PubMed Health⌕ Search

Biomedical subjects

A G Phillips

Publications and source records attributed to A G Phillips.

At least 37 records · Page 2Linked to original sources
PubMed1999

Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement.

Numerous studies have shown that withdrawal from sustained high doses of psychostimulant drugs such as cocaine or d-amphetamine produces depressive-like symptoms in both rats and humans. The majority of experiments with rodents have assessed the effects of amphetamine withdrawal on reinforcing electrical self-stimulation in different brain regions, but relatively few have examined effects on responding for natural reinforcers. In the present study, two groups of mildly food and water deprived male rats were trained to respond on a lever for a 4% sucrose solution under a progressive ratio schedule of reinforcement. One group was subsequently administered a 4-day regimen of injections of increasing doses of d-amphetamine based on a schedule shown previously to reduce self-stimulation behaviour. Break points were significantly reduced for up to 4 days after the termination of drug administration, suggesting a decreased motivation to obtain the natural reward. A further experiment demonstrated that the identical drug regimen produced no effect upon consumption of the 4% sucrose solution when it was freely available. These results demonstrate that the progressive ratio procedure may be a useful technique for evaluating changes in motivation for natural reinforcing stimuli following withdrawal from psychostimulant drugs.

Animals↗
PubMed1999

Facilitation of sexual behavior in male rats following d-amphetamine-induced behavioral sensitization.

The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, i.p.) or saline were given every other day for a total of ten injections, and this regimen induced behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit, and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore, sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive days). After repeated sexual experience, rats pre-treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female. Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can "cross-sensitize" to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e. level changes) after repeated experience in rats previously treated with d-amphetamine suggests that behavioral sensitization can influence incentive learning.

Animals↗
PubMed1999

Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat.

The present study sought to determine the effect of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in male rats. Tests were conducted every 5 days until stable levels of sexual behavior were obtained. With repeated testing, male rats displayed an increase in their exploration of the testing chambers prior to the introduction of an estrous female. Half of the male rats were then subjected to a 4-day escalating dose schedule of d-amphetamine administration (1-12 mg/kg), while half received vehicle. Twelve hours after the final drug injection, subjects were tested for sexual behavior. Withdrawal from the drug was associated with decrements in several motivational components of sexual behavior, including decreased anticipatory locomotor and increased postejaculatory intervals, while consummatory measures remained largely unaffected. This pattern of sexual deficits resembles those seen in human depressive disorders, and therefore, provides additional support for the use of psychostimulant withdrawal as a rodent model of depression.

Animals↗
PubMed1999

A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

Adaptation, Physiological↗
PubMed1999

Cavaterm thermal balloon ablation for the treatment of menorrhagia.

Fifty patients due to undergo endometrial ablation as a treatment of dysfunctional uterine bleeding were recruited to assess the efficacy and safety of a new thermal balloon ablation system (Cavaterm). The patients were followed up for a mean of 14 months (range 6-24): 34 (68%) have complete amenorrhoea, 12 (24%) only have spotting, two (4%) are eumenorrhoeic, and two (4%) have had failed treatments. There were no major complications, but two patients have required oral antibiotics for suspected endometritis. Although these preliminary results are encouraging, all patients remain under review to determine long term effect of the procedure. Further evaluation is also underway in the form of a randomised trial against endometrial laser ablation.

Catheter Ablation↗
PubMed1998

D1 receptor modulation of hippocampal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat.

Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D1 and D2 receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D1 antagonist SCH-23390 (0.05, 0.5, or 5 microg/&microl), but not the D2 antagonist sulpiride (0.05, 0.5, or 5 microg/microl), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D1 receptors in modulating activity in hippocampal-PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 receptor activation in the PFC and D1 receptor modulation of hippocampal inputs to the PFC. These data suggest that D1 receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA modulation of limbic-PFC circuits during behavior.

Animals↗
PubMed1998

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule.

Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug.

Animals↗
PubMed1998

Chronic mild stress has no effect on responding by rats for sucrose under a progressive ratio schedule.

Exposure of rats to chronic unpredictable mild stress (CMS) has been shown to produce a syndrome in which a wide range of consummatory behaviors are attenuated, resembling a state of anhedonia, which may be reversed by treatment with antidepressant drugs. The aim of the present study was to determine whether CMS would also affect a rat's motivation to respond for a sucrose solution, as assessed by its performance under a progressive ratio (PR) schedule of reinforcement. Control studies demonstrated that break points in nonstressed rats were sensitive to both the concentration of sucrose solution used, as well as the period of food and water deprivation used prior to testing. Exposure of rats to CMS had no effect upon break points when responding under a progressive ratio schedule for either a 1% or 7% sucrose solution, although subjects did display the typical reduction in consumption of a freely consumed 1% sucrose solution. These results are not readily understood within the theoretical framework of the CMS model of anhedonia and imply instead that both the neural and psychological correlates of motivation may be less susceptible to modulation by the effects of CMS than the free consumption of sweet solutions.

Animals↗
PubMed1998

The relation between dopamine oxidation currents in the nucleus accumbens and conditioned increases in motor activity in rats following repeated administration of d-amphetamine or cocaine.

Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellular dopamine.

Animals↗
PubMed1998

Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self-administration or yoked-administration of d-amphetamine.

In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked- or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4-7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of approximately 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were approximately 5 nA above baseline by the fourth day of drug administration and reached approximately 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of approximately 6 nA. These data are discussed with relation to the neurochemistry of drug craving.

Animals↗
PubMed1998

Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat.

Afferents from the basolateral amygdala and dopamine projections from the ventral tegmental area to the nucleus accumbens have both been implicated in reward-related processes. The present study used in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats to determine how basolateral amygdala efferents to the nucleus accumbens synaptically regulate dopamine efflux. Repetitive-pulse (20 Hz for 10 s) electrical stimulation of the basolateral amygdala evoked a complex pattern of changes in monitored dopamine oxidation currents in the nucleus accumbens related to dopamine efflux. These changes were characterized by an initial increase that was time-locked to stimulation, a secondary decrease below baseline, followed by a prolonged increase in the dopamine signal above baseline. The effects of burst-patterned stimulation (100 Hz, 5 pulses/burst, 1-s interburst interval, 40 s) of the basolateral amygdala on the basal accumbens dopamine signal were similar to those evoked by 20 Hz stimulation, with the lack of a secondary suppressive component. Infusions of the ionotropic glutamate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid (APV) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the nucleus accumbens dose-dependently blocked or attenuated the initial and prolonged increases in the dopamine signal following 20 Hz or burst-patterned basolateral amygdala stimulation. Infusions of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine selectively blocked the intermediate suppressive effect of 20 Hz basolateral amygdala stimulation on dopamine oxidation currents. Blockade of glutamate receptors or inhibition of dopamine neuronal activity via infusions of either APV + DNQX, lidocaine or gamma-hydroxybutyric acid, respectively, into the ventral tegmental area did not effect the pattern of changes in the accumbens dopamine signal evoked by basolateral amygdala stimulation. These data suggest that the glutamatergic basolateral amygdala inputs to nucleus accumbens dopamine terminals synaptically facilitate or depress dopamine efflux, and these effects are independent of dopamine neuronal firing activity. Moreover, these results imply that changes in nucleus accumbens dopamine levels following presentation of reward-related stimuli may be mediated, in part, by the basolateral amygdala.

Amygdala↗
PubMed1998

Is barakol anxiolytic?

A recent report suggested that barakol, a biologically active extract of the south-east Asian plant, Cassia siamea, has anxiolytic properties. The purpose of the present study was to replicate and extend these findings by examining the dose-response effects of barakol (0-20 mg/kg) in two pharmacologically validated tests of rat anxiety: the elevated plus-maze and the shock-probe burying tests. Although the purity of our sample of barakol was confirmed by chemical analysis, we found no evidence of its anxiolytic effects in either the plus-maze or shock-probe burying tests.

Analysis of Variance↗
PubMed1998

The validity of continuous automated fluid monitoring during endometrial surgery: luxury or necessity?

Thirty-four consecutive women undergoing endometrial laser ablation, as a treatment of menorrhagia, were recruited to assess the validity of fluid absorption monitoring by a new continuous automated system (AquaSens). The same group of women also had monitoring of fluid absorption carried out by our standard technique of weighing. The intra-class correlation coefficient for the fluid deficit estimated by AquaSens compared to our standard technique of manually weighing the irrigation bags was 0.98 (95% CI 0.96-0.99). Aquasens therefore provides a valid and non-invasive method of continuously monitoring fluid deficit amongst patients undergoing operative hysteroscopy procedures, thereby reducing the risk of unexpected fluid absorption and its potentially fatal sequelae.

Decision Making↗
PubMed1997

Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats.

The Coolidge effect describes the reinitiation of sexual behavior in a "sexually satiated" animal in response to a novel receptive mate. Given the role of the mesolimbic dopamine (DA) system in the initiation and maintenance of motivated behavior, microdialysis was used to monitor nucleus accumbens (NAC) DA transmission during copulation, sexual satiety, and the reinitiation of sexual behavior. In agreement with earlier reports, the presentation of an estrous female behind a screen and copulation were associated with significant increases in NAC DA efflux. Return of NAC DA concentrations to baseline values coincided with a period of sexual satiety, although concentrations of the DA metabolites, dihydroxyphenylacetic acid and homovanillic acid, remained elevated. The presentation of a novel receptive female behind a screen resulted in a slight increase in NAC DA, which was augmented significantly during renewed copulation with the novel female. The present data suggest that the stimulus properties of a novel receptive female may serve to increase NAC DA transmission in a sexually satiated male rat, and this, in turn, may be related to the reinitiation of sexual behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay.

The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that serial transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on serial transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic-cortical-striatal networks.

Afferent Pathways↗
PubMed1997

Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats.

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.

Amnesia↗
PubMed1997

Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens.

The effects of electrical stimulation of the ventral subiculum/CA1 region of the hippocampus on changes in dopamine oxidation current (corresponding to dopamine efflux) in the nucleus accumbens were examined using in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats. Burst-patterned monophasic pulses (10-100 Hz/burst delivered at 0.8-4 Hz) evoked a three-component change in dopamine efflux in the nucleus accumbens with an initial transient increase in the dopamine signal above baseline, followed by an immediate decrease below baseline, and thereafter by a prolonged increase in the dopamine signal above baseline. 6-Hydroxydopamine lesions of the mesoaccumbens dopamine pathway or transection of the fimbria-fornix blocked all of the evoked changes in the dopamine signal. Both the first and third components of enhanced dopamine efflux were blocked by microinfusion into the nucleus accumbens of the ionotropic glutamate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid, 6,7-dinitroquinoxaline-2,3-dione and kynurenate. Burst stimulation-evoked decreases in the dopamine signal were abolished following microinfusions into the nucleus accumbens of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine. These results suggest that ventral subiculum/CA1 glutamatergic inputs to the nucleus accumbens may presynaptically modulate dopamine efflux by synaptic activation of both ionotropic and metabotropic glutamate receptors in the nucleus accumbens. These glutamate-dopamine interactions may constitute part of the mechanisms by which hippocampal signals are integrated through selective modulation of dopamine release in the nucleus accumbens in both physiological and pathological conditions.

Animals↗