Biomedical subjects
Publications and source records attributed to R Lalonde.
There is a spontaneous degeneration of Purkinje cells, granule cells and inferior olivary neurons in lurcher mutant mice. It was found that, in comparison to littermate controls, the lurcher mutants alternated less often in a discrete two-trial procedure of spontaneous alternation and did not habituate to maze stimuli in a T-maze. Results are discussed in terms of a possible role for the cerebellum in spatial learning.
Weaver mutant mice, contrary to normal littermate controls, did not acquire the immobility response in a forced swimming task. In regard to swimming performance, the weaver mutants swam with less ability but with more vigor than normal mice. Results are discussed in terms of the role of the cerebellum in swimming behavior.
Nervous mutant mice have a selective degeneration of Purkinje cells and deep cerebellar nuclei. In comparison with littermate controls, nervous mutant mice did not alternate spontaneously in a successive trial procedure (six consecutive trials per day) and did not habituate in a restricted part of a t-maze in a 4-min session. These data indicate that the cerebellum may have a role in spatial learning.
Nervous mutant mice and normal littermate controls explored a 4 X 4 hole matrix for 3 consecutive days. No difference was found between the groups for the following measures: total number of hole visits, visits to the center holes, and visits to contiguous holes or different holes. However, nervous mutants persevered more in visiting the same hole than controls. These results are discussed in terms of a possible role for the cerebellum in spatial working memory, similar to that suggested for the hippocampus.
Male Sprague-Dawley rats were injected with phenytoin (PHT) once a day for 20 consecutive days and then tested as to their response to 5-methoxy-N,N-dimethyltryptamine (5-MDMT), a 5-hydroxytryptamine (5-HT) agonist, at 1 and 3 mg/kg on days 21 and 28. It was found that long-term PHT administration decreased the intensity of a stereotyped motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (1.7, 3.2 mg/kg). It is suggested that PHT increases the functional availability of 5-HT before its receptors, and thereby causes 5-HT receptor subsensitivity.
Male albino rats were injected with 25 mg/kg of phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 or 2 mg/kg of muscimol, a GABA receptor agonist. Rats treated with PHT showed a decreased responsiveness to muscimol-induced catalepsy (2 mg/kg) on day 21 but not on day 28. Acutely administered PHT, on the contrary, had a tendency to potentiate muscimol-induced catalepsy. Muscimol-induced catalepsy was not antagonized by acute treatment with bicuculline (0.5-2.0 mg/kg). It is proposed that withdrawal after long-term administration of PHT reduces the sensitivity of a GABA receptor site not sensitive to bicuculline.
The activity of 5-HT was manipulated by means of the peripheral injection of 5-HT reuptake inhibitors, fenfluramine and fluoxetine. These drug treatments, at doses higher than 1 mg/kg, produced retrograde amnesia in a one-trial appetitive learning task in rats. A non-specific inhibitor of 5-HT reuptake, imipramine, did not produce this amnesic effect, nor did the combination of fenfluramine with the MAOI tranylcypromine, although it produced, as expected, the "serotonergic syndrome." Results for the metabolic precursor of 5-HT, 5-HTP, also administered peripherally, were inconsistent, with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg.
Phenytoin (115 mg/kg) was given orally to rats in order to determine serum concentration levels of the drug. It was found that the peak concentration in serum was 8 micrograms/ml 1 h postadministration , with little variation being noted for up to 8 h. The relevance of these findings in terms of behavioral studies is discussed.
Rats learned one of two appetitive discrimination tasks varying in terms of cognitive difficulty. Contrary to previous reports showing an impairment in the acquisition of avoidance tasks under the effects of either chlorpromazine (CPZ) or lithium, the results of this experiment indicate that neither drug retards the acquisition of appetitive tasks. Instead, at the highest doses used (2 and 3 mg/kg), CPZ decreased the number of trials required for the difficult task. Rats administered CPZ had longer reaction times than rats administered placebo, and therefore might have achieved criterion earlier because they spent more time in front of and on the discriminanda. The contrary results reported with avoidance tests concerning the effects of CPZ are explained in terms of the anxiety-reducing properties of CPZ, which might reduce drive without impairing cognitive ability.
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In theories of motor learning, the cerebellum is assumed to be the storage site of the engram. Recent evidence is presented that the cerebellum, in addition to its mediation of learning of simple motor responses, has a role in cognitive behaviors. For this type of learning, it is possible that the storage site is not the cerebellum, but cerebellar target areas. The possible role of the cerebellum in spatial learning and discrimination learning is emphasized. Ascending cerebellar afferents to fronto-parietal association cortex, the limbic system and the superior colliculus and feedback loops from these areas may be the anatomical basis underlying cerebellar modulation of spatial learning. In regard to discrimination learning, the possible significance of pathways arising from the visual cortex to pontine nuclei projecting to the cerebellar hemispheres must be evaluated. Although much remains to be resolved, the cerebellum seems to contribute to various emotions such as fear, the neural basis of which being cerebellar contributions to the reticular activating system, the limbic system and two-way hypothalamo-cerebellar connections.
Nervous mutant mice have selective damage to deep cerebellar nuclei and Purkinje cells. Compared to normal littermate controls, nervous mutant mice did not show habituation of a hole poke response to a large hole. The nervous mutants showed both signs of increased contact with a novel stimulus (number of rearing responses) and decreased exploration (number of hole pokes in small holes). Results are discussed in terms of a similarity between the behavioral effects of cerebellar damage and hippocampal damage.
The Lurcher mutant mouse can be considered an adequate model of autosomal dominant spinocerebellar atrophy because of the severe degeneration of its cerebellar cortex and inferior olive. The purpose of this study was to determine whether the motor coordination deficits of Lurcher mutants could be improved after chronic administration of the serotonin (5-hydroxytryptamine; 5-HT) precursor, L-tryptophan, or of the 5-HT(1A) agonist, buspirone. During these treatments, the mice were submitted to behavioral evaluations using the coat hanger and the rotorod tests, as well as an inclined screen and a vertical grid test. At the end of treatments, 5-HT and 5-hydroxindole-3-acetic acid (5-HIAA) were measured in six brain regions. On the coat hanger test, administration of L-tryptophan accelerated movements along the horizontal bar by 44%, while buspirone increased the time spent on the apparatus by 11%. Neither drug had an effect on climbing ability or on the time spent on a rotating beam. Administration of L-tryptophan increased 5-HIAA levels in frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord, but elevated 5-HT only in neostriatum, brainstem and cerebellum. In contrast, buspirone led to 5-HT increases in cerebellum and augmented 5-HIAA in the spinal cord. The modest test-specific improvements are consistent with some of the clinical data concerning 5-HT pharmacotherapy in patients suffering from cerebellar atrophy.
Mice injected with either 8, 16 or 32 mg/kg of pentobarbital were as efficient as control subjects in learning and recalling the location of a submerged platform in a water maze. The highest dose of pentobarbital decreased fall latencies in the coat-hanger test of motor coordination. Exploratory activity was not affected by these doses of pentobarbital. The absence of a deficit in spatial learning and in exploratory activity occurred even at a dose sufficient to cause a deficit in motor coordination. These results stand in contrast to previous findings indicating spatial deficits in rats injected with benzodiazepines.
In this brief review of the possible link between age-related behavioral disorders and brain folate levels, preliminary data on humans and animals are presented. These data indicate that folate administration may improve some age-related behavioral dysfunctions. In aged humans and rats, there is a defect in the absorption of dietary folate, leading perhaps to a decrease in brain folate levels. If so, folate therapy may replenish brain stores of folates and may reverse some age-related behavioral deficits. Some questions concerning the possible relationship among mood status, intellectual functions, and folate levels in aging are discussed.
Male albino rats (n = 10) were injected with phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 mg/kg apomorphine, a dopamine-receptor agonist. Rats treated with PHT showed an increased responsiveness to apomorphine-induced stereotypy on day 28, which is evidence for dopaminergic supersensitivity after long-term treatment with the drug. In experiment 2, a supersensitivity response to apomorphine-induced stereotypy was noted on day 14 after 10 days of PHT administration. In experiment 3, after 17 days of PHT administration, rats were also supersensitive to the climbing response induced by apomorphine. These results may explain, in part, the clinical findings of orofacial dyskinesias produced by PHT in epileptic patients.
Simple reaction time (RT) is defined as the elapsed time between presentation of a single stimulus and onset of movement. In choice RT, there are at least two stimuli, requiring two distinct responses. The neurobiological basis of RT in humans has mostly been evaluated in patients with Parkinson's disease or cerebellar disease. Lesion studies in animals have assessed the different contributions of various subregions of the basal ganglia and the cerebellum. There is a prolongation of simple RT and in some cases of choice RT in Parkinson's disease. Both simple and choice RT are susceptible to modulation by brain dopamine levels. However, such is not invariably the case, attesting to the contribution of non-dopaminergic neurons in the sensori-motor slowing found in Parkinson's disease. An increase in simple RT and in choice RT are found in patients with cerebellar atrophy. The initiation of fast ballistic movements is associated with the dentate efferent system. This system is modulated by dopaminergic and glutamatergic pathways to the striatum.