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Biomedical subjects

G L Willis

Publications and source records attributed to G L Willis.

At least 37 records · Page 2Linked to original sources
PubMed1985

Amine accumulation in behavioural pathology.

When nigro-striatal and meso-cortical neurons degenerate there is a loss of dopamine in the terminal fields and an accumulation of amines in the axons of these systems as they traverse the hypothalamus through the medial forebrain bundle. Traditional lines of thought have attributed the occurrence of motor and consummatory deficits which occur after dopamine neuron degeneration to the loss of functional dopamine neurotransmitter in the terminal fields. However, we have hypothesized that hypothalamic amine accumulation represents an area of brain tissue where processes such as neurotransmitter release, ephaptic transmission or local axon swelling may be affecting adjacent neurons and may thereby participate in the production of behavioural deficits. There is a considerable amount of evidence from studies on both peripheral and central catecholamine-containing neurons indicating that when their axons degenerate a release of functional neurotransmitter can occur. Information from neuropharmacological studies indicates that several drugs which facilitate behavioural recovery from dopamine-depleting lesions may do so by affecting amine release or receptor sensitivity near areas of accumulation rather than depleted terminal fields. We conclude that amine accumulation is a component of dopamine neuron degeneration which should be considered when assessing the role of the central catecholamine systems in the control of various behavioural and physiological processes.

Animals↗
PubMed1985

Catecholamine-blocking drugs injected at sites of amine accumulation reverse catecholamine degeneration associated deficits.

It has been hypothesized that catecholamine (CA) accumulation in the axons of degenerating neurons may represent areas of functional neurotransmitter, and may be producing some of the consummatory and locomotory deficits which occur after central CA-depleting lesions. To test this hypothesis further, haloperidol (0.5 microliter of a 7 nM sol.), propranolol (0.5 microliter of a 175 nM sol.) or isotonic saline (0.5 microliter) were injected 1.5 h, 24 h and 48 h after the injection of 6-hydroxydopamine (6-OHDA; 2 microliter of 8 micrograms/microliters) into the lateral hypothalamus (LH) of Sprague-Dawley rats to determine if the hypothermia, motor impairment and consummatory deficits could be reversed. Although haloperidol injection significantly enhanced the hypothermia seen 1.5 h after 6-OHDA injection, open field performance and consummatory responses were significantly improved after haloperidol was injected into the LH where accumulation is known to occur. Three consecutive days of intracerebral haloperidol treatment produced a recovery of body weight regulation lasting for 6 days. Treatment with propranolol enhanced open field performance 1 day after 6-OHDA injection but failed to enhance recovery of consummatory behaviour and body weight control. These results suggest that CA released from areas of accumulation act on adjacent CA receptors to participate in the production of behavioural deficits previously attributed only to the loss of functional neurotransmitter in terminal fields in the forebrain.

Animals↗
PubMed1984

The masking of amine accumulation by catecholamine depletion.

6-Hydroxydopamine (2 microliter of 8 micrograms/microliter) was injected bilaterally into the lateral hypothalamus of male Sprague-Dawley rats to produce depletion of forebrain terminal fields and an accumulation of amines proximal to the site of injection. Two additional groups of animals were injected with either vehicle or were food and water intake-matched to those receiving 6-hydroxydopamine. Motor performance, food and water intake and body weight were measured in all animals for 2 days before and 6 days after injection. Animals were then sacrificed and brain tissue was prepared for biochemical assay or fluorescence histochemistry. The area of hypothalamic tissue proximal to 6-hydroxydopamine injection, that which contains the amine accumulation, was sectioned from the surrounding tissue with a biopsy punch and assayed for noradrenaline and dopamine content. The nucleus caudatus-putamen, basomedial hypothalamus, and tissue containing the olfactory tubercle and accumbens nucleus were also assayed. Fluorescent histochemical examination of tissue showed that in addition to the depletion of catecholamines in various terminal fields there was also an increase in the fluorescent amine accumulation proximal to the injection site in the impaired animals. This accumulation was not detected with the biochemical assay and is probably due to the occurrence of a masking effect by adjacent depletions. A significant rise in noradrenaline levels was seen in the basomedial hypothalamus of intake-matched controls. However, this too was not detected in 6-OHDA-treated animals and was probably due to masking by adjacent depletions in these areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Deficits in locomotor behaviour and thermoregulation produced by intrahypothalamic dopamine injections.

When nigrostriatal dopamine neurones degenerate, a loss of functional dopamine in the striatum occurs and is accompanied by increased dopamine in the degenerating axons which traverse the hypothalamus. While the behavioural deficits which occur after nigrostriatal degeneration have been attributed to the loss of functional dopamine neurotransmission, evidence produced by us suggests that the increased levels of amines in the degenerating axons may be neuroactive and participate in the production of these behavioural deficits. To test this hypothesis further, albino rats were injected bilaterally with 200 nmol of dopamine in a location just rostral to the diencephalon/mesencephalon border, where amine accumulation is commonly observed following lateral hypothalamic damage. The effect of these injections upon open field performance, thermoregulation and motor reflex control was determined 40 min after dopamine injection. In a second study, pargyline (15 mg/kg. i.p.) was administered 30 min before intracerebral dopamine to determine whether this treatment would increase the severity of motor and thermoregulatory deficits which occurred after dopamine injections alone. Deficits in locomotion, rearing and the ability to regulate body temperature were seen after the dopamine injections while motor reflex control in these animals was similar to that seen in vehicle-injected controls. The behavioural deficits displayed by pargyline pretreated, dopamine injected animals were slightly but not significantly more severe than those displayed by animals receiving dopamine injections alone. Fluorescent histochemical assessment of injection sites revealed that dopamine injection produced an increase in fluorescence or "amine accumulation" at the site of injection but this was considerably less than that seen after catecholamine degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Ventricular, paraventricular and circumventricular structures involved in peptide-induced satiety.

Cholecystokinin, bombesin or gastrin (2 microliter of 50 ng/microliter) was injected stereotaxically into the paraventricular nucleus of the hypothalamus, the arcuate/ventromedial area, the subfornical organ, the area postrema and the cerebral aqueduct of Sprague-Dawley rats and the effects of these injections on food and water intake were studied. While the injection of cholecystokinin reduced food intake when it was injected into both hypothalamic loci, food and water intake were most severely affected by the injection of this peptide into the cerebral aqueduct. Bombesin reduced food intake after its injection into all areas except the subfornical organ and reliable reductions in water intake were seen after injection of this peptide into all areas except the paraventricular nucleus. Minor reductions in food intake were seen following gastrin injection into the paraventricular nucleus while increased water consumption was observed after this peptide was injected into the paraventricular nucleus and cerebral aqueduct. In a second study 6-hydroxydopamine injections (2 microliter of 8 micrograms/microliter were made into the five areas studied 10 days before animals were injected with 100 micrograms/kg of cholecystokinin (i.p.). All 6-hydroxydopamine-injected animals reduced their food and water intake in response to the cholecystokinin challenge as did intact controls. These results indicate that while the changes in food and water intake produced by the central injection of cholecystokinin, bombesin or gastrin may involve central catecholamine systems, those occurring after its systemic administration do not. Therefore, if the release of gastrointestinal peptides during natural feeding is part of a homeostatic mechanism regulating hunger and satiety, this mechanism may operate without directly involving central catecholamine systems.

Animals↗
PubMed1984

A role for amine accumulation in the syndrome of ingestive deficits following lateral hypothalamic lesions.

Lesions of the lateral hypothalamus produce ascending catecholamine neuron degeneration which results in terminal depletion and proximal accumulation above the lesions. The occurrence of deficits in ingestive behaviour has been attributed traditionally to the loss of functional dopamine neurotransmitter in the terminal fields. However, release of functional amines may occur in the lateral hypothalamus at areas of accumulation, to produce at least some of the behavioural symptoms characterizing the lateral hypothalamic syndrome. Recovery from behavioural deficits as a result of various pharmacological treatments, after dopamine-depleting lesions, may be mediated by changes in amine release or modified sensitivity of receptors affected by released amines. We conclude that amine accumulation should be considered when interpreting experiments implicating central catecholamine systems in the control of consumatory behaviour and the regulation of body weight.

Animals↗
PubMed1983

Short-term effects of intrahypothalamic colchicine.

Colchicine was injected in the vicinity of the medial forebrain bundle to cause an accumulation of catecholamines in the lateral hypothalamus proximal to the injection site. Such injections caused severe deficits in consummatory behavior and motor performance within a few hours after injection, which were accompanied by the accumulation of catecholamines in the hypothalamus. Behavioural deficits occurring within 24 h after colchicine injection cannot be attributed to reduced synaptic transmission in the striatum or to dopamine depletion because these events do not commence until 24-48 h after colchicine administration. This study demonstrates the importance of considering all neurochemical changes which accompany catecholamine depletion when assessing the role of the catecholamine-containing system in the regulation of behaviour.

Animals↗
PubMed1983

Deficits in locomotor behaviour and motor performance after central 6-hydroxydopamine or peripheral L-DOPA.

Intracerebral injections of 6-hydroxydopamine (6-OHDA) which produce deficits in locomotor behaviour and motor performance cause localized accumulation of monoamines as well as depletion of central catecholamines (CA). To determine whether the localized increases in monoamines could be contributing to the behavioural deficits seen after intracerebral 6-OHDA injection, the behavioural and biochemical effects of peripherally administered L-DOPA were compared to those which occurred after central injections of 6-OHDA. Forty-five minutes after the injection of 40 mg/kg of L-DOPA, in animals pretreated with 50 mg/kg of R04-4602, the ability to step down, to retract a limb and to ambulate were significantly impaired. Locomotor behaviour and body temperature of L-DOPA-injected animals were similar to those displayed by animals receiving intracerebral injections of 6-OHDA. Fluorescent histochemical and biochemical assessment of diencephalic and telencephalic CA revealed that depletion of CA was not related to the severity of the motor deficits which occurred, but that increased diencephalic CA were present in impaired animals injected with either 6-OHDA or L-DOPA. These findings support the contention that increased CA in degenerating hypothalamic neurones may contribute to behavioural deficits seen after the injection of 6-OHDA.

Animals↗
PubMed1983

Peripheral DA receptor blockade facilitates behavioural recovery from nigrostriatal damage.

Animals were injected via the intraperitoneal route with the peripheral dopamine receptor blocker domperidone for three days before receiving bilateral lesions of the lateral hypothalamus. Pretreatment with domperidone significantly facilitated recovery from lesion imposed deficits in consummatory behaviour and motor reflex control. The enhanced behavioural recovery achieved with domperidone pretreatment was similar to that which occurs with other dopamine receptor blockers but such recovery has been attributed to the central effects of these compounds. The results from this study demonstrate that recovery from catecholamine depleting lesions, attributed previously to the development of striatal receptor hypersensitivity, may also be due to changes in dopamine receptors outside the blood-brain barrier.

Animals↗
PubMed1983

Neuroleptic-like anorexia produced by an extra-cerebral DA antagonist.

The effects of the DA receptor antagonists metoclopramide and pimozide on food and water intake in male Sprague Dawley rats were compared to those of domperidone, which does not cross the blood-brain barrier, in an attempt to determine whether any extracerebral DA receptors participate in neuroleptic induced anorexia. While metoclopramide caused only minor changes in food and water intake at the doses employed both pimozide and domperidone caused a significant reduction in food intake and water consumption 1 hr and 4 hr after injection during a 4 hr intake test. These results support the hypothesis that the nigrostriatal system may not be the system principally involved in the neuroleptic induced anorexia which occurs after the administration of these drugs.

Animals↗
PubMed1982

The behavioural effects of intrahypothalamic multistage versus single injections of 6-hydroxydopamine.

16 micrograms of 6-hydroxydopamine were injected bilaterally into the lateral hypothalamus of male Sprague-Dawley rats in either a single injection or in a series of multistage injections over a period of 75 days. While the single injection produced behavioural deficits typical of those seen following catecholamine depletion of the forebrain, the behaviour of animals injected incrementally with the same dose was indistinguishable from that of controls. Fluorescent histochemical assessment revealed that the animals in the multistage injection group, the behaviourally unimpaired, suffered more severe depletion of forebrain catecholamines than those in the single-stage injection group. Accumulation of amines proximal to the site of drug injection was extensive only in those animals displaying behavioural deficits, that is, the group with the lesser amount of forebrain catecholamine depletion. It is suggested that the severity of deficits in consummatory and motor behaviour occurring after hypothalamic trauma is determined by a lesion's effectiveness in producing amine accumulation rather than catecholamine depletion.

Animals↗
PubMed1982

Anorexic properties of three monoamine oxidase inhibitors.

The anorexic properties of 3 monoamine oxidase (MAO) inhibitors, pargyline, tranylcypromine and nialamide were determined 24 hr after their intra-peritoneal administration. The duration of anorexia occurring after the peripheral administration of the dose of pargyline commonly used in conjunction with 6-hydroxydopamine (6-OHDA) to enhance its dopamine-depleting properties was also determined. Body weight regulation and the control of food and water intake were severely impaired 24 hr after the administration of the three highest doses of pargyline, tranylcypromine and nialamide employed. Impairment in the ability to regulate body weight lasted for as long as 6 days in some animals injected with 50 mg/kg of pargyline. These findings bring to light the problems in interpretation of results from studies which employ MAO inhibitors and 6-OHDA simultaneously to enhance dopamine depleting properties of 6-OHDA.

Animals↗
PubMed1977

Outpatient treatment of schizophrenia.

The authors discuss the treatment of 575 schizophrenic patients over the past 15 years. They describe a shift the patients have experiences from reliance on inpatient treatment to heavy use of outpatient services. The have found that effective outpatient treatment for these patients involves a program of nearly continuous administration of neuroleptic medication combined with counseling and social and crisis services. A major component of the outpatient management of these schizophrenic patients is the education of the patients in how to regulate their own medication within a prescribed range. This educational component appears to add a measure of precision that enhances the safety and reliability of the treatment program.

Adolescent↗
PubMed1976

Intracranial injections of 6-OHDA. Comparison of catecholamine-depleting effects of different volumes and concentrations.

Fluorescence histochemistry was used to assess monoamine depletion after injections of 6-OHDA into selected brain areas. Two volumes (2 and 4 mul) and 4 concentrations (1, 2, 4 and 8 mug/mul) of 6-OHDA were injected into the olfactory tubercle, the posterior lateral hypothalamus and the lateral hyopthalamus. Selective destruction of catecholamine-containing neurons resulted from all injections of 6-OHDA with the exception of the 2 lowest doses (2 and 4 mul of 1 mug/mul) and the highest dose (4 mul of 8 mug/mul) which produced nonspecific damage of brain parenchyma. The results indicate that, in addition to the selection of an effective dose, it is also possible to choose a site of injection which will produce a maximal area of specific depletion. In cases where injections into terminal areas caused limited specific depletion the same dose injected into preterminal axons often caused a more widespread loss of fluorescence. With volume, concentration and anatomical location being important variables to consider, caution is needed in the interpretation of behavioural experiments. When using 6-OHDA it is necessary to show that specific depletion of catecholamines has been achieved.

Animals↗
PubMedDate not supplied

The role of some central catecholamine systems in cholecystokinin-induced satiety.

Cholecystokinin (CCK), bombesin and gastrin were stereotaxically injected into catecholamine (CA) innervated areas of the lateral hypothalamus (LH), the nucleus caudatus putamen (NP) and the olfactory tubercle (OT) in male Sprague Dawley rats. Bilateral injections of 100 ng of CCK in 2 microliters of vehicle into the LH produced a slight but significant decrease in food intake during the first hour of a 4 hour eating test. The other peptides when injected into any of the brain areas did not significantly alter food intake. Water intake was affected by the injection of all three hormones although differentially in all 3 sites. The observed changes in drinking were not related to the prandial characteristics of drinking typically seen in rodents. Denervation of the CA innervation of the OT, LH or NP with 6-hydroxydopamine did not change the satiety response to peripherally administered CCK displayed by intact animals. These results suggest that the satiety which occurs after the central and peripheral administration of CCK may be mediated by different mechanisms and that central CA systems may not be necessary for CCK-induced satiety to occur during natural feeding.

Animals↗
PubMedDate not supplied

Cholecystokinin, behavioral tolerance and tumor-induced anorexia.

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg, IP) was injected daily, for two 4-day periods, into rats bearing the Walker 256 carcinosarcoma (TB) and non-tumor bearing (NTB) control animals. All animals were on a 20 hr food and water deprivation schedule and monitored for food and water intake and bodyweight for 4 hr daily. Food intake was significantly reduced by the daily administration of CCK. Behavioral tolerance to CCK was not observed in either the NTB or TB rats. These results indicate that the parameters describing the phenomenon of behavioral tolerance to CCK are yet to be clearly defined and that peptides other than CCK may underlie the mechanism primarily responsible for producing anorexia associated with cancer.

Animals↗
PubMedDate not supplied

Biochemical and pharmacological basis for the lateral hypothalamic syndrome.

The lateral hypothalamic (LH) syndrome characterized by impairment of the ability to regulate food and water intake has been reported to occur after injections of 6-hydroxydopamine (6-OHDA) into this region. In the present experiment the fluorescence histochemical technique was used to assess monoamine depletion of noradrenaline and dopamine containing neurons following intrahypothalamic injection of 6-OHDA. Results show that the intensity and area of monoamine accumulation in axons served by 6-OHDA is correlated with the severity of behavioral deficits but that actual catecholamine depletion of either the corpus striatum or the hypothalamus is unrelated to the syndrome. Possible mechanisms of action of this accumulation in producing behavioral deficits are discussed.

Animals↗