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Biomedical subjects

A G Phillips

Publications and source records attributed to A G Phillips.

At least 91 records · Page 5Linked to original sources
PubMed1989

Neurochemical correlates of conditioned circling within localized regions of the striatum.

Two experiments were conducted to determine the effects of conditioned circling on the concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) within discrete regions of the striatum (STR). The first study assessed the inherent regional distributions of these compounds with respect to the three primary axes: anterior-posterior, dorsal-ventral and medial-lateral. Concentrations of DA, DOPAC and HVA and the ratios of each metabolite to DA were found to vary across each dimension. However, the topographical distribution of each compound was unique. The results of the first experiment confirm that the STR is not a homogeneous structure. It is possible that the regional variations in dopamine metabolism underly the diverse functions which the STR is thought to modulate. The second experiment determined whether specific regions of the STR were differentially involved in the mediation of conditioned circling. DA metabolism, as estimated by metabolite concentrations and metabolite to DA ratios, was bilaterally increased within the anterior dorsomedial and dorsolateral STR, relative to noncircling, water-deprived controls. DOPAC and the corresponding ratio were enhanced selectively within the dorsomedial region, whereas HVA and its ratio to DA were increased preferentially within the dorsolateral STR. The ratio of DOPAC to DA was also enhanced within the anterior ventromedial STR. No other significant neurochemical effects were detected. These results support the hypothesis that the dorsal STR critically subserves circling. Moreover, it is possible that the medial and lateral regions of the dorsal STR are differentially involved in circling. These results also confirm previous reports of bilateral augmentation of striatal DA metabolism in association with high rates of conditioned circling.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Differential effects of cholinergic drugs on discriminative cues and self-stimulation produced by electrical stimulation of the ventral tegmental area.

Cholinergic receptors have been shown to modulate a subset of discriminative cues produced by electrical stimulation of the ventral tegmental area (VTA) in rats. The present study identified the specific cholinergic receptor type modulating these electrical brain-stimulation (EBS) cues, and assessed whether these receptors also mediated the rewarding effects of VTA EBS. The EBS cues were enhanced by the acetylcholinesterase inhibitor physostigmine and the muscarinic receptor agonists pilocarpine and RS-86, whereas the nicotinic receptor agonist nicotine had no effect. The enhancing effects of pilocarpine or RS-86 were attenuated by the muscarinic antagonist scopolamine. The EBS cues were not affected when scopolamine was injected alone, although high doses disrupted discriminated responses. Intracranial self-stimulation (ICSS) rates were depressed by physostigmine and pilocarpine and increased by nicotine and scopolamine. These results indicated a facilitatory influence of muscarinic receptors on the EBS cues, and an inhibitory role in VTA ICSS. Nicotinic receptor activation did not affect the EBS cues, but facilitated ICSS. These differential effects of cholinergic receptor activation point to a dissociation of the specific EBS cues measured in this study from the rewarding effects of VTA stimulation.

Animals↗
PubMed1989

Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs.

The classical neuroleptic drugs haloperidol and pimozide have a strong disruptive effect on the acquisition of conditioned avoidance responding (CAR), yet have relatively little impact on the performance of previously acquired responses. Separate experiments compared the effects of haloperidol, two atypical neuroleptics, thioridazine and clozapine, and a substituted benzamide, metoclopramide, on one-way avoidance by rats. Thioridazine (10-50 mg/kg) and clozapine (1.25-10.0 mg/kg) disrupted both acquisition and performance of CAR. In contrast, haloperidol (0.075-0.150 mg/kg) and metoclopramide (5.0-7.5 mg/kg) completely blocked the acquisition of CAR, yet initially produced only a slight disruption in the performance of a previously acquired response. The ineffectiveness of the atypical neuroleptics in producing a complete disruption of acquisition of CAR may be due to the anticholinergic properties of these drugs. Alternatively, the differences between metoclopramide and the atypical neuroleptics may be due to a preferential effect of metoclopramide on striatal or amygdaloid dopamine neurotransmission. These results suggest that caution should be exercised in using CAR as an animal model for assessing the antipsychotic potential of new pharmacological agents.

Animals↗
PubMed1989

Differential effects of dopamine receptor antagonists on the sexual behavior of male rats.

In the present experiments, the dose-response effects of the dopamine (DA) receptor antagonists haloperidol, pimozide, clozapine, sulpiride, and metoclopramide, were assessed on patterns of copulatory behavior in intact, sexually active male rats with a high level of sexual experience and performance. The typical neuroleptics haloperidol (0.01-0.5 mg/kg) and pimozide (0.1-5.0 mg/kg) dose-dependently delayed the initiation of copulation and reduced the number of intromissions that preceded ejaculation. The atypical neuroleptics clozapine (0.1-5.0 mg/kg), and sulpiride (0.1-5.0 mg/kg) dose-dependently delayed the initiation of copulation but had no effect on copulatory behavior once it was initiated. In contrast, metoclopramide dose-dependently reduced ejaculation but had no effect on the ability of rats to initiate copulation. These experiments suggest that aspects of copulatory behavior in male rats are affected differently by DA antagonists depending upon their site of action in the brain. Blockade of mesolimbic DA receptors by typical and atypical neuroleptics may delay the initiation of copulation, whereas blockade of mesostriatal DA receptors by typical neuroleptics and metoclopramide may decrease the ejaculation threshold.

Animals↗
PubMed1989

Dopamine and preparatory behavior: II. A neurochemical analysis.

Changes in the activity of dopamine-containing systems in relation to preparatory and consummatory feeding responses were investigated. In Experiment 1 rats were conditioned to associate food delivery with the presentation of a conditional stimulus (CS+). When sacrificed after exposure to the CS+ alone on a test trial, the ratio of the dopamine metabolite 3,4-dihydroxyphenylacetic acid to dopamine (DOPAC/DA ratio) was increased significantly in the nucleus accumbens. A similar trend in the ratio of homovanillic acid to dopamine (HVA/DA ratio) was also observed. Similar increases were observed in the striatum, but these were not statistically significant. In contrast, no increases were observed in the DOPAC/DA ratio or the HVA/DA ratio in either brain region when rats were permitted to consume an unsignaled meal for 7 min. These findings suggest that activation of dopamine terminals in the nucleus accumbens occurs during the anticipation of a meal, at which times the rat is engaged in preparatory feeding behaviors, but does not accompany the performance of short bouts of consummatory feeding behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Influence of inherent directional biases on neurochemical consequences of conditioned circling.

High rates of conditioned circling have been associated with a bilateral increase in striatal (STR) dopamine (DA) metabolism in rats. Experiments 1 and 2 examined the extent to which inherent directional biases, which are critical in determining the magnitude and direction of drug-induced circling, would influence the acquisition and performance of conditioned circling. No behavioral effects were evident. However, a symmetrical bilateral enhancement in DA metabolism was observed in the STR irrespective of directional biases. These results provide further evidence for the bilateral involvement of the mesotelencephalic DA projection in conditioned circling. Although conditioned circling could be established and maintained by reinforcing the response with food (Experiment 3), food itself influenced DA metabolism and therefore precluded the detection of changes in DA metabolism specific to the circling response. Specifically, DA metabolism was augmented to a similar extent in animals given noncontingently presented food.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Dopamine and preparatory behavior: III. Effects of metoclopramide and thioridazine.

The effects of metoclopramide and thioridazine on feeding behaviors of male hooded rats were investigated in 2 experiments. Metoclopramide (2.5-7.5 mg/kg) attenuated conditioned preparatory responses to a conditional stimulus signaling delivery of a meal. However, consummatory responses were affected only by the highest dose. Similar effects had previously been observed following administration of pimozide (Blackburn, Phillips, & Fibiger, 1987). Thioridazine (10-30 mg/kg) had no significant effect on any measure of feeding behavior. The different effects of the 2 drugs may be related to their preferential actions at dopamine terminals in anatomically distinct regions of the forebrain.

Animals↗
PubMed1988

Independence of amphetamine reward from locomotor stimulation demonstrated by conditioned place preference.

The conditioned place preference (CPP) paradigm is used widely as a measure of a drug's rewarding properties. The present study examined whether the CPP produced by amphetamine is dependent on the locomotor stimulation that is produced by the drug. An earlier study (Swerdlow and Koob 1984) found that interfering with locomotor stimulation using restraint during the drug treatment blocked CPP. The present study examined whether this effect of restraint was indeed due to restriction of locomotion or was due to restraint maintaining the stimulus novelty of the CPP apparatus. The first experiment showed that novelty of the apparatus itself was a potent factor in the CPP paradigm and was capable of producing a place preference. The second experiment showed that restraint alone could produce a CPP, as would be expected if it maintained stimulus novelty of the apparatus. It also showed that although a CPP to amphetamine could be blocked by restraining the animals during drug treatment, prior habituation to the apparatus to reduce stimulus novelty before treatment negated the effect of restraint on amphetamine CPP. These results indicate that rats can demonstrate a CPP produced by amphetamine even when their activity is restrained. This suggests that the drug's rewarding properties are not dependent on locomotor stimulation.

Amphetamine↗
PubMed1988

Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events.

Three experiments were performed to determine if stimuli previously paired with the reinforcing effects of fentanyl elicit changes in the activity of dopaminergic neurons that are similar to the unconditional effects of the drug. Experiment 1 characterized the unconditional effects of fentanyl (0.04 mg/kg SC) on neurochemical indices of dopaminergic activity in rats. Both acute and repeated fentanyl injections (five injections administered at 48-h intervals) increased the concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) within the striatum (STR), nucleus accumbens (NAS), and olfactory tubercle (OT). Acute injections elicited a greater increase in metabolite concentrations in the NAS than in the STR, suggesting that there are regional differences in the sensitivity of dopaminergic neurons to fentanyl. In experiments 2 and 3, fentanyl (five injections; 0.04 mg/kg SC) was paired with environmental stimuli using a place preference conditioning paradigm. The fentanyl-paired stimuli failed to elicit conditional changes in DOPAC or HVA concentrations within the STR, NAS, or OT even though rats exhibited a preference for the drug-paired compartment of the shuttle box. These results indicate that the secondary reinforcing effects of stimuli previously paired with fentanyl may not reflect the ability of these stimuli to elicit measurable changes in the activity of mesolimbic or nigrostriatal dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Conditioned circling in rats: bilateral involvement of the mesotelencephalic dopamine system demonstrated following unilateral 6-hydroxydopamine lesions.

High rates of conditioned circling have previously been associated with a bilateral augmentation of striatal dopamine metabolism. These results suggest that both striata subserve this response. The present experiment further assessed this possibility by determining the effects of unilateral 6-hydroxydopamine lesions of the mesotelencephalic dopamine system on conditioned circling. Rats were initially trained to circle in their preferred direction for water reinforcement. Upon establishment of this response, they received unilateral lesions at the level of the lateral hypothalamus either contralateral or ipsilateral to the reinforced direction of circling. Reinforced responding was virtually abolished in rats with contralateral lesions. In contrast, rats lesioned ipsilateral to the direction of reinforced circling exhibited only a 50% decrease in rate of reinforced responding. Non-reinforced responding was increased only in rats with contralaterally placed lesions. Following 5 postoperative test sessions, the experimental contingencies were reversed. 'Ipsilaterally lesioned' rats were now required to circle away from their lesion whereas 'contralaterally lesioned' rats had to turn towards their lesion. The 'Contralateral' group acquired the reversal, such that reinforced responding occurred more frequently than non-reinforced responding. However, reinforced rates of responding did not reach preoperative rates. Conversely, 'ipsilaterally lesioned' rats could not learn to turn contraversively and now made more non-reinforced than reinforced responses. These findings suggest that conditioned circling is mediated by a bilateral involvement of the mesotelencephalic dopaminergic systems. However, the specific role of each side appears to be dependent upon its relationship with the direction of circling emitted.

Animals↗
PubMed1987

Cholecystokinin facilitates ejaculation in male rats: blockade with proglumide and apomorphine.

Systemic administration of the active, sulfated form of cholecystokinin-octapeptide (CCK-8S), at a dose known to inhibit dopamine (DA) release, significantly reduced the latency to ejaculate and number of intromissions preceding ejaculation in sexually active male rats. This effect was identical to that reported for low doses of the DA receptor agonist apomorphine, which bind preferentially to presynaptic DA autoreceptors. The facilitatory effect of CCK-8S on ejaculation was blocked by the putative CCK receptor antagonist proglumide and by a presynaptic dose of apomorphine. Blockade of the effect of CCK-8S with a presynaptic dose of apomorphine is consistent with CCK induction of depolarization block in DA neurons. These data suggest that CCK-8S and apomorphine may reduce the ejaculation threshold in sexually active male rats by inhibition of DA release via two different mechanisms of action.

Animals↗
PubMed1987

Increased in vivo tyrosine hydroxylase activity in rat telencephalon produced by self-stimulation of the ventral tegmental area.

Changes in the activity of dopaminergic neurons associated with intracranial self-stimulation of the ventral tegmentum were assessed by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD-1015. When compared to implanted unstimulated controls, DOPA concentrations were elevated significantly in the nucleus accumbens, striatum and olfactory tubercle in the hemisphere ipsilateral to the electrode, after a 30 min session of self-stimulation. The concentration of DOPA in the contralateral nucleus accumbens and striatum did not differ from control levels, although relative to control values it was significantly increased in the contralateral olfactory tubercle. A similar analysis of in vivo tyrosine hydroxylase activity in these brain regions following a 30 min session of lever pressing for food reward on a fixed-ratio (FR-8) schedule failed to reveal any significant changes relative to control subjects. These results are consistent with a role for dopamine in brain-stimulation reward obtained from electrical stimulation of the ventral tegmental area but do not provide evidence for dopaminergic mediation of the rewarding properties of food.

Animals↗
PubMed1987

Evidence of Pavlovian conditioned fear following electrical stimulation of the periaqueductal grey in the rat.

Stimulation of the periaqueductal grey (PAG) has been used to support aversive conditioning in a variety of species with several experimental paradigms. However, it has not been clearly demonstrated whether the behavioral changes produced by PAG stimulation in these paradigms are mediated by associative or nonassociative mechanisms. The present studies demonstrate that electrical stimulation of the PAG in the rat may be used to support associative learning in a Pavlovian paradigm. In each experiment, a fully controlled conditional emotional response (CER) procedure was used to examine the unconditional aversive properties of PAG stimulation. In Experiment 1a, weak associative conditioning was observed when a light CS was paired with PAG stimulation over 6 conditioning trials. In Experiment 1b, robust associative conditioning was obtained with a light CS when 18 conditioning trials were used. In Experiment 2, robust associative conditioning was demonstrated with a tone CS when 6 conditioning trials were used. The results parallel those found when other aversive stimuli are used as a UCS (e.g., footshock or intraorbital air puff), and because the present experiments included the proper control procedures the results clearly indicate that the behavioral changes produced by PAG stimulation are mediated by associative Pavlovian learning mechanisms rather than nonassociative mechanisms such as sensitization or pseudoconditioning. The present technique may be useful for assessing the neuroanatomical and neurochemical substrates underlying the aversive effects of brain-stimulation, and for screening the effects of drugs on the conditional and unconditional responses produced by such stimulation.

Acoustic Stimulation↗
PubMed1987

Dissociation of dopaminergic and non-dopaminergic substrates for cues produced by electrical stimulation of the ventral tegmental area.

The present study provides evidence for the existence of multiple substrates for cues produced by electrical stimulation of the ventral tegmental area in rats. Two different procedures were employed to assess the effects of amphetamine and haloperidol on the discrimination of high and low intensity cues produced by electrical brain stimulation (EBS). When the procedure involved frequent presentation of brief trials, amphetamine and haloperidol had no effect on the discrimination of EBS. In contrast, when the trials were less frequent and extended in duration, amphetamine enhanced the perceived intensity of the cues whereas haloperidol had the opposite effect. These results indicate that the use of different discrimination procedures may result in the measurement of separate dopaminergic and non-dopaminergic substrates for cue properties of EBS in the ventral tegmental area.

Amphetamine↗
PubMed1987

Differential effects of physostigmine on cues produced by electrical stimulation of the ventral tegmental area using two discrimination procedures.

Two procedures were employed to assess the effects of physostigmine on the discrimination of cues produced by either high or low intensity electrical brain stimulation (EBS) of the ventral tegmental area in rats. When the procedure involved frequent presentation of brief trials, physostigmine enhanced the perceived intensities of the cues, causing the rats to respond to low intensities as though they had higher values. In contrast, physostigmine had no effects on the discrimination when the trials were less frequent and extended in duration. These results confirm the existence of multiple substrates for cues produced by stimulation of the ventral tegmental area in rats and implicate cholinergic neurons as substrates for the non-dopaminergic cues identified in the companion paper.

Animals↗
PubMed1987

Reversal by cholecystokinin of apomorphine-induced inhibition of dopamine release in the nucleus accumbens of the rat.

In vivo electrochemical techniques were used to study the effects of the sulfated (CCK8-S) and unsulfated (CCK8-US) forms of cholecystokinin octapeptide on apomorphine-induced inhibition of dopamine (DA) release in the nucleus accumbens of the anesthetized rat. A dose-dependent inhibition of DA release was observed with intravenous (i.v.) injections of apomorphine. CCK8-S administered i.v. at the nadir of the apomorphine-induced inhibition of DA release produced a transient and dose-dependent increase followed by a prolonged decrease in DA release CCK8-US was ineffective in altering apomorphine's inhibitory effects on DA release. The CCK receptor antagonist proglumide injected i.v. 10 min after apomorphine administration had no effect on apomorphine-induced inhibition of DA release, but blocked the effects of CCK8-S on this inhibition. Given that apomorphine may inhibit DA release by a direct hyperpolarizing action on DA neurons, the observation that CCK8-S temporarily reverses apomorphine-induced effects and further inhibits DA release suggests that CCK8-S exerts its inhibitory effects via a process of depolarization block in DA neurons. These findings indicate that apomorphine and CCK8-S may inhibit DA release in vivo by opposite effects on DA cell membrane potentials and suggest that endogenously released CCK may serve to modulate mesolimbic DA neurotransmission.

Animals↗