Upregulation of striatal dopamine-2 receptors in Brattleboro rats with prepulse inhibition deficits.

BACKGROUND: Brattleboro rats (BRATs) have natural deficits in prepulse inhibition (PPI) of the startle response similar to those exhibited by schizophrenia patients, which are reversed by antipsychotics. We sought to determine whether they also have increases in striatal dopamine-2 (D2) receptors found in some studies examining the brains of schizophrenia patients. METHODS: Several days after startle testing, the brains of BRAT and Long Evans (LE) rats were removed, and D1 and D2 receptor levels were measured by autoradiography. RESULTS: PPI was lower in BRATs consistent with previous reports. D2, but not D1, receptor binding was significantly higher in the nucleus accumbens shell and the dorsomedial caudate of BRAT compared with LE rats, consistent with some findings in schizophrenia patients. Furthermore, individual rat PPI was inversely correlated with D2 binding density. CONCLUSIONS: These findings suggest that the dopamine system in BRATs is dysregulated and these abnormalities may contribute to the PPI deficits observed in these rats.

Gene expression and chemical diversity in hypothalamic neurosecretory neurons.

Hypothalamic neurosecretory neurons transcribe, translate, store, and secrete a large number of chemical messengers. The neurons contain hypothalamic signal substances that regulate the secretion of anterior pituitary hormones as well as the neurohypophysial peptides vasopressin and oxytocin. In addition to the classical hypophysiotropic hormones, a large number of neuropeptides and classical transmitters of amine and amino acid nature are present in the same cells. This is particularly evident in the magnocellular neurons of the supraoptic and paraventricular nuclei, and in parvocellular neurons of the arcuate and paraventricular nuclei. The changes in gene expression induced by experimental manipulations and the colocalization chemical messengers in hypothalamic neurosecretory neurons and its possible significance is summarized in this review.

Adrenoceptors and cardiovascular regulation in conscious, unrestrained, Long Evans and Brattleboro rats.

In conscious rats, in the presence of prazosin and idazoxan (alpha 1- and alpha 2-adrenoceptor antagonists, respectively), blood pressure (BP) and heart rate (HR) become unstable, due to the occurrence of 'spontaneous' depressor and tachycardic episodes. These events could be triggered also by auditory stimuli, and were blocked by antagonism of beta 2-adrenoceptors. In adrenal-demedullated animals treated with prazosin and idazoxan, BP was less variable than in sham-operated animals, but bolus injections of adrenaline or salbutamol could simulate the 'spontaneous' depressor events seen in the latter. The marked swings in HR were not explained by sensitization of the cardiac baroreflex in the presence of idazoxan, but were probably due to blockade of prejunctional autoinhibitory alpha 2-adrenoceptors, amplifying the effects of intermittent sympatho-adrenal activation.

Hypothalamo-pituitary regulation of thyrotrophin secretion in chronically catheterized Brattleboro rats.

Plasma TSH rhythms were measured in Brattleboro (DI) and control Long-Evans (LE) rats with an intracardiac catheter allowing repeated sampling in conscious unstressed animals. The TSH response to thyrotrophin-releasing hormone (TRH; 500 ng/100 g body weight) was also determined. Finally, hypothalamic and pancreatic TRH concentrations and TRH-degrading activity (TRH-DA) were measured by specific radioimmunoassay. Long-Evans rats had a 24-h rhythm with a major modulatory 8-h component. In DI rats, only the 24-h rhythm was detected. The mean 24-h rhythm-adjusted mean TSH level was higher in DI than in LE rats (1.38 +/- 0.05 and 1.14 +/- 0.06 micrograms/l respectively, P less than 0.01). The peak TSH response to TRH was significantly increased in DI rats while the pituitary concentration of TSH was also higher (0.93 +/- 0.09 vs 0.39 +/- 0.06 micrograms/mg wet weight in LE, P less than 0.001). Hypothalamic TRH and TRH-DA were similar in both strains. The response to propylthiouracil-induced hypothyroidism was identical in both strains. We conclude that DI rats have a normal pituitary sensitivity to tri-iodothyronine but a central dysfunction in the pituitary environment leading to some alterations of TSH secretion.

Immunoreactive arginine-vasopressin in Brattleboro rat ovary.

Homozygous (di/di) Brattleboro rats have normal hypothalamic levels of oxytocin and neurophysin I, but undetectable levels of neurophysin II and arginine-vasopressin (AVP). This defect has been presumed to be at the genomic or transcriptional level, as AVP messenger is reported to be drastically reduced, if not absent, from the hypothalamus of Brattleboro rats. Recent studies suggest de novo production of various neuropeptides in the mammalian gonad, including AVP. We report here the detection and localization of immunoreactive (ir) AVP in the luteal cells of adult homozygous Brattleboro rats, and the modulation of this ovarian ir-AVP by gonadotropins. These findings are thus consistent with a tissue-specific defect of AVP expression in the magnocellular neurones of the Brattleboro rat, and suggest that a comparable defect does not occur in the ovaries of such animals.

Brattleboro rat adrenal contains vasopressin.

Arginine-vasopressin (AVP) is a neurohypophysial nonapeptide with antidiuretic activity involved in the control of blood volume and plasma osmolality. Recently, by immunological methods, the presence of AVP has been demonstrated in extrahypothalamic areas of the brain, in the spinal cord and in the ovary, testis and adrenal gland. The Brattleboro rat is regarded as having an autosomal recessively inherited lack of neurohypophysial vasopressin and its associated neurophysin. Since its discovery over 20 years ago this animal has been widely used in studies on the physiological role of vasopressin. We have recently investigated the presence of immunoreactive vasopressin and the related nonapeptide oxytocin in the adrenal glands of the human, rat and cow, and report here the isolation from the Brattleboro rat adrenal of material with similar immunological, physical and biological properties to synthetic vasopressin.

Hyperreflexive behavior in Brattleboro rats.

In two experiments we compared the size of the startle response elicited by shock and acoustic stimuli in animals having a congenital absence of vasopressin (Brattleboro rats) with closely related controls, which do synthesize vasopressin. The rats lacking vasopressin were hyperresponsive to both shock and acoustic stimuli. Inhibition of the acoustic startle by shock prestimuli also was greater in these animals. These results are consistent with reports which indicate that vasopressin attenuates responses to noxious stimuli.