Kappa opioid agonists produce anxiolytic-like behavior on the elevated plus-maze.

The selective kappa agonist U-50,488H was evaluated on the elevated plus-maze test of anxiety. U-50,488H was administered intraperitoneally to male Sprague-Dawley rats 20 min before testing, first in an open field apparatus, then followed immediately on the elevated plus-maze. No significant change in spontaneous locomotor activity was measured in the open field apparatus, suggesting that U-50,488H was devoid of sedative effects in the dose range tested (0.1-1000 micrograms/kg, IP). Doses between 10 and 1000 micrograms/kg produced significant increases in elevated plus-maze behavior that were consistent with anxiolytic actions for U-50,488H. These anxiolytic-like effects were antagonized by naloxone (2.0 mg/kg, IP), suggesting an opioid receptor site of action. In addition, we tested the kappa 1-selective U-50,488H-derivative, U-69,593 (100 micrograms/kg, IP), which was also shown to mimic the anxiolytic-like effects produced by U-50,488H. These results suggest that low doses of the selective kappa 1 agonists U-50,488H and U-69,593 are endowed with anxiolytic properties in rodents and that the kappa opioid system may be involved in the behavioral response to anxiety.

Dentate granule cells as a central cardioregulatory site in the rat.

Dentate granule cells can be selectively destroyed by intrahippocampal injections of colchicine. This study evaluates the consequences of granule cell destruction on blood pressure regulation in the normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR). Bilateral destruction of dentate granule cells at 6 weeks of age produced a significant increase in blood pressure in the WKY that lasted for approximately 3 weeks, and a biphasic effect (increase then decrease) in the SHR that resulted in a significant hypotensive period that persisted for 6 weeks. Granule cell destruction at 11 weeks produced a maximal hypertension in the SHR that preceded age-matched controls by 4 weeks, but produced only a small transient increase in WKY blood pressure. Dentate granule cells are the exclusive source of prodynorphin-derived peptides in the hippocampal formation and their synthesis is regulated by glucocorticoids. Evidence suggests glucocorticoids may be involved in the regulation of blood pressure and hypertension. We determined that chronic high levels of corticosterone significantly reduced hippocampal dynorphin B levels in normotensive Sprague-Dawley rats. In addition, we confirmed that naive SHRs also contain significantly lower levels of hippocampal dynorphin B. These results suggest (i) that dentate granule cells represent a discrete neural site that may exert a tonic inhibitory influence on blood pressure, (ii) that dentate granule cells are not required for the full expression of hypertension in the SHR, and (iii) that chronic high levels of corticosterone can reduce dynorphin B levels in the dentate granule cells of normotensive rats.

The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms.

Neural and systemic somatotrophic effects of the ultraviolet component of sunlight through the skin-vitamin D endocrine system are considered as alternate or additional to the neuroendocrine effects of the visual component of light through the retino-diencephalic input. The extensive distribution of soltriol nuclear receptor cells, revealed by autoradiography with tritium-labeled 1,25 dihydroxycholecalciferol (vitamin D, soltriol) and related effects, indicate an involvement of vitamin D-soltriol in the actinic induction of seasonal biorhythms. This is considered to be independent of the traditionally assigned effects of vitamin D on systemic calcium regulation. Skin-soltriol mediated seasonal, and to a degree daily, genomic activation involves many target regions in the brain. These include neurons in the central nucleus of the amygdala, in the linked part of the bed nucleus of the stria terminalis, in periventricular hypothalamic neurons, dorsal raphe nucleus, reticular thalamic nucleus and autonomic, endocrine as well as sensory and motor components of the brainstem and spinal cord. Additional to the eye-regulated "suprachiasmatic clock", existence of a soltriol-vitamin D regulated neural "timing circuit(s)" is proposed. Both, activational and organizational effects of soltriol on mature and developing brain regions, respectively are likely to play a role in the regulation of neuronal functions that include the modulation and entrainment of biorhythms. Soltriol's central effects correlate with peripheral effects on elements in skin, bone, teeth, kidney, intestine, heart and blood vessels, endocrine organs, and tissues of the immune and reproductive system.

Domoic acid enhances the K(+)-evoked release of endogenous glutamate from guinea pig hippocampal mossy fiber synaptosomes.

The presynaptic effects of domoic acid (Dom) on hippocampal mossy fiber synaptic transmission were examined using a subcellular fraction enriched in mossy fiber synaptosomes. Domoic acid significantly increased the K(+)-evoked release of endogenous glutamate from superfused guinea pig mossy fiber synaptosomes. The presynaptic facilitation produced by Dom was dose-dependent and was antagonized by the prior application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). At a concentration of 30 microM, both domoic acid and kainic acid significantly increased the extent to which membrane depolarization augmented the availability of cytosolic free calcium in mossy fiber synaptosomes. These results are consistent with the suggestion that domoic acid enhances the release of mossy fiber neurotransmitters in the guinea pig hippocampus through the activation of a CNQX-sensitive presynaptic receptor.

Distribution of soltriol [1,25(OH)2-vitamin D3] binding sites in male sex organs of the mouse: an autoradiographic study.

After injection of [3H]-1,25(OH)2-vitamin D3 (soltriol), nuclear labeling is found in Sertoli cells of testes, being highest at the stage of spermiosis, in epithelium of efferent ductules and caput epididymidis and in connective tissue cells of epididymis, in lamina propria and muscular sheath of deferent duct, and in epithelium and muscular sheath of dorsal and ventral prostate of the mouse. This labeling pattern is characteristic for [3H]-soltriol and differs from that for [3H]-dihydrotestosterone and [3H]-estradiol, although with overlap. The nuclear labeling with [3H]-soltriol suggests an action of the hormone on certain processes during spermatogenesis, on sperm maturation, on epididymal fluid resorption, and on secretion and transport of spermatozoa.

Anatomical mapping of tetrahydropapaveroline-reactive sites in brain mediating suppression of alcohol drinking in the rat.

In a previous study, anatomically circumscribed sites were identified within limbic-midbrain and limbic-forebrain structures of the rat in which injections of tetrahydropapaveroline (THP) evoked the drinking of alcohol even at aversive concentrations. The purpose of the second part of this study was to identify specific sites in the same limbic structures which also were reactive to THP but which mediated the suppression of alcohol consumption. Cannulae for repeated microinjection of THP were implanted stereotaxically in male Sprague-Dawley rats at sites extending from the ventral tegmental-substantia nigra complex rostrally to the region of the olfactory tubercle. Postoperatively, the rats were tested for their self-selection of water versus alcohol offered in solutions increased over 10 consecutive days in 10 concentrations from 3 to 30%. THP was dissolved in a CSF vehicle containing Na2S2O5 or ascorbate and microinjected in a dose of 25, 50 or 250 ng contained in a volume of 1.5-2.0 microliters. Following a sequence of 5 microinjections of THP, given over 3 days, the same 10-day alcohol drinking test was repeated. Ordinarily, sites at three depths 1.0-1.5 mm beneath the tip of the guide tube were tested for their reactivity to the amine-aldehyde adduct. When injected at 21 sites within coronal planes 1.0-10.5, THP attenuated the intake of alcohol significantly. Structures sensitive to the inhibitory action of the aldehyde adduct included the substantia nigra, reticular formation, medial lemniscus, preoptic area, nucleus accumbens, olfactory tubercle, cingulate gyrus and rostral hippocampus. Within 65 loci contained within the same AP planes, little or no effect of alcohol intake was exerted by THP independent of the dose microinjected. Nonreactive loci were identified within fiber pathways including the corpus callosum and optic tract, motor systems of the caudate nucleus, and both sensory and motor relay nuclei of the thalamus. An analysis of the critical part played by the dose of THP revealed that 81% of reactive sites given the 25 ng dose mediated enhanced drinking of alcohol, as demonstrated in the first study. Conversely, the 50 and 250 ng doses injected at THP-sensitive loci reduced alcohol consumption three to seven times more often than they augmented drinking. Anatomical sites mediating an attenuation of alcohol consumption in response to the higher doses of THP overlapped with both enkephalinergic and dopaminergic systems which project from the ventral tegmentum and substantia nigra to the rostral limbic-forebrain.(ABSTRACT TRUNCATED AT 400 WORDS)

A neuroanatomical substrate for alcohol drinking: identification of tetrahydropapaveroline (THP)-reactive sites in the rat brain.

Certain endogenously synthesized adducts, derived from a condensation reaction of a catechol- or indole-amine with a biogenic aldehyde, act in the brain to augment or suppress the drinking of ethyl alcohol. When infused directly into the cerebral ventricles, a tetrahydro-isoquinoline such as tetrahydropapaveroline (THP) can enhance markedly the consumption of alcohol even in noxious concentrations. The present study was undertaken to isolate and identify specific anatomical structures in the limbic-midbrain, limbic-forebrain which mediate the changes in the ingestion of alcohol induced by THP. In adult male Sprague-Dawley rats, a 23 ga guide tube was implanted stereotaxically either unilaterally or bilaterally in cerebral regions extending from coronal planes AP 1.0-10.0. Following recovery, each animal was tested by a standard screen for its self-selection of water versus an alcohol solution offered in 10 concentrations increased on each of 10 days from 3 to 30%. THP was dissolved in an artificial CSF vehicle containing Na2S2O5 or ascorbate and then microinjected in a volume of 1.5-2.0 microliters at a depth 1.0-1.5 mm beneath the tip of the guide. After a set of 5 microinjections of THP in a dose of 25, 50 or 250 ng was given over 3 days, the same 10-day alcohol preference sequence was repeated. In nearly all rats, the microinjection series was repeated at either one or two depths 1.0-1.5 mm ventral to the first, after which the same alcohol test was repeated. The results showed that THP induces or sustains significant increases in alcohol intake when the adduct was injected at 16 sites within caudal AP planes 1.0-5.0. Structures sensitive to THP included the substantia nigra, reticular formation, medial lemniscus, zona incerta and medial forebrain bundle. When injected at 21 sites located more rostrally within AP planes 6.5-10.0, THP also evoked significant increments in alcohol intake of a similar magnitude. The reactive loci included the N. accumbens, olfactory tubercle, lateral septum, preoptic area, stria terminalis, medial forebrain bundle and rostral hippocampus. In terms of the efficacy of the dose of THP microinjected, 25, 50 and 250 ng induced alcohol self-selection in 81%, 5% and 14% of the sites, respectively. Repeated microinjections following identical procedures of two control solutions at 46 homologous sites within corresponding coronal planes from AP 1.5-10.0 produced no significant alterations in g/kg or proportional intakes of alcohol. Composite anatomical maps of the THP-reactive sites revealed their integral overlap with dopaminergic pathways which originate in the ventral tegmentum and substantia nigra and project rostrally to s

Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes.

This is a review and a prospectus of effects of vitamin D on the brain. Effects of sunlight and equivalent artificial light on physiological and behavioral processes are probably mediated, in large part, through the skin-vitamin D-endocrine system. Experimental evidence from our laboratory reveals sites of action and concomitant direct effects of 1,25(OH)2 vitamin D3 (soltriol) on brain, spinal cord, pituitary and other endocrine tissues. This appears relevant for the activation and modulation of mental and endocrine processes, particularly related to seasonal and daily biorhythms. Effects of sunlight and corresponding artificial light are likely to be mediated through direct actions of soltriol on brain and endocrine tissues that are independent of its effect on calcium levels. Those direct actions are receptor mediated and appear to be dose related as they depend on intensity of light and length of exposure, considering light (photons) as a drug. A role for soltriol, the steroid hormone of sunlight, in the etiology and helio- or phototherapy of affective disorders with cyclic seasonal onset (seasonal affective disorder) is discussed and the significance of research in the new frontier of vitamin D and brain relationships is noted.

Peristaltic versus syringe pumps for push-pull perfusion: tissue pathology and dopamine recovery in rat neostriatum.

The characteristics of performance were compared for two types of pump, peristaltic and infusion-withdrawal, commonly used for localized push-pull perfusion of brain tissue. Guide cannulae were stereotaxically implanted bilaterally in the caudate-putamen complex of the rat at homologous sites in the coronal plane. Consecutive 5.0 min push-pull perfusions were carried out simultaneously with one pump perfusing ipsilaterally while the other pump perfused the contralateral caudate nucleus. 3H-dopamine (DA) diluted with an artificial CSF was used as the radiotracer and was perfused at a rate of 25 microliters/min. Following the collection of 7-8 samples, the brain was fixed, removed, and histological sections taken through the sites of perfusion. Microscopic examination of the perfusion site showed that the circumscribed lesion at the tip of the cannula connected to either pump was generally indistinguishable. A comparison of the values of 3H-DA recovery in samples obtained with the peristaltic and infusion-withdrawal pumps demonstrated that: (1) the respective uptakes of the catecholamine into caudate tissue paralleled one another in most experiments, and (2) the content of 3H-DA in push-pull perfusates recovered from sample to sample varied independently of the pump used. Based on the results of histopathological examination and DA radioactivity values, it is concluded that the peristaltic pump as well as the syringe-driven push-pull pump can yield valid experimental observations which are comparable to one another.

Tetrahydropapaveroline and salsolinol alter 45Ca2+ efflux within perfused hippocampus of unrestrained rats.

The kinetics of 45Ca2+ efflux were examined at circumscribed sites in the perfused hippocampus of the freely moving rat with either one of two tetrahydroisoquinoline (TIQ) products, tetrahydropapaveroline (THP) or salsolinol. Guide tubes for unilateral push-pull perfusion were implanted stereotaxically to rest just above sites within the dorsal hippocampus. Upon recovery from surgery, a tissue site in the hippocampus was prelabeled with 1.0 microliter of 45Ca2+ (2.0 microCi) injected through the indwelling guide tube. After 16-20 hr had elapsed, successive push-pull perfusions of the site were carried out with an artificial cerebrospinal fluid (CSF), at 5.0 min intervals and at a rate of 20 microliters/min, in order to obtain a control washout curve of declining radioactivity. On the fifth of a series of 5.0 min perfusions, either THP or salsolinol was added to the perfusion medium in a concentration of 10 or 100 ng/microliters. Then the hippocampal site was perfused again with control CSF for the collection of an additional three samples. Although THP in both of the test concentrations generally augmented the efflux of 45Ca2+, the temporal course and magnitude of the enhancement depended on the anatomical site of the perfusion. In the more rostral hippocampal planes of AP 3.0 and AP 4.0, THP caused a delayed efflux of the cation, after the perfusion of THP had been discontinued, in nearly half of the loci reactive to the TIQ. Similarly, salsolinol enhanced significantly the efflux of 45Ca2+ in a concentration-dependent manner during the interval of its perfusion within the hippocampal plane of AP 3.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways.

The effect of the novel anxiolytic, buspirone, administered systemically was determined in Sprague-Dawley rats induced to drink ethyl alcohol chronically by repeated microinjections of 25 ng/microliter tetrahydropapaveroline HBr (THP) into brain-stem monoaminergic pathways. Self-selection of alcohol in concentrations from 3% to 30% was determined for each rat in a free-choice drinking situation with water available as the alternative fluid. After stereotaxic implantation of guide tubes, THP was microinjected repeatedly into striatal lemniscal and preoptic sites which were found to mediate significant increases in alcohol preference. After the baseline level of intake of a single, maximally preferred alcohol concentration was established, each rat was treated with either saline vehicle or buspirone given intramuscularly b.i.d. in doses of 5.0 mg/kg or 20 mg/kg. Overall, the repeated administration of either dose of buspirone produced a significant decrease in the voluntary alcohol intake of the rats as measured by the proportion measure and absolute g of alcohol ingested. However, the alteration in drinking varied from animal to animal with respect to both magnitude and duration of the anxiolytic's effect. The response to buspirone seemed to be dependent in part on the individual site in each animal at which THP had been infused to evoke alcohol intake. Post-mortem histological analysis revealed that buspirone-treated rats reduced alcohol consumption by 83% if THP had been microinjected into substantia nigra; by 60% if given in the nucleus accumbens-preoptic area; and by 34% when injected into the medial lemniscus-zona incerta. These results suggest, therefore, that buspirone can exert a specific effect in attenuating the consumption of alcohol of the rat in a free-choice situation. In relation to the differential actions of the anxiolytic, it is envisaged that on an anatomical basis the antagonism of alcohol drinking may be mediated by a pharmacological alteration of circumscribed pathways associated with dopaminergic or serotonergic neurons.