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A G Phillips

Publications and source records attributed to A G Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1996

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats.

Rats were prepared with jugular catheters and assigned randomly to one of three groups: intravenous (IV) self-administration of cocaine, yoked administration of cocaine or vehicle. Rats experienced intermittent administration of cocaine (0.75 mg/kg per injection) or vehicle (0.1 ml/injection) for six test sessions, in accordance with the pattern of injections made by the self-administration group. Sensitization of motor activity between pre-and post-treatment challenges of cocaine (3 mg/kg, IV) was observed after both self- and yoked administration of cocaine but not in the yoked-vehicle group. These data indicate that sensitization as a consequence of drug self-administration may be an important factor in the etiology of addiction.

Animals↗
PubMed1996

Schedule-induced polydipsia and the nucleus accumbens: electrochemical measurements of dopamine efflux and effects of excitotoxic lesions in the core.

The efflux of dopamine (DA) in the nucleus accumbens (NAcc) core during the acquisition of schedule-induced polydipsia (drinking in response to intermittent food presentation) was measured using rapid scan voltammetry. DA efflux increased throughout the SIP sessions, always reaching a peak after the session had terminated. There was, however, no relationship between the acquisition of the drinking response to intermittent food presentation and DA efflux. When water was absent from the test chamber, DA efflux still increased and reached a peak after food delivery was terminated, dissociating drinking and increased DA efflux. Taken in conjunction with previously presented data, these results suggest that the presence of DA in the NAcc core might be necessary for the development of SIP but that its efflux does not bear a systematic relationship to the acquisition of adjunctive behaviour. In a second experiment the effects of NMDA-induced lesions of the NAcc core on the acquisition and performance of SIP were examined. Lesioned rats did not differ to controls in terms of water intake, mean drinking bout length, latency to panel press for food or to begin drinking. The number of drinking bouts/min was reduced in lesioned rats, but did not reach statistical significance; the number of panel presses/min was significantly reduced in lesioned rats. These data demonstrate that the NAcc core is not necessary for the development of SIP but that elements of performance are affected. This suggests that the development of SIP can be fractionated and that different neural elements control different aspects of its expression. These data are used to support the hypothesis that the NAcc core is involved in focusing behaviour and regulating switching between response options.

Animals↗
PubMed1996

A selective role for dopamine in the nucleus accumbens of the rat in random foraging but not delayed spatial win-shift-based foraging.

The role of mesoaccumbens dopamine (DA) in radial-arm maze foraging is assessed by infusing low doses of the DA antagonist haloperidol into the nucleus accumbens (N.Acc.). Infusions of haloperidol (0, 125, 250 or 500 ng/0.5 microliter) into the N.Acc. of well-trained rats dose-dependently increase the number of re-entries to arms (errors) during the random foraging task, in which 4 arms on an 8-arm maze are baited randomly. However, in a separate group of animals, similar infusions produce no impairment when delivered prior to the test phase of the delayed spatial win-shift task, which require the animal to acquire information during a training phase, and to use that information 30 min later, during a test phase. These results suggest that DA neurotransmission in the N.Acc. is crucial for foraging behavior when there is ambiguity about the location of reward in a spatial environment, but is not needed for efficient foraging behavior when an animal has previous information as to the location of rewarding stimuli. The results are discussed with respect to of the underlying physiological interactions between limbic glutamate and mesoaccumbens DA transmission in the N.Acc.

Animals↗
PubMed1996

Does monoamine oxidase inhibition by pargyline increase extracellular dopamine concentrations in the striatum?

The present study examined the possibility that pargyline-induced stimulation of dopamine neurotransmission in the striatum measured by intracerebral microdialysis may be related to alterations in the function of dopamine nerve terminals in close proximity to the implanted microdialysis probe. Changes in extracellular concentrations of dopamine were determined bilaterally in the striata of awake rats by microdialysis with concentric dialysis probes and by chronoamperometry with electrochemical (stearate-graphite paste) recording electrodes, after inhibition of monoamine oxidase by pargyline and subsequent blockade of dopamine uptake by nomifensine. Pargyline (75 mg/kg, i.p.) increased dopamine overflow by 14 nM from a mean basal value of 9 nM as determined from dialysis probes implanted in the right striatum. Pargyline failed, however, to increase basal concentrations of dopamine measured by electrochemical electrodes implanted alone in the contralateral striatum. In contrast, 3 h following pargyline, administration of nomifensine (10 mg/kg, i.p.) increased extracellular dopamine concentrations to a similar magnitude above baseline levels in both right and left striata (135 and 127 nM, respectively). In a separate group of rats, electrochemical electrodes were implanted in the left striatum with the tip of the electrode placed directly adjacent to the lumen of a dialysis probe. In contrast to pargyline's inability to increase basal extracellular dopamine measured at individually implanted electrochemical electrodes in the striatum, pargyline administration increased dopamine concentrations measured at electrodes implanted adjacent to non-perfused dialysis probes to an extent similar to that observed by dialysis alone (25 vs 14 nM, respectively). The present study indicates that pargyline increases dopamine concentrations in the region of striatal tissue immediately adjacent to the shaft of a permanently implanted dialysis probe, but not at the tip of an electrochemical electrode. The former effect appears to reflect an interaction between monoamine oxidase inhibition and the effects elicited by the physical presence of the dialysis probe in tissue.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Improved electrochemical properties of stearate-graphite paste electrodes after albumin and phospholipid treatments.

Stearate-graphite paste electrodes (SGEs) exhibit enhanced dopamine sensitivity and insensivity to asorbic acid electrocatalytic effects in vitro following exposure to unidentified contituents of rat brain tissue homogenates. The present study utilized voltammetry and chronamperometry to compare the electrochemical characteristics of brain-treated SGEs to those treated with potential brain constituent candidates (albumin proteins and phospholipids). Albumin treatments markedly attenuated interference from ascorbate catalytic effects whereas lipids enhanced both electrode capacitance and sensitivity to dopamine. Combined treatments resulted in electrochemical properties that were similar to brain-treated SGEs. Potential mechanisms by which albumin may attenuate ascorbate electrocatalysis of dopamine were investigated using high performance liquid chromatography, with electrochemical detection. The reduction in ascorbate electrocatalytic effects at albumin-treated SGEs may be due to nucleophilic binding of dopamine oxidation products to albumin attached to the electrode surface. Therefore, the unambiguous detection of dopamine by SGEs in vivo may be related to interactions with factors in brain having similar surface-modifying properties.

Animals↗
PubMed1996

Differential effects of lidocaine infusions into the ventral CA1/subiculum or the nucleus accumbens on the acquisition and retention of spatial information.

Reversible, lidocaine-induced lesions of the CA1/subicular subfield of the ventral hippocampus or the shell region of the nucleus accumbens (N.Acc.) were used to assess the roles of these structure during the acquisition and retention of a spatial response as measured by the Morris water-maze task. Acquisition and retention tests were administered over 2 phases of 6 trials, respectively. Rats receiving reversible lesions of the ventral CA1/subiculum prior to the acquisition phase of this task required significantly longer path lengths to find a hidden platform than animals which received control infusions of artificial cerebrospinal fluid. Rats with similar lesions to the N.Acc. were unimpaired. During the retention phase, 30 min after the acquisition phase, rats with prior ventral CA1/subiculum or N.Acc. lesions had similar path lengths to control animals. Lidocaine infusions into either the ventral CA1/subiculum or N.Acc. prior to the retention phase did not impair performance relative to control animals. These results suggest that the N.Acc. is not involved in either the acquisition or retention of spatial information. In contrast, the ventral CA1/subiculum does appear to be involved in the initial use of novel spatial information necessary for the performance of a spatially mediated escape response, but is not involved in the retention or retrieval of previously acquired spatial information.

Anesthetics, Local↗
PubMed1996

Ischemia-induced object-recognition deficits in rats are attenuated by hippocampal ablation before or soon after ischemia.

The literature on the role of the hippocampus in object-recognition contains a paradox: Transient forebrain ischemia (ISC) produces hippocampal damage and severe deficits on the delayed nonmatching-to-sample (DNMS) task, yet hippocampal ablation (ABL) produces milder deficits. Experiment 1 confirmed that pretrained rats display severe DNMS deficits following ISC, but not ABL. Ischemia produced loss of CA1 neurons, but no obvious extrahippocampal damage. In Experiments 2 and 3, ISC rats from Experiment 1 received ABL, and ABL rats received ISC; neither treatment affected DNMS performance. In Experiment 4, rats that received ISC followed 1 hr later by ABL displayed only mild deficits. It is hypothesized that ISC-induced DNMS deficits are due to extrahippocampal damage produced by pathogenic processes that involve the hippocampus.

Animals↗
PubMed1995

Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes.

Huntington's disease (HD) is an incurable neuropsychiatric disease associated with CAG repeat expansion within a widely expressed gene that causes selective neuronal death. To understand its normal function, we have created a targeted disruption in exon 5 of Hdh (Hdhex5), the murine homolog of the HD gene. Homozygotes die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the Hdhex5 mutation display increased motor activity and cognitive deficits. Neuropathological assessment of two heterozygous mice shows significant neuronal loss in the subthalamic nucleus. These studies show that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia.

Animals↗
PubMed1995

Functional differences between the prelimbic and anterior cingulate regions of the rat prefrontal cortex.

The effects of reversible lidocaine-induced lesions of 2 subregions of the rat medial prefrontal cortex (mPFC) were examined on a series of cognitively based foraging behaviors on a radial-arm maze. Lesions of the prelimbic (PL) or anterior cingulate (AC) cortex prior to the retention phase of a delayed-foraging task disrupted performance differentially; rats with PL lesions visited arms in a random manner, whereas rats with AC lesions revisited previously baited arms preferentially. Rats with AC lesions were also impaired on a single-trial foraging task; they made numerous revisits to previously baited arms. PL lesions had no effect on performance of this task in well-trained rats. However, rats trained on the 2-phase task did not adapt to a new foraging strategy after a PL lesions, when they were switched unexpectedly to the single-trial foraging task. These data demonstrate functional heterogeneity within the rat mPFC and suggest that the PL is involved in processes through which recently acquired information is used to organize and modify foraging behavior, whereas the AC may play an important role in response flexibility.

Animals↗
PubMed1994

Selective memory impairments produced by transient lidocaine-induced lesions of the nucleus accumbens in rats.

Reversible lidocaine-induced lesions of the nucleus accumbens (N.Acc.) impaired performance on the spatial win-shift, but not on the cued win-stay, radial arm maze task. Pretraining lesions on the former task did not affect foraging for 4 pellets during either the training or test phases. In contrast, lesions given prior to the test phase significantly disrupted retrieval of 4 pellets on the 8-arm maze. Comparable deficits also were observed in rats trained to forage for 4 pellets on an 8-arm maze without prior win-shift experience. State-dependent drug effects were ruled out by replicating the disruptive effects of lidocaine infusions into the N.Acc. on spatial win-shift performance in rats receiving this treatment prior to both training and test phases. These results suggest that the N.Acc. may interact with the hippocampus to guide foraging behavior requiring memory of previous spatial locations on a maze.

Animals↗
PubMed1993

Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat.

In vivo microdialysis with HPLC-ED was used to measure dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens of the rat, prior, during, and after 15-min periods of electrical brain stimulation at sites in the ventral tegmental area (VTA) that supported intracranial self-stimulation (ICSS). In the first experiment, both ICSS and yoked stimulation of the VTA evoked significant increases in extracellular concentrations of DA, its metabolites, and 5-HIAA. Comparable results from ICSS and yoked groups were interpreted as evidence that the rewarding properties of VTA stimulation were a causal factor in the elevated DA transmission in the nucleus accumbens, rather than intense operant behavior. Further evidence for this hypothesis came from a second set of data in which changes in extracellular DA levels during the measurement of rate/intensity functions for ICSS were positively correlated. 5-HIAA concentrations also increased during ICSS but these changes were not correlated with either ICSS rate or current intensity, suggesting that changes in serotonin metabolism were unlikely to subserve brain stimulation reward in the VTA. These results add to the growing body of evidence linking changes in extracellular DA in the mesolimbic DA system with both brain stimulation reward and the conditioned and unconditioned rewarding effects of biologically relevant stimuli.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Impaired object recognition memory in rats following ischemia-induced damage to the hippocampus.

Transient cerebral ischemia can produce irreversible neuronal damage and permanent learning and memory impairments in humans. This study examined whether ischemia-induced brain damage in rats results in impairments on the delayed nonmatching-to-sample (DNMS) task, a nonspatial recognition task analogous to tests on which amnesic patients display impairments. Male Wistar rats received either sham surgery or 20-min forebrain ischemia induced by bilateral carotid occlusion and hypotension. Four weeks after surgery, ischemic rats were significantly impaired in both learning and performing the DNMS task at retention intervals up to 5 min. Extensive presurgical training did not reduce this impairment. Observable cell loss in ischemic rats was limited to CA1 pyramidal neurons and a subset of cells in the dentate gyrus. The results indicate that ischemic damage to the hippocampus in rats results in recognition memory deficits similar to those produced by ischemic damage in humans.

Animals↗
PubMed1993

A glycine antagonist 7-chlorokynurenic acid attenuates ischemia-induced learning deficits.

Transient global ischemia can result in permanent neuronal damage and impairments in learning and memory. We investigated the therapeutic potential of 7-Chlorokynurenic acid, a potent antagonist at the glycine-modulatory site on the NMDA receptor, in terms of both neuroprotection and behavioral outcome in rats following transient forebrain ischemia. Intraventricular administration of the drug immediately before ischemia significantly attenuated ischemia-induced CA1 pyramidal cell loss. Moreover, ischemic rats treated with 7-Chlorokynurenic acid showed unimpaired acquisition of a delayed nonmatching to sample task 8 weeks following surgery, whereas saline-treated ischemic rats were significantly impaired. These data provide preliminary evidence that the glycine site may be an appropriate target for therapeutic agents in ischemia.

Analysis of Variance↗
PubMed1992

A glycine antagonist reduces ischemia-induced CA1 cell loss in vivo.

Excessive activation of the N-methyl-D-aspartate (NMDA) receptor-channel complex has been implicated as one of the mechanisms by which ischemia-induced neuronal damage is mediated. Elevated glycine levels during ischemia may contribute to damage mediated by the NMDA receptor as glycine binding potentiates NMDA responses, and may be necessary for channel opening. We investigated the protective effects of 7-chlorokynurenic acid--a competitive antagonist at the glycine binding site associated with the NMDA receptor--against hippocampal CA1 cell loss induced by transient forebrain ischemia in rats. Intraventricular administration of the drug immediately before the onset of ischemia significantly attenuated neuronal loss compared to vehicle-treated animals.

Animals↗
PubMed1992

Extracellular dopamine in the rat striatum during ischemia and reperfusion as measured by in vivo electrochemistry and in vivo microdialysis.

The effects of transient global forebrain ischemia and reperfusion on striatal extracellular dopamine levels were analyzed using both in vivo electrochemistry and in vivo microdialysis in urethane-anesthetized rats. Electrochemical records showed that extracellular dopamine levels increased once during the period of ischemia, and a second time during reperfusion. This biphasic pattern was not detected by microdialysis, probably because of the relatively low time resolution of this technique. Microdialysis provided evidence that the voltammetric signal was a measure of dopamine, and also allowed measurement of the metabolites dihydroxyphenylacetic acid and homovanillic acid, both of which decreased during ischemia. The biphasic dopamine pattern seen in rats is similar to that reported previously in gerbils, suggesting that it is a phenomenon common to transient ischemia and reperfusion across different species and models of transient global ischemia. This phenomenon may have important implications for therapeutic intervention in cerebral ischemia.

3,4-Dihydroxyphenylacetic Acid↗