Robert E. Hruska

Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum

Estrogen (125 micrograms/rat) was administered, subcutaneously, to male rats six days before measurements were made. Estrogen treatment increased the number of dopamine receptor sites labeled by [3H]spiroperidol in vitro and the intensity of stereotypy induced by dopamine agonists in vivo. These two measures suggest that estrogen administration significantly influences the number of striatal DA receptors and a response to in vivo striatal DA receptor stimulation.

Quantitative aspects of normal locomotion in rats

Abstract The basic quantitative aspects of walking are described for a group of normal rats. Within the range of speed from 20 to 80 cm/sec, rats walk consistently with no spatial or temporal alterations. All four feet show similar walking parameters. Walking can be described spatially, in terms of placement of the four feet, and temporally, in terms of stride duration and of its two components, swing time and stance time. As rats walk more quickly, their stance time decreases, while their stride length increases. The swing time does not change with speed of walking. Normal gait is a lateral sequence, diagonal couplet. This sequencing does not vary with speed of locomotion within the range for walking. The ability to quantify normal rat locomotion permits precise description of the locomotion dysfunction observed in animal models of neurological diseases.

Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats

Abstract Estrogen treatment of male rats produced an increase in the number of striatal dopamine receptors, without altering their affinity. This effect only occurs in vivo and has a slow onset. Only the β-diastereomer of 17-estradiol was active. Other striatal receptors appeared to be unchanged as was the presynaptic uptake of dopamine. Hypophysectomy completely blocked the response to estrogen as measured on striatal dopamine receptors and on stereotypy, a behavior associated with striatal dopamine receptor stimulation. These results are relevant to the clinical observations of chorea associated with the use of oral contraceptives or with pregnancy.

Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats

Administration of prolactin to adult male rats, by S.C. injection, significantly increases the density of the striatal dopamine (DA) receptors, without altering the apparent affinity of the receptors for [3H]spiroperidol. Larger doses of prolactin are required to increase the density of the striatal DA receptors in hypophysectomized rats compared to normal rats. These results suggest that prolactin might be the common mediator of the increase in striatal DA receptor density produced by either estrogen or haloperidol administration. Monitoring and/or altering prolactin levels might be informative in neurologic or psychiatric disorders involving striatal DA neurotransmission.

Effects of Lead In Vivo and In Vitro on GABAergic Neurochemistry

Abstract: Alterations in aspects of neurotransmission utilizing ‐γ‐aminobutyric acid (GABA) are associated with in vivo exposure of rats to lead at doses that do not produce convulsions, but sensitize animals to convulsant agents. These effects are observed regionally and include: decreased GABA levels in cerebellum; increased activity of glutamate decarboxylase (GAD) in caudate; and decreased GABA release (both resting and K+‐stimulated) in cortex, caudate, cerebellum and substantia nigra. Sodium‐dependent uptake of GABA by synaptosomes of cerebellum, substantia nigra and caudate was also affected: in these regions, affinity (Km) was increased and maximal velocity (Vmax) was reduced. Sodium‐independent binding of GABA to synaptic membranes was increased in cerebellum, but was observed only when tissue was Tritonized and prepared without freezing and washing. No effects on GAD or on GABA uptake, release, or binding were observed when lead was added to brain tissue in vitro in concentrations as high as 100 μM. The results suggest that lead may produce chronic inhibition of presynaptic GABAergic function, notably in the cerebellum, which is associated with supersensitivity of postsynaptic GABA receptors. Failure of lead to affect GABAergic function in vitro may indicate that these effects are secondary to another neurotoxic action of lead in the CNS or are consequent to a nonneuronal metabolic action of lead.

Distribution and Localization of Estrogen‐Sensitive Dopamine Receptors in the Rat Brain

Abstract: Administration of estrogen to adult male rats increases the density of striatal dopamine receptors. The densities of the dopamine receptors in the nucleus accumbens and cortex are not altered, while the density of those in the hippocampus is decreased. In the pituitary the density, on a whole pituitary basis, is not changed. The increased density of striatal dopamine receptors normally observed after estrogen treatment is prevented by prior injection into the striatum of kainic acid, which destroys the intrinsic neurons in the striatum. In addition, the benzodiazepine receptors in the striatum, cortex, hippocampus, and cerebellum are not altered by estrogen treatment, showing the specificity of the estrogen treatment and suggesting that the effects of estrogen are not mediated through benzodiazepine receptors.

Lisuride and LSD: dopaminergic and serotonergic interactions in the "serotonin syndrome".

A characteristic behavioral syndrome has been associated with stimulation of central serotonin receptors in rats. This behavior can be produced by inhibition of monoamine oxidase and administration of 5-hydroxytryptophan as well as by direct acting serotonergic agonists. LSD and the novel ergot derivative lisuirde produced this syndrome in rats. These drugs possess both serotonergic and dopaminergic properties. Since changes in dopaminergic function have also been reported to affect the so-called serotonin syndrome, it was not clear how the two ergot drugs acted to produce this syndrome. The syndrome produced by pargyline and 5-hydroxytryptophan methyl ester was blocked by haloperidol, methysergide, parachlorophenylalanine, and alpha-methylparatyrosine; these treatments failed to block the effects of lisuride. Metoclopramide did not block the syndrome produced by either lisuride or pargyline plus 5-hydroxytryptophan methyl ester. Methysergide partially blocked the behavioral effects of LSD; pretreatment with either haloperidol or metoclopramide potentiated and prolonged the behavioral effects of LSD. The results suggest that dopaminergic modulation of the serotonin syndrome occurs before the serotonin receptor involved in this behavior. Also, the differences between LSD and lisuride may be relevant to their different psychopharmacological properties.

Abnormal locomotion in rats after bilateral intrastriatal injection of kainic acid

Abstract The locomotion changes, after bilateral injection of kainic acid into the striata, are characterized by increased swing time and decreased stance time. This may be analogous to the locomotion pattern in patients with Huntingtons Disease.

Estrogen and haloperidol-induced versus handling-related catalepsy in male rats

A single injection of 17 beta-estradiol valerate produces, 6-7 days later, potentiation of neuroleptic catalepsy. Multiple behavioral measures demonstrate that this effect occurs with an acute dose of haloperidol of 0.25 mg/kg IP. An even lower dose of haloperidol (0.10 mg/kg), which fails to make control rats cataleptic, produces catalepsy in estrogen-treated animals. Thus, estrogen lowers the threshold of haloperidol-induced catalepsy. Repeated testing alone induces cataleptic reactions in control rats. Estrogen suppresses such handling-related catalepsy in animals that subsequently show potentiation of catalepsy at a dose of haloperidol (0.10 mg/kg), which has virtually no effect on control rats. Thus, in these behavioral paradigms, estrogen by itself does not produce cataleptic effects, and estrogen-induced potentiation of haloperidol catalepsy is not merely additive to an antecedent, neuroleptic-like effect of this hormone. We interpret our results in terms of (1) the relationship of cataleptic reactions in normal rats to drug-induced cataleptic states; (2) the possible relevance of our behavioral results to basal ganglia disorders; and (3) the relationship of neuroleptic catalepsy to striatal DA receptors and their modulation by estrogen.

Gabaergic actions of thip in vivo and in vitro: A comparison with muscimol an GABA

GABAmimetic actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were evaluated both in vivo and in vitro and compared with the actions of muscimol and GABA. The GABAergic potencies of these agents were assessed in vivo by measuring their ability to inhibit firing of rat substantia nigra pars reticulata neurons after systemic administration and iontophoretic applications, and in vitro by measuring their ability to inhibit 3H-GABA binding to rat cerebellar membranes. The effects of THIP were found to be similar to those of muscimol and GABA with regard to inhibition of reticulata cell firing and 3H-GABA binding. The order of potency was muscimol > GABA > THIP. The magnitude of the differences between drug potencies in iontophoretic studies closely paralleled their relative potencies in binding studies, with muscimol approximately 3 times more potent than GABA and 25-40 times more potent than THIP. After systemic (i.v.) administration, however, muscimol was only 3 times more potent than THIP in inhibiting reticulata cell firing, possibly because THIP passes the blood-brain barrier more readily.