Biomedical subjects

T Archer

Publications and source records attributed to T Archer.

At least 19 recordsLinked to original sources

PubMed1994

Effects of typical and atypical antipsychotic drugs on two-way active avoidance. Relationship to DA receptor blocking profile.

The dose-dependent and time-dependent effects of the novel antipsychotic compound remoxipride, as well as the reference compounds chlorpromazine, clozapine, haloperidol, pimozide and sulpiride upon the retention of two-way active avoidance (conditioned avoidance responses, CARs) were studied in male rats. The dose-dependent effects of remoxipride as well as haloperidol and chlorpromazine on the acquisition of CARs were also studied. The acquisition and retention of CARs were tested in shuttleboxes using a 1.0-mA shock intensity and a 10-stone signal (1000 Hz). All the compounds studied, including remoxipride, caused a dose-dependent impairment of acquisition and retention of CARs. The effect of remoxipride on CAR acquisition correlated with remoxipride's effectiveness to block the hyperactivity induced by the dopamine (DA) agonist apomorphine. Unlike chlorpromazine and haloperidol, the potency of remoxipride and clozapine for antagonising CAR retention was found at dose levels much lower than those producing cataleptic effects or blocking apomorphine-induced stereotypies. Based on the DA receptor blocking profile and the relative effectiveness to block CAR it is concluded that the mechanism(s) by which clozapine and remoxipride affect CAR differ from typical neuroleptic drugs. This difference may reflect an action upon different subtypes of functionally coupled DA D2 receptors.

Animals↗

PubMed1994

MPTP-induced behavioural and biochemical deficits: a parametric analysis.

Two experiments were performed to study the parametric effects of long-term administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as a functional model of parkinsonism in mice. The behavioural deficits induced by different doses of MPTP (5, 10, 20, 30 or 40 mg/kg, s.c., each injected on two occasions) at a 3-week or a 3-month treatment-testing interval were evidenced by significant reductions of spontaneous motor activity, from the 10 mg/kg dosages upwards at the 3-week interval and from 30-40 mg/kg at the 3-month interval. Significant dopamine (DA) reductions in the mouse striatum were obtained at these dose levels and intervals. The behavioural deficit of the 40 mg/kg dose (injected on two occasions) and tested at the 3-, 6-, 12-, 24- and 40-week intervals (separate as well as repeated testing groups) indicated marked and relatively comparable reductions of all three parameters of motor activity, locomotion, rearing and total activity. DA depletions were severe at all five test intervals. These results offer functional and neurochemical evidence that MPTP treatment produces permanent damage to the nigrostriatal motor system in mice.

Animals↗

PubMed1994

Synergistic interactions between NMDA-antagonists and L-dopa on activity in MPTP-treated mice.

Four experiments were performed to investigate whether or not coadministration of NMDA-antagonists potentiate the effect of an ineffective dose of L-Dopa on motor activity in hypoactive MPTP-treated mice. Motor activity was measured in an automated system recording both locomotion (horizontal) and rearing (vertical) activity. L-Dopa alone, at doses of 10 and 20 mg/kg, but not 5 mg/kg, expressed an anti-akinesia effect in MPTP-treated mice. The non-competitive NMDA-antagonist MK-801 (0.03, 0.1, and 0.3 mg/kg) increased by itself both locomotion (0.1 and 0.3 mg/kg) and rearing (0.03 mg/kg) in control (saline-treated) mice whereas no effect was seen in the MPTP-treated mice. Combined with 5 mg/kg L-Dopa, MK-801 (0.1 mg/kg) increased locomotion in MPTP-treated mice. There was no interaction seen between L-Dopa and MK 801 in the control mice. CGP40116 and CGP40117, the active D- and the inactive L-stereoisomer of the competitive NMDA-inhibitor CGP37849, respectively, were also administered together with 5 mg/kg L-Dopa. Both doses (0.003 and 0.03 mg/kg) of CGP40116 in contrast to CGP40117, produced anti-akinesia effect in MPTP-treated mice. CGP40116 (0.0001 to 0.1 mg/kg) together with 5 mg/kg L-Dopa did not affect behaviour in control mice but produced (0.01 mg/kg CGP40116 and 5 mg/kg L-Dopa) in the MPTP-treated mice an anti-akinesia effect. Our findings indicate that the non-competitive NMDA-antagonist MK-801, at doses with reported side-effects, only increase locomotion while rearing remained unaltered in MPTP-treated mice when combined with 5 mg/kg L-Dopa. Only the active stereoisomer CGP40116 in contrast to CG40117, at doses far below reported side-effects, dose-dependently modulated the anti-akinesia effect of a subthreshold dose of L-Dopa. Such data thus support the notion that this behavioural modulation was regulated via NMDA-receptors. The synergism between L-Dopa and the competitive NMDA-antagonist CGP40116 has a potential in treatment of Parkinson's disease to reduce the side-effects of doses of L-Dopa that are used today.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1994

A new operant discrimination test procedure for resident rats.

An automated method for testing visual discrimination with water reinforcement using a modified residential Y-maze is described. The visual stimulus is presented above one of two water holes. Rats have been tested with different lengths of water periods and different intervals between the periods. During the 10 days of testing, overall activity decreased. Activity on the initial days was low during daytime, with few drinking attempts. Discrimination learning acquisition was measured as the increase in the percentage of water periods with drinking attempts in which the first attempt occurred on the correct side, and/or as the increase in the number of correct drinking attempts as a percentage of all drinking attempts. Acquisition was observed both when light indicated water and when it indicated no water. This test model may offer a useful method for standardized measurement of left/right, light on/off discriminations.

Acoustic Stimulation↗

PubMed1994

Effects of D1 and D2 agonists on spontaneous motor activity in MPTP treated mice.

Two experiment were performed to study the effect of combining bromocriptine with SKF 38393 (SKF), or vice/versa, upon parameters of spontaneous motor activity in MPTP treated and saline (control) treated mice. Treatment with MPTP (2 x 40 mg/kg, subcutaneously) induced a hypoactive condition compared with saline treated mice. Bromocriptine (10 mg/kg, subcutaneously), administered to MPTP mice 2 hr, but not 1 or 4 hr, after SKF (6 mg/kg, subcutaneously) caused a marked increase in locomotion and rearing behaviour. The administration of bromocriptine (10 mg/kg, subcutaneously) 4 hr before SKF (6 mg/kg, subcutaneously) elevated all three parameters of spontaneous activity in the MPTP treated mice, independent of the injection of SKF. Bromocriptine injection 1 or 2 hr before SKF decreased locomotion in both MPTP and control mice. Neurochemical analysis confirmed the dopamine depletion in the MPTP treated mice. These results are discussed in terms of the reliability of the MPTP model of parkinsonism in mice and the dopamine D1/D2 receptor hypersensitivity following denervation with the neurotoxin.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1993

Behavioural retardation in the neuropathology of mental retardation.

A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviours in the laboratory in order to derive animal models of behavioural retardation. Rat dams were administered either methylazoxymethanol, metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams were studied on the behavioural tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-OHDA (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adult. The behavioural battery that the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviours, and a parameter under which diverse behaviours were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spacial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphetamine induced activity. It was shown that prenatal methylazoxymethanol, metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride, altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded on the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85% depletion compared to control values) caused notable impairments. These diverse findings seem to implicate dopaminergic processes in brain development.

Animals↗

PubMed1992

Nerve growth factor (NGF) in rat brain following long-term barbital treatment: relation to convulsions and cognitive function.

Nerve growth factor (NGF) protein has been implicated in alterations of cognitive function either following brain damage, selective lesions or aging. Groups of rats were given long-term (48 weeks) oral barbital treatment or tap water and following an extended period of abstinence (14 weeks) were tested for spatial learning ability in the Morris swim maze. Following the maze test, they were sacrificed and the NGF content of hippocampal and cortical brain regions were analyzed. Barbital treated rats were divided into convulsing and non-convulsing groups. It was found that there was a slight, significant increase (12%) in NGF content of the hippocampus in convulsing rats. Correlations between maze learning performance, brain weight and NGF in the cortex indicated a significant negative relationship between (a) performance and brain weight on day 1 of testing and (b) NGF content and performance on day 2. These data indicate some involvement of NGF in functions derived from a considerably different animal model to those applied previously.

Animals↗

PubMed1992

Behavioural effects of neonatal metallic mercury exposure in rats.

The effect of neonatal exposure of rats to mercury vapour (Hg0), at the concentration 0.05 mg/m3, 1 h (low dose) or 4 h (high dose), on the behaviour in adulthood were studied. Exposure occurred on days 11-17 (the period of rapid brain growth). Tests for spontaneous motor activity were performed at the ages of 2 and 4 months. Rats exposed to the high dose Hg0 showed a marked increase in variables locomotion and total activity but a decrease for rearing when tested at 2 months of age. At 4 months of age these rats showed a marked hypoactivity with respect to all three variables. Rats exposed to the low dose showed no significant differences at 2 months compared to controls. However, at the age of 4 months the same pattern (increase in variables locomotion and total activity but a decrease for rearing) already noticed in the high dose group at 2 months was observed. In the spatial learning tasks applied, the radial arm maze and circular swim maze, neonatally exposed pups showed a retarded acquisition to the former, while there was no difference compared to controls in the latter. These data indicate that neonatal exposure to mercury vapour results in similar behaviour changes as reported from offspring prenatally exposed to mercury vapour or methylmercury. Furthermore, exposure for 1 week to concentrations around Swedish threshold values (TLV) for 1 or 4 h resulted in dose and age-related behavioural changes.

Age Factors↗

PubMed1992

Purposive behaviour in cognition and perception: considerations of awareness in memory.

The responses to the original article by Rönnberg (1990a) provoked interesting and thoughtful points of view that are covered by Gärling (1990), Hjelmquist (1990), Montgomery (1991), and Runeson (1990). These articles do not merely present a different outlook but also provide concepts that are certainly worthy of consideration and add more substance to the general topic under discussion. The purpose of this commentary is to seek an understanding of the ideas presented by the above authors within a synthesis of our views of current conceptualizations in cognition and perception. Each of the original criteria (Rönnberg, 1990a) will be treated in turn.

Animals↗

PubMed1992

5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety.

The effects of different doses of buspirone, 3-dipropyl-amino-5-hydrochromar (NDO 008) and 8-hydroxydipropyl-aminotetralin (8-OH-DPAT) (administered intraperitoneally) were studied in tests of anxiolytic and antidepressant action in rats. These tests included the elavated plus maze test, the forced swim test, stress-induced suppression of open-field behavior, and the differential-reinforcement-of-low-rates-of-behaviour-72 sec (DRL 72 s) test. Buspirone (0.125 mg/kg) and NDO 008 (1.0 to 2.0 mg/kg) produced anxiolytic activity in the elevated plus maze, whereas 8-OH-DPAT did not in the doses employed. All three compounds increased activity in the forced swim test, although buspirone did so at a lower dose than NDO 008 and 8-OH-DPAT. In the stress-induced suppression test of open field activity all three compounds induced an antidepressant-like effect at different doses dependent on whether footshock (stressor) was presented 24 hr before or just prior to the open-field test. All three compounds even caused some reduction of activity in the non-shocked rats. 8-OH-DPAT (1.0 mg/kg) produced a significant and reliable increase in the Reinforcement/Response rate quotient in the DRL 72s test. These diverse results may provide an indication of potential clinical efficacy of the 5-HT1A agonists in the treatment of anxiety and depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Functional changes implicating dopaminergic systems following perinatal treatments.

A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviors in the laboratory. Rat dams were administered either metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams was studied with behavioral tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-hydroxydopamine (6-OHDA) (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound, or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adults. The behavioral battery the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviors, and a parameter under which diverse behaviors were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spatial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphetamine-induced activity. It was shown that prenatal metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine-induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded according to the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine-induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85% depletion compared to control values) caused notable impairments. One tentative conclusion from the pattern of behavioral changes, generally in the absence of any measurable neurochemical changes, observed after these treatments is that the functional development of dopaminergic systems had, to a greater or lesser degree, been altered.

Animals↗

PubMed1990

Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: a model for Parkinson's disease.

The long-term effect of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on pre- and postsynaptic structures of the nigrostriatal and mesolimbic dopamine (DA) system in adult C57BL/6 mice (2 x 40 mg/kg s.c.) was investigated using neurochemical and behavioral methods. It was found that MPTP induced a severe depletion of striatal DA levels (-80%) that persists for 4 weeks after treatment, with less severe effects in nucleus accumbens (-36%) and the olfactory tubercle (-52%). These depletions are associated with decreased tyrosine hydroxylase (TH) activity as determined in vivo and increased turnover of DA. MPTP treatment did not induce any change in the DA2-receptor as determined by [3H]spiperone binding or by two different behavioral tests, i.e. apomorphine-induced climbing and apomorphine-induced stereotypies. No significant weight loss during 4 weeks after MPTP was found. The spontaneous motor activity in these mice was profoundly and persistently depressed (-66%) as a result of the MPTP-induced DA denervation and the motor deficit was completely reversed by L-DOPA treatment. We suggest that MPTP-treated C57BL/6 mice may serve as a suitable model for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1990

Altered behaviour in adult mice exposed to a single low dose of DDT and its fatty acid conjugate as neonates.

DDT, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane is one of the best-known insecticides which produces neurotoxic syndrome in mammals. DDT is also a world-wide environmental contaminant which is still used in several countries. We have previously reported on pronounced retention of DDT in the neonatal mouse brain. We have also observed that DDT and a DDT metabolite, DDOH, conjugated to palmitic acid (DDOH-PA), which have been found in DDT-treated female rats, affect the muscarinic cholinergic receptors in the brain of the neonatal mouse. We now report that neonatal exposure to a single low oral dose of DDT and DDOH-PA (1.4 mumol/kg b.wt.) also can lead to a permanent hyperactive condition in the mice as adults.

Animals↗

PubMed1990

Behavioral effects after intrathecal administration of cholinergic receptor agonists in the rat.

Behavioral effects of nicotine and cytisine, and the cholinesterase inhibitors physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (THA), administered intrathecally (IT) at the lumbar level in the rat have been evaluated. Antinociceptive dose relationships were established using the tail immersion test. Total activity, locomotion and rearing were also measured in computerized test boxes. The nicotinic receptor antagonist, mecamylamine, and the muscarinic receptor antagonist, atropine, were used to study the selectivity of the effects. Physostigmine and THA significantly decreased total activity, locomotion and rearing as compared to control animals. The motor effects of physostigmine were completely antagonized only partly. Mecamylamine had no antagonistic effect. Nicotine did not affect any activity parameter. Cytisin reduced total activity and locomotion 1-6 min after dose. IT physostigmine, 15 micrograms, increased tail immersion latency for 30 min. No significant increase in response latency in this test was observed after the IT administration of nicotine or THA, whereas cytisine elicited a small increase. The IT administration of THA, nicotine and cytisine was also associated with gnawing, vocalization and hyperactivity and in the case of THA, diarrhoea. These effects were blocked by mecamylamine. Physostigmine antinociception as well as the behavioral effects including total activity, locomotion and rearing caused by physostigmine and by THA are most probably due to an action on spinal muscarinic receptors. Nicotinic receptors do not seem to be involved in spinal antinociception. Some aversive behavioral effects caused by the IT administration of nicotinic receptor agonists could, however, be attenuated by the spinal administration of the antagonist mecamylamine, which may indicate the involvement of nicotinic receptors in afferent sensory transmission.

Alkaloids↗

PubMed1990

Learning deficits in aged rats pretreated chronically with barbital and tested late in abstinence: alleviation by tetrahydroaminoacridine.

Physostigmine and tetrahydroaminoacridine (THA) have been reported to improve cognitive function in patients with Alzheimer's disease. Two experiments were conducted to examine the effects of these anticholinesterase agents on learning in aged rats pretreated chronically with barbital. In the first experiment animals received barbital in their drinking water for 46 weeks. Controls were given only water. On days 100-104 of abstinence, when the animals were 20 months old, acquisition of the Morris maze task was initiated after treatment with physostigmine. It was found that physostigmine improved learning of the maze task in control but not barbital treated rats. In the second experiment animals received barbital solution or water as in experiment one. On days 100-103 of abstinence they were injected with THA before being tested in the Morris water maze. It was found that THA improved learning in both barbital treated and control rats. These results corroborate clinical findings of improved cognitive function following treatment with THA, and suggest that the therapeutic effects of THA may be mediated by mechanisms distinct from cholinesterase inhibition. Furthermore chronic barbital treatment could be used as a model to study cognitive disturbances in experimental animals.

Age Factors↗

PubMed1990

MPTP-induced hypoactivity in mice: reversal by L-dopa.

Three experiments were performed to study the subchronic effects of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 2 x 40 mg/kg subcutaneously two weeks before testing) in C57 BL/6 mice upon spontaneous motor activity and the reversal of the long-term behavioural changes by acute treatment with L-Dopa. Mice treated with MPTP showed a drastic reduction of striatal dopamine levels (-88%) associated with reductions of all three parameters of spontaneous motor activity, i.e. locomotion, rearing and total activity, during both the initial, exploratory, stage (first 90 min), and later stages of the 3- or 4-hr test periods. L-Dopa (5-80 mg/kg subcutaneously) injected 60 min. after the start of testing dose-dependently improved all three parameters studied in MPTP treated mice with 10 mg/kg being the lowest dose causing a significant effect, while doses above 20 mg/kg caused hyperactivity. During the initial period, rearing activity in MPTP mice was to a variable degree suppressed by the L-Dopa treatment (20-80 mg/kg); these reductions were followed by enormous increases in motor activity by the 40 mg/kg (locomotion) and 80 mg/kg (total activity) L-Dopa groups. Both the degree and duration of the L-Dopa-induced hypoactivity for locomotor behaviour increased dose-dependently in control mice. No suppressive effects of L-Dopa were obtained for total activity in control mice, although the 80 mg/kg L-Dopa doses evoked hyperactivity for up to 90 min. following treatment for both locomotion and total activity.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage.

Different parameters of motor behavior (locomotion, rearing and total activity counts) were studied in the adult rat following neonatal intracisternal 6-hydroxydopamine (6-OHDA, 50 micrograms) treatment combined with noradrenaline (NA) uptake blocker (desipramine) or dopamine (DA) uptake blockers (amfolenic acid or GBR 12909) to obtain selective DA or NA lesions respectively. At 61-65 days of age, selective DA-lesioned animals showed an initial decrease in spontaneous motor behavior at test days 1 and/or 2, while at test days 4 and 5 hyperactivity was observed. However, following amfolenic acid or GBR 12909 pretreatment leading to a selective NA lesion, no difference in spontaneous motor behavior was seen on any of the 5 test days. Determination of regional brain levels of NA and DA confirmed the type of lesion predicted from the various pretreatments with selective uptake blockers. These data suggest that changes in motor behavior in the adult rats, following neonatal 6-OHDA treatment, are specifically related to a DA-denervation, whereas an NA lesion does not seem to influence the spontaneous motor behavior. However, following the selective DA lesion, significant increases of serotonin levels in striatum and cerebellum were observed, while following selective NA lesions an increase of cerebellar NA levels was found concomitant with drastic reductions of NA levels in frontal cortex and spinal cord.

Aging↗

PubMed1989

Effects of d-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment.

Neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA, 50 micrograms on day 1 after birth) caused a marked hyperactivity when the rats were tested as adults. These rats also showed severe DA depletions in striatum and nucleus accumbens. Pretreatment with the noradrenaline (NA) uptake inhibitor desipramine provided protection against NA depletion in frontal cortex and nucleus accumbens. Pretreatment with DA uptake inhibitors, amfolenic acid or GBR 12909, before 6-OHDA, provided full protection against DA depletion but produced marked NA depletion in frontal cortex. These rats did not demonstrate any degree of hyperactivity. Low doses of d-amphetamine (0.25 mg/kg SC) or methylphenidate (1 mg/kg SC) reversed the hyperactivity in DA-depleted rats but increased motor activity in vehicle-treated and NA-depleted rats. Higher doses of d-amphetamine (1 mg/kg) or methylphenidate (4 mg/kg) produced potentiated levels of locomotion but attenuated levels of rearing in DA-depleted animals. The results further suggest the utility of the neonatal DA lesion in rats as a potential animal model for derivation of therapeutic agents that may be efficacious in the treatment of the hyperkinetic syndrome.

Animals↗