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Mood disorders are a severe health burden but molecular mechanisms underlying mood dysfunction remain poorly understood. Here, we show that wild-type p53-induced phosphatase 1 (Wip1) negatively responds to the stress-induced negative mood-related behaviors. Specifically, we show that Wip1 protein but not its mRNA level was downregulated in the hippocampus but not in the neocortex after 4 weeks of chronic unpredictable mild stress (CUMS) in mice. Moreover, the CUMS-responsive WIP1 downregulation in the hippocampus was restored by chronic treatment of fluoxetine (i.p. 20 mg/kg) along with the CUMS procedure. In addition, Wip1 knockout mice displayed decreased exploratory behaviors as well as increased anxiety-like and depression-like behaviors in mice without impaired motor activities under the non-CUMS condition. Furthermore, the Wip1 deficiency-responsive anxiety-like but not depression-like behaviors were further elevated in mice under CUMS. Although limitations like male-alone sampling and multiply behavioral testing exist, the present study suggests a potential protective function of Wip1 in mood stabilization., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Recent findings from our lab indicate that metabotropic glutamate receptor (mGluR) activation elicits eating, and the goal of the current study was to specify whether the lateral hypothalamus (LH) is the actual brain site mediating this effect. To examine this issue we injected the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) unilaterally into the LH and surrounding regions (n=5-8 subjects/brain site) of satiated adult male Sprague-Dawley rats and measured elicited feeding. We determined that 1.0 nmol elicited food intake only within the LH. Increasing the dose to 10 or 25 nmol produced a more sustained effect in the LH, and also elicited eating in several other brain sites. These results, demonstrating that the LH mediates the eating elicited by low doses of DHPG, suggest that the LH may contain mGluR whose activation can produce eating behavior., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Whole-cell patch-clamp recordings obtained from 36 hypothalamic supraoptic nucleus neurons in explant preparations evaluated a role for GABA(B) receptors in modulating postsynaptic inhibitory and excitatory currents evoked by electrical stimulation in the organum vasculosum of the lamina terminalis. At a holding current of -65 mV, application of baclofen (1-10 microM) induced a dose-dependent reduction in the amplitude of pharmacologically isolated inhibitory and excitatory postsynaptic currents, converted paired-pulse depression in inhibitory postsynaptic currents to paired-pulse facilitation, and enhanced paired-pulse ratios for excitatory postsynaptic currents. In media containing 2-hydroxysaclofen (200-400 microM), baclofen-associated events were blocked and paired-pulse depression in evoked inhibitory postsynaptic currents was abolished. In addition, a progressive increase in the amplitude of inhibitory postsynaptic currents implied that GABA was endogenously active at presynaptic GABA(B) receptors. In contrast, no paired-pulse depression was observed for inhibitory postsynaptic currents evoked in six non-magnocellular neurons. Neither baclofen nor 2-hydroxysaclofen altered holding currents or input resistances in supraoptic neurons, or altered the kinetics of the evoked responses.These observations imply that the terminals of both inhibitory (GABAergic) and excitatory (glutamatergic) afferents to supraoptic nucleus neurons from organum vasculosum lamina terminalis neurons are subject to modulation by presynaptic GABA(B) receptors, and that this modulation is preferentially directed to the inhibitory inputs.

This study investigated the origin of a dopaminergic innervation of the hypothalamic supraoptic nucleus. In pentobarbital-anaesthetized male Long-Evans rats, a transpharyngeal approach was used to inject a retrograde tracer, rhodamine latex microspheres, into the supraoptic nucleus. After 13-26 h survival under anaesthesia, animals were perfused transcardially, the brain sectioned and processed for tyrosine hydroxylase immunofluorescence, a marker for hypothalamic dopaminergic neurons. In six cases with injections restricted to the supraoptic nucleus, rhodamine-labelled microspheres were observed in a population of tyrosine hydroxylase-positive neurons located in the A15 cells below the anterior commissure (A15 dorsal) and above the optic chiasm (A15 ventral), and the dorsal and lateral periventricular A14 cell group. Occasional double-labelled cells were seen in the medial and lateral hypothalamus and bed nucleus of the stria terminalis, but rarely in other known dopaminergic cell groups, notably the ventral tegmental area (A10), zona incerta (A13) and substantia nigra. In support of a role for dopamine in neurohypophysial regulation, these observations indicate that the major dopaminergic input to magnocellular neurons in the hypothalamic supraoptic nucleus is derived from a relatively sparse population of neurons located in the A14 and A15 cell groups.

Corticostriatal neurons linking the prefrontal cortex and the nucleus accumbens connect the terminal fields of the ascending mesotelencephalic dopamine neurons and may potentially mediate cortical dopaminergic modulation of subcortical dopamine transmission. In our attempt to develop a brain slice preparation that maximally preserves this prefrontal accumbens pathway for in vitro electrophysiological studies, knowledge of the complete course of its projection is critical. Microinjection of biotin-dextran amine as an anterograde tracer into the prefrontal cortex revealed the following in the coronal, sagittal and oblique planes of rat brain. (1) Axonal fibers from the rostral prelimbic cortex projected at an angle of approximately 60 degrees to the horizontal plane through the infralimbic region and mainly entered the rostromedial accumbens. Some also chose a ventral route to enter the "core" of the accumbens. (2) From the central ventral prelimbic regions, axons spread out diffusely and descended to the dorsal accumbens. They then entered throughout the rostral-caudal "shell" of the nucleus accumbens. (3) From the caudal prelimbic region of the prefrontal cortex, axonal fibers descended approximately 10 degrees to the coronal plane and entered the dorsal nucleus accumbens and the caudate nucleus. The denser caudate-projecting fibers gave rise to collaterals that entered the accumbens "core". These results suggest that brain slices that preserve the rostral prelimbic-medial accumbens pathway can be obtained by an oblique (approximately 60 degrees) cut, whereas preservation of the caudal prefrontal-accumbens neurons necessitates a 10 degrees cut. Finally, in whole-cell patch-clamp recordings of accumbens neurons in such slices, orthodromically evoked excitatory postsynaptic potentials to deep layer prefrontal cortical stimulation were observed, thus confirming the functional preservation of portions of this prefrontal cortex nucleus accumbens pathway.

1. Dehydrozingeronolol (DZPN; 0.1, 0.5, 1.0 mg/kg, i.v.) produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. DZPN inhibited the tachycardia effects by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. 2. In in vitro study, DZPN antagonized (-)isoproterenol-induced positive chronotropic effects in guinea-pig isolated right atria and relaxation responses in rat isolated uterus horns. 3. DZPN causes mild direct cardiac depression at high concentrations without intrinsic sympathomimetic activity (ISA). 4. The order of potency of beta-adrenoceptor antagonists in competing for the [3H]dihydroalprenolol binding sites was (-)propranolol >> DZPN > or = atenolol.

We have performed penile vein ligation on 35 patients with venogenic impotence from July 1989 to December 1991. The criteria for surgery were (1) age less than 60 years; (2) negative vasoactive agent intracavernous injection but normal penile arterial function, and (3) abnormal venous leakage documented by dynamic infusion cavernosometry and cavernosography. The procedure in venous ligation is excision of the deep dorsal vein from coronary sulcus to pubic arch, and ligation of cavernous veins after identification. The average follow-up was 27.5 months (range 12-37 months) for 30 patients. The 2 patients who revealed no erection at all immediately after operation had dense adhesion of penile hilar region caused in one case by severe pelvic trauma and in the other by pubic bone fracture. Twenty-eight (93.3%) patients were found to sustain excellent erection within 3 months postoperatively. However, only 12 (40.0%) patients sustained spontaneous erection at long-term follow-up, while another 7 (23.3%) responded to intracavernous injection. It is worth mentioning that tortuous and marked dilation of the deep dorsal vein and/or cavernous veins were found intraoperatively in 6 patients who were observed to have excellent erections postoperatively. Inadequate elimination of the leakage veins, especially crural veins, is the most likely factor in those who had a recurrence of erectile dysfunction. However, the corpus cavernosum, particularly a myopathic condition or inadequate neurotransmitters, also plays an important role. Complications included shortness of penis (3 patients), penile deviation (3), numbness of glans penis (4) and wound infection (1).(ABSTRACT TRUNCATED AT 250 WORDS)

Repeated intracavernous injections in healthy monkeys with 2 kinds of vasoactive agents [papaverine and prostaglandin E1 (PGE1) 3 monkeys each] and normal saline (2 monkeys) were conducted in this study. The purpose was to observe the effect of long-term injection on histopathological changes of the cavernous tissue, as well as the change in drug sensitivity (dosage dependence). Different dosages of the same volume (double, single and half dose) of these 3 agents were injected, twice weekly, 10 times alternatively, with rigidity and maintenance of erection recorded. After long-term injection (papaverine group: 37, 60, 60 times; PGE1 group: 26, 60, 60 times; normal saline group: 60, 60 times), all monkeys were sacrificed and the penises were collected for light-microscopic (LM) and electron-microscopic (EM) examinations. Dose-dependent response with reversed drug sensitivity was found in the papaverine group, but only elongation to tumescence was found in the PGE1 group, even with double dosage (probably because of scarce PGE1 receptors in monkey's penile tissue). Histopathologically, mild to moderate fibrotic changes and distortion of normal architecture were predominant findings in LM while aggregation of mitochondria, irregular shape or atrophy of cells were obvious in EM observation in the papaverine group. On the other hand, limited fibrosis with preservation of corpora cavernosa and hypertrophy of smooth muscle were noted in the PGE1 group. This study indicated that less histopathological change occurred in the PGE1 group after long-term intracavernous injection.

The integrative role of the nucleus accumbens and subpallidal area in relaying hippocampal signals to the mesencephalic locomotor region in the brainstem was investigated electrophysiologically in urethan-anaesthetized rats. A behavioural study of the functional connections was also performed in freely moving rats. In the electrophysiological experiments, subpallidal output neurons to the pedunculopontine nucleus and the adjacent ventral gray were first identified by their antidromic responses to electrical stimulation of the pedunculopontine nucleus. Hippocampal stimulation was then shown to inhibit orthodromically some of these subpallidal neurons. The inhibitory response was attenuated following microinjection of a dopamine D2 agonist (LY 171555), but not a D1 agonist (SKF 38393), into the accumbens. This suggests that signal transmission from the hippocampus to the subpallidal output neurons to the pedunculopontine nucleus is modulated by a D2 receptor-mediated mechanism in the nucleus accumbens. Injections of N-methyl-D-aspartate into the ventral subiculum of the hippocampus resulted in a threefold increase in locomotor responses. Injection of a D2 agonist into the accumbens reduced the hyperkinetic response dose-dependently and suggests that D2 receptors regulate locomotor responses initiated by the hippocampal-accumbens pathway. Injection of nipecotic acid, a GABA uptake inhibitor, into the subpallidal area or of procaine, a neural transmission blocker, into the region of the pedunculopontine nucleus, also reduced significantly the hippocampal-induced hyperkinetic response. These results provide evidence of limbic (e.g. hippocampus) influences on locomotor activity by way of nucleus accumbens-subpallidal-pedunculopontine nucleus connections which may contribute to adaptive behaviour. Signal transmission from the hippocampus may be regulated by a dopamine D2 receptor mechanism in the accumbens, presumably mediated by the converging mesolimbic dopaminergic input from the ventral tegmental area.

The integrative role of the ventral striatum in transmitting signals from the hippocampus to the ventral pallidal and subpallidal areas was investigated in urethane-anaesthetized rats using an extracellular single-unit recording technique. Neurones of the nucleus accumbens were first activated by single-pulse stimulation of the ventral subiculum of the hippocampus. Further tests were made to investigate whether these accumbens neurones could be activated antidromically by stimulation of either the ventral pallidal or subpallidal areas. More than 4 times as many accumbens neurones, activated by hippocampal stimulation, responded antidromically to stimulation of subcommissural ventral pallidum than to stimulation of the sublenticular subpallidal area. This observation suggests that the hippocampus has preferential inputs to accumbens efferent neurones which project monosynaptically to the ventral pallidum. Spontaneously active neurones in the ventral pallidum and subpallidal area were inhibited by stimulation of the ventral subiculum of the hippocampus. These inhibitory responses were reduced when glutamic acid diethyl ester, a glutamate antagonist, was microinjected into the medial accumbens, apparently blocking the hippocampal-accumbens glutamatergic synapses to both the ventral pallidal-directed and the subpallidal-directed accumbens efferents. This evidence suggests that signals from the hippocampus reach ventral pallidal and subpallidal regions by way of the nucleus accumbens. The presence of a projection from ventral pallidal and subpallidal regions to the brainstem mesencephalic locomotor region further supports the hypothesis that limbic (e.g. hippocampus) can influence somatomotor activities by way of the nucleus accumbens and its efferent projection to ventral pallidal and subpallidal regions.