Matti Saari

Potentiation of amygdala kindling in adult or infant rats by injections of 6-hydroxydopamine

Abstract Rats with bilateral amygdala electrodes were pretreated with 6-hydroxydopamine and/or desmethylimipramine (DMI) to deplete norepinephrine (NE) and/or dopamine (DA). Subsequently they were subjected to kindling procedures in which daily low-intensity amygdala stimulation resulted eventually in the development of clonic motor seizures. The NE depletion, but not the DA depletion, resulted in a marked reduction in the number of stimulations required to kindle convulsions (i.e., faster kindling), but increased the latency to onset of convulsions; the convulsion or after-discharge durations were unaffected. Interestingly, the control animals that received DMI alone manifested no obvious permanent neurochemical effect yet exhibited retarded after-discharge evolution. The above data were replicated in two experiments using adult- and infant-injected rats. These data confirm previous reports that the central catecholamines are capable of inhibiting a variety of forms of seizure.

Neonatal 6-hydroxydopamine attenuates the neural and behavioral effects of enriched rearing in the rat.

Newborn male rats were administered subcutaneous 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine and after weaning were reared in normal or enriched environments. Subsequently the 6-OHDA treated rats and their vehicle controls were trained in a Lashley type III maze and then sacrificed for assay of regional brain weights and brain catecholamines. Whereas for the control rats, enriched rearing was found to: (1) increase hypothalamic and posterior cortical dopamine; (2) increase forebrain and decrease hypothalamic weight; and (3) to enhance maze acquisition, none of these consequences of enriched rearing was found in the 6-OHDA treated rats. We conclude that forebrain norepinephrine plays a permissive role in the neuroanatomical, neurochemical and behavioral alterations induced by the enriched rearing of weanling rats and that it is essential to at least some aspects of the shaping of the brain by experiential factors.

Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: no support for the dopamine depletion model of minimal brain dysfunction.

Bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in rats 1 and 2 days of age, severely depleted brain dopamine (DA) particularly in the neostriatum, where levels in adulthood were about 7% of control. Compared to vehicle-injected controls these rats were hyperactive only at 15 and 20 days of age, and in adulthood were impaired in a two-way avoidance. Rats with similar 6-OHDA treatment but without DMI pretreatment showed severe depletion of brain norepinephrine (NE) as well as DA, and were behaviorally similar to the DA-depleted only rats. This behavioral syndrome is similar to that reported after intracisternal injection of 6-OHDA in 5-day-old rats, which has been argued as a model for minimal brain dysfunction (MBD). Contrary to expectation from this model, however, challenge doses of either d-amphetamine or methylphenidate did not reduce, but instead increased activity of these rats. The 6-OHDA treatments also did not alter the enhancement of locomotor activity by scopolamine, which was present at 30 days but not at 15 days.

Neonatal 6-hydroxydopamine sympathectomy in normotensive and spontaneously hypertensive rat☆

Abstract Neonatal sympathectomy was produced in rats from either a normotensive or spontaneously hypertensive (SHR) strain by repeated s.c. injections of hydroxydopamine (6-OHDA). The SHR rats were considerably more active than the normotensive rats in the open field and activity wheels. Emotionality, defined by the profile of open field activity and defecation scores, was lower in the SHR. Neonatal 6-OHDA had no effect upon emotionality or running wheel activity. Adult endogenous brain norepinephrine was increased in brainstem and decreased in cortex of both strains by 6-OHDA. Tyrosine hydroxylase activity in the brains of normotensive, 6-OHDA injected rats varied directly with altered endogenous NE levels. Preliminary data also indicated increased serotonin synthesis in the brainstem of 6-OHDA injected rats. It was concluded that neonatal injections of 6-OHDA may cause selective degeneration of the descending and dorsal NE brain pathways, and that the behavioral effects of this treatment, while yet obscure, seem to resemble those produced by hippocampal lesions.

Intraspecies aggression and monoamine levels in rainbow trout (Salmo gairdneri) fingerlings

The dominance hierarchy was determined in six groups of rainbow trout fingerlings. The dominant fish in each group were compared to the same-sized submissive members with respect to whole brain monoamine levels. The dominant fish exhibited significantly lower levels of norepinephrine and higher levels of dopamine than the submissive members. Further, the submissive fish most frequently attacked indicated a greater reduction in dopamine levels than those submissive fish which were rarely attacked. There were no differences in serotonin. These data were compared to the mammalian data concerned with catecholamines and aggression.

Behavioural effects of neonatal systemic 6-hydroxydopamine

Abstract Rats were injected systemically (2 × 50 μg/g) with 6-hydroxydopamine either on the first, fifth or tenth day of life. Whereas brain dopamine was generally unaffected, norepinephrine assays during adult-hood showed age-dependent effects of the injections, with the greatest effect observed after injections on day 1. Day 1 injections depleted forebrain and heart norepinephrine while elevating it throughout the hindbrain. Less forebrain depletion was observed after the day 5 injections and the day 10 injections depleted only the heart. The earliest injections probably damaged forebrain and spinal terminations from the locus coeruleus and altered input to the cerebellum from this structure. Three behavioural alterations were also evident only after treatment at one day of age. There were no clonic decapitation convulsions in these rats, a finding attributed to the damage to spinal projections. They also performed poorly on motor tests, an abnormality which cannot be attributed as yet to alteration of any specific terminal field. While locomotor activity, startle or appetitively-motivated learning and extinction were unaffected, the response to punishment in water and food rewarded tasks was also reduced. Thus, neonatal lesions of the terminal fields of the locus coeruleus seem to effect a third behavioural deficit observable on punishment tasks which induce conflict.

The postweaning housing environment determines expression of learning deficit associated with neonatal monosodium glutamate (M.S.G.).

Perinatal M.S.G. treatment causes a syndrome characterized by damage to the hypothalamic arcuate nucleus, other circumventricular areas, parts of the visual system and the dentate gyrus of the hippocampus. The resulting hormonal dysfunction may be responsible for developmental anomalies of organ systems, obesity, and alterations in sensory/motor performance. We have shown that some behavioral indicators of M.S.G. toxicity in rats can be masked by rearing them in enriched housing conditions. Here, we evaluated the impact of six housing conditions on M.S.G.-induced alterations of organ systems and behavior. Perinatal M.S.G. treatment reduced adrenal, heart and testes weights, as well as total white blood cell (WBC) counts, and increased tail flick latencies. These measures were unaffected by the housing condition. M.S.G.-induced reductions in body weight, grip strength, water maze and dominance task performance varied as a function of housing. Deficits in water maze performance were most evident following social and isolated single-cage housing. We propose that deficits in water maze performance following perinatal M.S.G. may be attributable to hippocampal damage that can be alleviated by rearing the rats in stimulating environments.

Forebrain norepinephrine and neurobehavioral plasticity: Neonatal 6-hydroxydopamine eliminates enriched-impoverished experience effects on maze performance

Newborn male rats were depleted of forebrain norepinephrine (NE) by systemic 6-hydroxydopamine injection and then reared from 25 to 60 days under either isolated or enriched conditions. They were subsequently tested for acquisition of either the Lashley III maze or the Hebb-Williams maze problems. Isolated rearing impaired Lashley maze performance of the controls but not the 6-OHDA injected rats. Similarly, for the Hebb-Williams maze, the isolation-reared controls made more errors than their enriched-reared counterparts while no differences were observed between the isolated and enriched reared, 6-OHDA injected rats. These results are consistent with the hypothesis that forebrain NE is permissive to the deleterious behavioral consequences of restricted experience during maturation.

Neonatal 6-hydroxydopamine alters the behavior of enriched-impoverished rats in a novel test environment

The hypothesis that neonatal norepinephrine (NE) depletion lessens the behavioral consequences of differential housing was tested. Male Wistar rats were injected with 6-hydroxydopamine (6-OHDA) or vehicle twice within 24 hr of birth, weaned at 25 days, and reared under either impoverished (IC) or enriched conditions (EC) for 30 days. In 3 experiments, rats were tested in the Morris water maze, the colony-intruder test, and 2 tests of dominance. 6-OHDA treatment reduced cortical and hypothalamic NE concentrations and increased brainstem NE concentrations. EC housing increased cortical dopamine (DA). Behavioral differences caused by postweaning enrichment-isolation were reduced by neonatal NE depletion, primarily in early test trials. The authors conclude that forebrain NE afferents from the locus coeruleus are important for housing-related behavioral changes and responsivity to novel testing environments.

Ontogeny of the post-decapitation convulsion in the rat: effects of neonatal systemic 6-hydroxydopamine.

Abstract Two systemic injections of 6-hydroxydopamine (6-OHDA) on the first day of life caused transient elevations of spinal dopamine and serotonin but permanent depletion of norepinephrine. In untreated rats, the spinal concentrations of these amines peaked at 10, 15 and 20 days respectively. 6-Hydroxydopamine abolished decapitation convulsions during adult-hood but the convulsion latency and duration were normal at 20 days of age. These data are consistent with others suggesting maturation of aspects of seizure manifestations at around 20 days. The tonic-clonic aspects of seizures may consist of an early maturing trigger involving spinal noradrenergic projections from the locus cocruleus and a later maturing modulator involving spinal serotonergic neurones.