of (1) the addictive/reward potential of cannabis and the cannabinoids and (2) the multiple roles of the endocannabinoid physiological control system (EPCS) in behavioral functions, including memory, emotionality, and feeding, a number of behavioral techniques have been used to assess the effects of cannabinoids in these functions. In this chapter we will describe the tetrad of cannabinoid-induced effects as well as a series of behavioral assays used in the behavioral pharmacology of marijuana-cannabinoid research. Since the EPCS plays an important role in the developing organism, methods used in the assessment of physical and behavioral development will also be discussed. The techniques include the tetrad, drug discrimination, self-stimulation and self-administration, conditioned place preference/aversion, the plus-maze, chronic mild stress (CMS), ultrasonic vocalizations, cognitive behaviors, and developmental assessment in mouse (and rat) pups.

Animals↗

PubMed2004

mu-Opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine-induced locomotion.

The mu-opioid receptor (OPRM1) is expressed in brain regions implicated in reward and locomotor processes. Reduced reward, not only from opiates, but also from several other abused substances has been observed in mice with lifelong deletions of the OPRM1 gene. To further define the roles of mu-opioid receptors in psychostimulant actions, cocaine psychomotor stimulant and rewarding effects were examined in wild-type (WT), heterozygous and homozygous mu-opioid receptor knockout mice. While mu-opioid receptor knockout did not affect basal locomotion, locomotor stimulant effects of cocaine were enhanced in a within-subjects dose-response experiment. However, further study revealed that in mice injected with 20 mg/kg for the first time, there was no difference in the locomotor-stimulating effects of cocaine between knockout and wild-type mice. In a sensitization study (modeled after the conditions in the dose-response experiment) although not observed in WT mice, OPRM1-/- mice did exhibit cocaine sensitization. By stark contrast, and similar to the effects of other rewarding drugs in OPRM1 KO mice, cocaine reward, as assessed by conditioned place preference, was reduced in both homozygous and heterozygous OPRM1 KO mice. The present results confirm a central role of the mu-opioid receptor in drug reward but opposing effects on locomotor sensitization. The reduced cocaine reward identified in heterozygous mu-opioid receptor knockout mice supports the possibility that humans with fewer available mu-opioid receptors might experience less cocaine reward.

Analysis of Variance↗

PubMed2004

Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DAex) and serotonin (5-HT(ex)) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT(ex) in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DAex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT(ex) can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.

Animals↗

PubMed2004

Molecular mechanisms underlying the rewarding effects of cocaine.

The initially surprising observation that cocaine retains its rewarding effects in dopamine transporter (DAT) knockout (KO) mice led our laboratory to examine the effects of deletion of other monoaminergic genes on cocaine reward. Our initial approach to this problem was to combine DAT KO mice with serotonin transporter (SERT) KO mice to make combined DAT/SERT KO mice. The combination of these knockouts eliminates cocaine reward as assessed in the conditioned place preference (CPP) paradigm. We have also identified evidence that, in the absence of DAT, there is greater participation in cocaine reward by serotonin (SERT) and norepinephrine (NET) transporters. Both NET and SERT blockers (nisoxetine and fluoxetine) produced significant CPPs in DAT KO mice, but not in wild-type (WT) mice. The striking elimination of cocaine CPP in combined DAT/SERT KO mice contrasts with effects that we have identified in combined NET/SERT knockout mice, which display increases in cocaine reward, and with recent reports that suggest that DAT/NET combined KOs retain substantial cocaine CPP. Overall, these studies indicate important requirements for several monoaminergic system genes to fully explain cocaine reward, in particular those expressed by dopamine and serotonin systems.

Animals↗

PubMed2003

Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice.

Brain-derived neurotrophic factor (BDNF) affects the development of brain neurotransmitter systems, including dopamine and serotonin systems that are important for cocaine's rewarding and locomotor stimulatory properties. Human genomic markers within or near the BDNF locus have been linked to or associated with substance abuse. Post-mortem human brain specimens reveal individual differences in the levels of BDNF mRNA and in mRNA splicing patterns. To assess the effects of lifelong alterations in the levels of BDNF expression on a measure of psychostimulant reward, we have compared locomotor stimulant and rewarding effects of cocaine in heterozygous BDNF knockout mice with effects in their wild-type littermates. Heterozygous BDNF knockout mice displayed less locomotion during habituation and less locomotion after cocaine injections. Cocaine-conditioned place preferences were reduced in the BDNF heterozygotes. These mice displayed no significant difference from saline control values at a dose of 10 mg/kg s.c. cocaine, although they exhibited cocaine-induced preference at a 20 mg/kg dose. These data confirm important roles for BDNF in psychostimulant actions, presumably via neurotrophic effects on dopamine and serotonin systems. Furthermore, these data support suggestions that differences in human BDNF expression may underlie associations between markers near the human BDNF gene locus and drug addiction.

Animals↗

PubMed2003

Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review.

Studies in humans suggest that exposure to life stressors is correlated with compulsive drug abuse and relapse to drugs during periods of abstinence. The behavioral and neurobiological mechanisms involved in the effect of stress on drug abuse, however, are not known. Here, we review data from studies using preclinical models in rats on the effect of environmental stressors on opiate and psychostimulant reinforcement, as measured by the intravenous drug self-administration and conditioned place preference procedures, on relapse to these drugs, as measured by the reinstatement procedure, and on the subjective effects of these drugs, as measured by the drug discrimination procedure. The results of the studies reviewed here suggest that while stressors are important modulators of the behavioral effects of opiate and psychostimulant drugs, the effect of stress on behavior in these animal models is stressor-specific, and to some degree, procedure- and drug-class-specific. The review of studies on the neurobiological mechanisms underlying stress-drug interactions in these animal models indicate that central noradrenaline and extrahypothalamic corticotropin-releasing factor mediate the effect of one form of stress (intermittent footshock) on reinstatement of opiate and psychostimulant seeking after prolonged drug-free periods. At present, however, little is known about the neuronal events that mediate the effect of environmental stressors on opiate and psychostimulant reinforcement or discrimination. The broader implications of the data reviewed here for future research and for the treatment of opiate and psychostimulant addiction are briefly discussed.

Animals↗

PubMed2002

Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice.

Several lines of evidence suggest that monoaminergic systems, especially dopaminergic and serotoninergic systems, modulate ethanol consumption. Humans display significant differences in expression of the vesicular and plasma membrane monoamine transporters important for monoaminergic functions, including the vesicular monoamine transporter (VMAT2, SLC18A2) and dopamine transporter (DAT, SLC6A3). In addition, many ethanol effects differ by sex in both humans and animal models. Therefore, ethanol consumption and preference were compared in male and female wild-type mice, and knockout (KO) mice with deletions of genes for DAT and VMAT2. Voluntary ethanol (2-32% v/v) and water consumption were compared in two-bottle preference tests in wild-type (+/+) vs heterozygous VMAT2 KO mice (+/-) and in wild-type (+/+) vs heterozygous (+/-) or homozygous (-/-) DAT KO mice. Deletions of either the DAT or VMAT2 genes increased ethanol consumption in male KO mice, although these effects were highly dependent on ethanol concentration, while female DAT KO mice had higher ethanol preferences. Thus, lifetime reductions in the expression of either DAT or VMAT2 increase ethanol consumption, dependent on sex.

Alcohol Drinking↗