Biomedical subjects

A G Phillips

Publications and source records attributed to A G Phillips.

At least 109 records · Page 6Linked to original sources

PubMed1987

Cholecystokinin-induced inhibition of dopamine neurotransmission: comparison with chronic haloperidol treatment.

A dose-dependent inhibition of DA release was observed by in vivo electrochemical techniques after acute i.v. injections of CCK8-S (1.0-8.0 micrograms/kg). The threshold dose was 1.0 microgram/kg, and maximum inhibition of release (90%) was obtained with doses of 4 and 8 micrograms/kg. Injections of CCK8-US (4-20 micrograms/kg) had no effect on DA release. Repeated treatment with haloperidol (0.5 mg/kg s.c.) for 21 days produced a 47% inhibition of DA release in the nucleus accumbens. Apomorphine (50 micrograms/kg) reversed the inhibitory effects of both acute injections of CCK8-S and prolonged haloperidol treatment on DA release. In contrast, apomorphine (50 micrograms/kg) administered alone inhibited DA release, presumably via hyperpolarization of DA neurons. The attenuation of DA release by either an acute injection of CCK8-S or repeated treatment with haloperidol is attributed to the induction of depolarization block in mesolimbic DA neurons. These data may be indicative of antipsychotic properties of CCK8-S.

Animals↗

PubMed1987

Cognition and the basal ganglia: a possible substrate for procedural knowledge.

Disruption of neural activity within the basal ganglia of experimental animals causes selective learning deficits in tasks requiring switching between response strategies. These data along with reports of both general and specific intellectual impairment in patients with neurodegenerative disorders such as Parkinson's disease, appear to support the theory of cognitive functions of the basal ganglia. Recent studies have failed to confirm general cognitive or memory deficits in parkinsonian patients, but have identified deficiencies in devising and executing certain cognitive strategies. Following the lead of theorists such as Squire and Mishkin, this brief review emphasizes the distinction between procedural and declarative knowledge and examines the possible role of the basal ganglia in the acquisition and retention of procedural knowledge.

Animals↗

PubMed1987

Dopamine and preparatory behavior: I. Effects of pimozide.

The involvement of dopaminergic systems in appetitive and ingestive feeding behaviors was investigated in two experiments. Conditioned preparatory responses to a conditional stimulus (CS+) signaling delivery of a meal were attenuated in rats by doses of 0.4 and 0.6 mg/kg of the dopamine receptor antagonist pimozide. In contrast, animals responded in a normal fashion following the delivery of food. Similarly, in a separate study, the 20-min free-feeding intake of liquid diet by rats that had been deprived of food for 23 hr was unaffected by doses of pimozide as high as 0.6 mg/kg. These findings are consistent with the involvement of dopamine in the production of preparatory behaviors elicited by incentive stimuli.

Animals↗

PubMed1987

The role of dopamine in intracranial self-stimulation of the ventral tegmental area.

The role of dopaminergic (DA) neurons in brain stimulation reward produced by electrical stimulation of the ventral tegmental area (VTA) was investigated in the rat. In the first experiment, extensive 6-hydroxydopamine lesions of the ascending fibers of the mesotelencephalic DA projections resulted in significant changes in intracranial self-stimulation (ICS) rate-current intensity functions when the lesion was ipsilateral to the stimulating electrode. Similar contralateral lesions had no effect on these functions, thus ruling out lesion-induced performance deficits as being responsible for the decreases in ICS rates across the wide range of current intensities that occurred after the ipsilateral lesions. In the second experiment, ICS obtained from electrodes in the VTA resulted in significant increases in the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, nucleus accumbens, and olfactory tubercle ipsilateral to the stimulating electrode. The ratios of DOPAC and HVA to DA, considered to be indices of DA utilization, were also increased in these brain regions ipsilateral to the electrode. No changes were observed in the contralateral striatum, nucleus accumbens, and olfactory tubercle. Similar increases were observed in stimulated "yoked" animals that received brain stimulation at identical rates and currents but did not lever-press for this stimulation. The third experiment examined the effects of lever-pressing for food on an FR8 schedule of reinforcement on DA utilization in the striatum, nucleus accumbens, and olfactory tubercle. Despite high rates of responding, no effects were observed on DOPAC:DA or HVA:DA ratios in these brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Long-term increases in dentate granule cell responsivity accompany operant conditioning.

The efficacy of synaptic transmission from the perforant path (PP) to the granule cells in the dentate gyrus (DG) of freely moving rats was monitored electrophysiologically over the course of training in an appetitively motivated, discriminated operant paradigm. Every day, 22 hr after behavioral sessions, evoked potentials were recorded from the DG following stimulation of the PP over range of current intensities and the amplitudes of the population spikes were measured. Behavioral conditions involved training in an operant conditioning paradigm or a session of free-feeding. Significant increases in population spike amplitudes were observed over the 8 d of training, but not over the 8 d of free-feeding. This training-induced increase in granule cell responsivity persisted for at least 10 d following the cessation of behavioral trials and was in many ways comparable to long-term potentiation (LTP), subsequently observed in these same rats 24 hr after tetanic stimulation. These data confirm and extend previous reports of synaptic enhancements following conditioning and suggest that such increases in synaptic efficacy may encode some aspect of learning.

Animals↗

PubMed1986

In vivo electrochemical analysis of cholecystokinin-induced inhibition of dopamine release in the nucleus accumbens.

In vivo electrochemical techniques were used to study the effects of the sulfated (CCK8-S) and unsulfated (CCK8-US) forms of the cholecystokinin octapeptide on dopamine (DA) release in the nucleus accumbens. A dose-dependent inhibition of DA release was observed only with CCK8-S. This inhibitory effect was blocked by the CCK receptor antagonist proglumide, and was reversed by systemic injections of apomorphine. Given that apomorphine can hyperpolarize DA neurons, these data indicate that CCK may inhibit the release of DA by a process of depolarization block and suggest a mechanism by which CCK may regulate overactive mesolimbic DA transmission.

Animals↗

PubMed1986

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.

Animals↗

PubMed1986

Selective effects of pirenperone on analgesia produced by morphine or electrical stimulation at sites in the nucleus raphe magnus and periaqueductal gray.

Pirenperone, a new serotonin antagonist with a selective affinity for the 5-HT2 receptor, was administered in conjunction with tests for the antinociceptive effects of morphine sulphate and electrical brain-stimulation at sites in the periaqueductal gray (PAG) and nucleus raphe magnus (NRM). Nociception was assessed by tail-flick latencies in a warm water bath and pirenperone (0.04-0.16 mg/kg) had no effect on baseline scores. When administered prior to morphine, pirenperone (0.16 mg/kg) caused significant attenuation of analgesia induced by morphine. Comparable effects of pirenperone were observed when analgesia was produced by electrical stimulation of the NRM. In contrast, pirenperone had no effect on the analgesic effects of PAG stimulation. This pattern of results suggests that a system involving supraspinal 5-HT2 receptors may modulate some of the antinociceptive effects of morphine and stimulation of the NRM. The differential effects of pirenperone on stimulation-produced analgesia at sites in the NRM and PAG is consistent with separate neural substrates for the analgesia observed from stimulation of these two brain regions.

Animals↗

PubMed1986

Increased dopamine metabolism in the nucleus accumbens and striatum following consumption of a nutritive meal but not a palatable non-nutritive saccharin solution.

This study examined the concentrations of dopamine (DA) and its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of rats that were either 20 hr food deprived or had been given 1 hr of access to food pellets, a liquid diet, or a palatable 0.4% saccharin solution. Significant increases were observed in the HVA/DA ratio in both structures following ingestion of either liquid diet or food pellets. Increases in the DOPAC/DA ratio were observed only after the ingestion of liquid diet. Ingestion of saccharin solution had no effect on any index of DA activity. These results indicate that the type of food ingested can influence dopaminergic responses to feeding, and argue against an exclusive role for motor or reward processes in determining DA activity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Effects of pimozide on positive and negative incentive contrast with rewarding brain stimulation.

Positive and negative contrast effects with brain-stimulation reward were inferred from significant differences in rate/intensity curves obtained by ascending, random and descending orders of current presentation. The neuroleptic drug pimozide caused a dose-related attenuation of both positive and negative contrast. A dose of 0.1 mg/kg blocked positive contrast obtained by comparing ascending and random rate/intensity curves. Negative contrast and threshold current intensities for brain-stimulation reward at sites in the ventral tegmental area were unaffected by the low dose (0.1 mg/kg) of pimozide. Higher doses of pimozide (0.25, 0.4 mg/kg) blocked both positive and negative contrast effects, and caused a significant elevation in threshold current intensities under the random order condition. Two doses (0.25, 0.4 mg/kg) of pimozide were associated with performance deficits as the response rates at the maximum current intensities were attenuated significantly with each order of current presentation. These demonstrations of both positive and negative contrast are consistent with the theoretical position linking brain-stimulation reward to incentive motivation. Furthermore the effects of the dopamine receptor antagonist pimozide are consistent with a role for dopamine in brain-stimulation reward and also raise the possibility of dopaminergic involvement in incentive contrast phenomena.

Analysis of Variance↗

PubMed1986

Dopaminergic and serotonergic correlates of stimulation-induced circling.

Rotation induced by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus was associated with increases in dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum ipsilateral to the site of stimulation (i.e. contralateral to direction of turning). The concentrations of DA, DOPAC and HVA within the nucleus accumbens (NAS) were not altered. In the olfactory tubercle (OT), concentrations of DA and both metabolites were, in general, elevated ipsilateral to the electrode. However, relative to non-stimulated controls, HVA concentrations were increased bilaterally in rats exhibiting circling. Stimulation-induced circling also resulted in a bilateral enhancement of striatal serotonin (5-HT) metabolism as indicated by elevated 5-hydroxyindoleacetic acid: 5-HT ratios. No changes in 5-HT metabolism were observed in the NAS. The utilization of 5-HT was elevated in the OT ipsilateral to the electrode in rats that exhibited stimulation-induced rotation. While most subjects that exhibited contraversive rotation in response to the stimulation demonstrated enhanced DA activity, the neurochemical changes were not observed in all subjects. As such, it is concluded that while stimulation of the mesotelencephalic DA system can be associated with stimulation-induced rotation it is not necessary for its elicitation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Bilateral augmentation of dopaminergic and serotonergic activity in the striatum and nucleus accumbens induced by conditioned circling.

The involvement of dopaminergic (DA) and serotonergic (5-HT) systems in circling was assessed by determining the neurochemical correlates of circling induced and maintained by two different schedules of water reinforcement. The conditioned circling paradigm was employed in an attempt to replicate reports that levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were increased in the striatum and nucleus accumbens septi (NAS) contralateral to the direction of circling. Rats trained to circle using a continuous schedule of reinforcement did not exhibit any changes in concentrations of DA, DOPAC, or homovanillic acid (HVA). Bilateral increases in 5-HT concentrations were observed in the striatum. Use of an intermittent schedule of reinforcement (FR-2) produced higher rates of circling. In rats maintained on the FR-2 schedule, no changes in DA or its metabolites were observed in the striatum. The ratio of HVA to DA was, however, increased bilaterally, suggesting a bilateral augmentation of DA utilization. Concentrations of DA were lower in the NAS contralateral to direction of turning. While NAS levels of HVA were elevated bilaterally when compared to non-circling controls, HVA was lower in the NAS contralateral to the direction of circling. DA utilization, as estimated by HVA: DA ratios, was increased bilaterally in the NAS. None of the measures of DA activity within the olfactory tubercle (OT) were influenced by circling. Turnover of 5-HT, as estimated by the ratio of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA), was increased bilaterally in the striatum, NAS, and OT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The effects of progabide (SL 76002) on locomotor activity and conditioned place preference induced by d-amphetamine.

The effect of prior treatment with a GABA mimetic, SL 76002 (100 mg/kg i.p.), on amphetamine-induced locomotor activity and conditioned place preferences with amphetamine (1.5 mg/kg i.p.) was investigated. SL 76002 significantly attenuated the motor stimulant effects of amphetamine, without influencing the rewarding properties at least as determined by the place preference procedure. When injected alone, SL 76002 did not affect handling-induced locomotor activation, nor did it exhibit any aversive or reinforcing properties. The results suggest that separate neural systems may subserve the motor and rewarding properties of amphetamine.

Animals↗

PubMed1985

Long-term potentiation facilitates behavioral responding to single-pulse stimulation of the perforant path.

Three experiments were conducted to determine whether long-term potentiation (LTP) could enhance the stimulus properties of electrical brain stimulation. First, a paradigm was developed in which single-pulse stimulation of the perforant path (PP) could acquire control over operant responses. Evoked potentials were recorded from the dentate gyrus (DG) on every trial in order to measure the postsynaptic consequences of the stimulus and to monitor synaptic efficacy in the PP-DG synapses. The second experiment confirmed the relation between the amount of evoked activity and acquisition rate and also showed that transecting the PP impaired performance. In the third experiment, high-frequency stimulation of the PP produced LTP and accelerated subsequent acquisition of behavioral responding to PP stimulation. These results document a clear link between increases in synaptic efficacy and changes in behavior and thereby demonstrate the ability of LTP to serve as at least one component of the neural bases of learning and memory.

Animals↗

PubMed1984

Brain reward circuitry: a case for separate systems.

Anatomical, lesion and pharmacological data pertaining to intracranial self-stimulation are reviewed in the context of multiple independent substrates of brain-stimulation reward. Subsystems related to chemosensitive pathways, motor control and mood are identified. Forebrain dopamine pathways are recognized to be important components of two separate subsystems of reward. Nigrostriatal DA neurons are linked to an extrapyramidal circuit with reinforcement derived from response initiation and it is conjectured that the meso-limbic DA pathway is related to the control and perception of positive affect. Other candidate systems include a trigeminal system in the hind brain that may function independently from forebrain substrates of reward.

Amygdala↗

PubMed1983

Dopaminergic mediation of reward produced by direct injection of enkephalin into the ventral tegmental area of the rat.

A conditioned place preference paradigm was employed to demonstrate the rewarding property of unilateral injections of 200 ng (D-ala2)-met5-enkephalinamide into the ventral tegmental area of the rat brain. This effect was attenuated in a dose-related manner by systemic injections of the dopamine receptor blocker haloperidol. In addition, selective lesions of the ascending dopamine (DA) pathways ipsilateral to the injection site blocked the rewarding effect when DA levels were reduced by more than 90%. Similar lesions in the contralateral hemisphere had no influence on this behavior. These data suggest that forebrain DA pathways can mediate some of the rewarding properties of opioid drugs.

Animals↗

PubMed1983

Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system.

The rewarding properties of systemically administered heroin were investigated with a conditioned place-preference paradigm. Reinforcing effects were observed with all doses of heroin tested (0.5, 1.0, 2.0 mg/kg) as indicated by a significant increase in preference for the place paired with drug injections. No similar change in preference was observed following saline injections. The rewarding effect of heroin (2 mg/kg) was attenuated by pretreatment with haloperidol (0.2 mg/kg), but haloperidol alone did not produce a place aversion. Lesions induced by 6-hydroxydopamine (6-OHDA) of the mesolimbic dopaminergic pathway at the level of the nucleus accumbens also attenuated the heroin-induced place preference. In contrast, depletion of central and peripheral noradrenaline induced by 6-OHDA had no significant effect on heroin-induced place preference. These data suggest an important role for the mesolimbic DA system in mediating the reinforcing effects of heroin.

Animals↗

PubMed1983

Prior training and intermittent retraining attenuate pimozide-induced avoidance deficits.

Although the effects of neuroleptics on avoidance behavior have been studied extensively, no studies have systematically investigated the possible relationship between these effects and prior training. This paper reports the effects of prior training and intermittent retraining on pimozide-induced avoidance deficits. Experiment 1 investigated the effects of pimozide (0.5 or 1.0 mg/kg IP) on one-way avoidance responding in groups of rats (n = 15 or 16) that had received 0, 2, 3, or 10 prior sessions of training (10 trials per session). All trained groups were more resistant to the disruptive effects of the drug than the groups receiving no prior training but the 2, 3, and 10 session pretrained groups did not differ significantly from one another. However, the avoidance responding of the pretrained groups eventually was impaired across the 15 sessions of testing under the drug condition; this effect was shown not to be attributable to an accumulation of the drug with repeated dosing. Experiment 2 showed that periodic retraining in the absence of pimozide reversed the cumulative session-to-session disruptive effects of the low and high dose of pimozide on avoidance responding, a finding not previously reported. The results suggest that dopaminergic systems play a role in the acquisition and maintenance of operant response learning. Avoidance learning fails to occur if training is conducted in untrained, pimozide-treated animals. Pretrained animals, when injected with pimozide, can maintain avoidance responding for several sessions but lose this ability in the continued absence of normal dopamine function; however, intermittent retraining can prevent this eventual loss of avoidance responding.

Animals↗