Involvement of D1 dopamine receptors in the cognitive effects of angiotensin IV and des-Phe6 angiotensin IV

An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now been well established. We have previously found that intracerebroventricular (ICV) administration of Ang IV as well as des-Phe6-Ang IV enhances learning of conditioned avoidance responses (CARs), facilitates recall of a passive avoidance (PA) task, and improves object recognition (OR) in rats. Since the dopaminergic system is crucial for the cognitive processes, in this study our aim was to determine the dopaminergic D1 mediation of these effects using SCH 23390 as a selective D1 receptor antagonist. Male Wistar rats (180-200 g), pretreated with SCH 23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 0.05 mg/kg intraperitoneally (IP), were given Ang IV or des-Phe6-Ang IV (1 nmol ICV) 1 h later and then tested in the above cognitive paradigms, as well as in the open field and an elevated 'plus' maze to control for the unspecific, respectively, motor and emotional, effects of our treatments. Both, Ang IV and des-Phe6-Ang IV effectively enhanced learning of CARs (P < 0.05), recall of PA (P < 0.001), and improved OR (P < 0.001). Pretreatment with SCH 23390 abolished the cognitive effects of both peptides. SCH 23390, Ang IV, and des-Phe6-Ang IV, given at the same doses and routes as in the cognitive tests, did not significantly influence crossings, rearings and bar approaches in the open field, nor the parameters measured in the elevated 'plus' maze, thus making a major contribution of the unspecific effects of our treatments to the results of the memory tests improbable. In conclusion, these results indicate that the functional dopaminergic D1 receptors are necessary for the Ang IV and des-Phe6-Ang IV cognitive effects to occur.     

Hypothermic and antipyretic effects of centrally administered ACTH (1--24) and alpha-melanotropin

ACTH (1--24) and alpha-melanotropin (alpha-MSH), peptides previously shown to influence body temperature when administered centrally and to occur naturally in brain regions important to temperature control, were injected intracerebroventricularly (ICV) in rabbits. The peptides in doses of 1.25, 2.5 and 5.0 micrograms produced dose-related hypothermias in a 23 degrees C environment, and greater decreases in body temperature when the experiments were repeated in the cold (10 degrees C), but the largest dose had no effect on temperature in the heat (30 degrees C). These results indicate that the peptides do not reduce the central set-point of temperature control. Rather, they appear to selectively inhibit heat conservation and production responses. Five microgram of ACTH reversed vasoconstriction and inhibited rises in temperature caused by leukocytic pyrogen (LP) given IV and ICV. The same dose of alpha-MSH also reduced fever produced by IV and ICV LP, but the reduction was not as great as after ACTH. Both peptides (5 micrograms) also reduced temperature rises and vasoconstriction caused by ICV PGE2. ACTH reduced d-amphetamine-induced hyperthermia without altering vasoconstriction which suggests that this peptide can reduce temperature rises by inhibiting heat production alone. One of the most important findings was that the peptides are antipyretic in that they reduce fever at doses (0.25 microgram, ICV) that do not affect normal temperature. The powerful effects of these peptides on resting body temperature, hyperthermia and fever, together with their presence in brain tissue important to temperature control, suggest that the endogenous central peptides participate in thermoregulation, perhaps by limiting fever and influencing normal temperature.     

The effect of corticotropin-releasing factor (CRF) on autonomic and behavioral responses during shock-prod burying test in rats

When administered intracerebroventricularly (ICV) in rats, corticotropin-releasing factor (CRF) possesses arousing and anxiogenic properties, which may be found reflected in autonomic and behavioral activation. As these responses are dependent on dose and situation, ICV-injected CRF may affect behavioral responses to a defined stimulus in a different fashion than autonomic concomitants. Two experiments were conducted in order to test this hypothesis. In both experiments, rats were treated ICV with CRF or an artificial cerebrospinal fluid (aCSF) 5 min prior to a 15-min exposure to an electrified prod (shock-prod burying test, SPB test) in their home cages. In the first experiment, 0.3 ng CRF injected ICV in unhandled rats significantly reduced the prod-burying response to electric shock, in favor of immobility, whereas following 300 ng CRF ICV, the predominant behavioral response was grooming behavior. In contrast, habituated rats, implanted with telemetric devices to measure heart rate, core temperature, and gross activity in the second experiment, showed a significant increase of burying behavior after 0.3 ng CRF ICV, in comparison to vehicle-treated controls. However, simultaneous cardiac acceleration was of the same magnitude and duration in both groups. In addition, whereas similar rises in CT were observed in both groups during the SPB test, CRF-treated rats showed more marked rise in core temperature during the first 15 min of the posttest period. At the 24-h retention test, rats belonging to the CRF group showed burying behavior and HR responses, in onset, magnitude, and duration similar to day 1, whereas extinction of the burying response and tachycardia was found in controls. Changes in CT, although less marked, showed the same pattern as on day 1 in both groups. These results show a differential effect of central CRF on behavioral and autonomic activation induced by a well-defined stressful stimulus. The response to CRF seems to be not only situation related, but also dependent on the pretest experience of the animal.     

Pressor, tachycardic and behavioral excitatory responses in conscious rats following ICV administration of ACTH and CRF are blocked by naloxone pretreatment

Experiments were conducted to compare the blood pressure and heart rate responses of conscious rats given intracerebroventricular (ICV) injections of adrenocorticotropin (ACTH 1-24) and corticotropin releasing factor (CRF). Under sodium pentobarbital anaesthesia, rats were implanted with a stainless-steel cannula into the lateral cerebral ventricle and had their right femoral artery and vein cannulated. Upon recovery (24-48 hr later) conscious, unrestrained rats were given ICV injections (total volume 5 microliter by gravity flow) of sterile saline, ACTH (1-24) (0.85 and 1.7 nmoles) or CRF (0.55 and 1.1 nmoles) and blood pressure and heart rate were monitored over the next 2 hr (from the abdominal aorta via the femoral arterial catheter). Both ACTH and CRF caused mean arterial pressure (MAP) to increase, which was paralleled with increases in mean heart rate (MHR). Moreover, these elevations in MAP and MHR were temporally associated with excessive grooming (for ACTH) and locomotor activity (for CRF), which occurred before and lasted as long as MAP and MHR were enhanced. Intravenous (IV) pretreatment whereby naloxone was given 10 min before ICV administration of ACTH (1.7 nmoles) or CRF (1.1 nmoles), showed that naloxone blocked the behavioral, pressor and tachycardic effects of both ACTH and CRF. The results demonstrate that the pressor, tachycardic and locomotor effects evoked in conscious rats by ICV administration of ACTH or CRF are antagonized by naloxone and that their hemodynamic changes may, in part, be mediated by prior behavioral activation.     

Anorexigenic effects of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide in the chick brain are mediated by corticotrophin-releasing factor

Intracerebroventricular (ICV) injection of pituitary adenylate cyclase-activating polypeptide-38 (PACAP) or vasoactive intestinal peptide (VIP) inhibits feeding in chicks. However, the underlying anorexigenic mechanism(s) has not yet been investigated. The present study investigated whether these peptides influence the activity of corticotrophin-releasing factor (CRF) neural pathways in the brain of chicks. Firstly, we found that ICV injections of PACAP and VIP increased plasma corticosterone concentrations. The corticosterone-releasing effect of PACAP was completely attenuated by co-injection of astressin, a CRF receptor antagonist, but this effect was only partial for VIP. These results demonstrated that CRF neurons mediate the actions of PACAP and, to a lesser extent, VIP, and suggest that the signaling mechanisms differ between the two peptides. This difference may arise from the two peptides interacting with different receptors because the corticosterone-releasing effect of PACAP, but not VIP, was completely attenuated by co-injection of PACAP (6–38), a PACAP receptor antagonist. Finally, we examined the effect of ICV co-injection of astressin on the anorexigenic effects of PACAP and VIP and found that the effects of both peptides were attenuated by astressin. Overall, the present study suggests that the anorexigenic effects of PACAP and VIP are mediated by the activation of CRF neurons.     

A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice

Corticotropin-releasing factor (CRF) administered intracerebroventricularly (ICV) to rats and mice has been shown to elicit a variety of behaviors resembling those that occur in stress. In a novel multicompartment chamber, ICV CRF altered the behaviors in a manner closely resembling that observed following a period of restraint. In particular, 75 ng CRF ICV or 30-40 min restraint markedly reduced the time mice spent in contact with novel stimuli. ICV injections of a peptide antagonist of CRF, alpha-helical CRF9-41 (ahCRF), reversed the effects of restraint on this measure. This effect of ahCRF was dose dependent, with a minimal effective dose of 10 micrograms. Other behavioral measures appeared normal, and ahCRF did not significantly alter the stimulus-contact time in unrestrained mice. These results provide strong evidence to support the hypothesis that endogenous CRF may be a factor affecting stress-induced changes in exploratory behavior in mice.     

Neophobia and cortical and subcortical binding of the dopamine D2 receptor antagonist [3H]-raclopride

The potential role of dopamine system in response to novelty was analysed using the selective dopamine D2 receptor antagonist, raclopride, in behavioral and biochemical assays, in rats (the open field test, and specific binding of [3H]-raclopride, within different brain structures measured with autoradiography). It was found that raclopride at a low dose (50 microg/kg, IP) caused anxiolytic-like effect (increased the anti-thigmotactic index), whereas at a higher dose (500 microg/kg, IP) produced general inhibitory influence, and decreased the anti-thigmotactic index. Analysis of the behavioral and biochemical results of the experiment revealed a significant negative correlation between the ligand binding in the substantia nigra pars reticulata (SNR), and the number of entries into the central sector of the open field (r=-0.48, p<0.05), as well as the positive correlation between time spent in the central sector of the open field and [3H]-raclopride binding within nucleus accumbens septi (r=0.57, p<0.05). Factor analysis revealed a Factor 1 (eigenvalue=3.361) grouping parameters of central entries into the open field and [3H]-raclopride binding in the SNR (factor loadings are 0.814 and 0.703 respectively), indicating that both phenomena are under control of a similar central process. The above data are discussed in relation to the structure dependent dopamine D2 receptor mechanisms in a rat response to novelty.     

Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III

We compared the in vivo efficacy of two selective CRF2 agonists, mouse urocortin II (mUcn II) and human urocortin III (hUcn III), using food intake, anxious behavior, or ACTH release in CD-1 or Balb/c mice as indices of biological stress responses. All three peptides produced anorexia (Minimal Effective Dose (M.E.D.) for CRF and mUcn II = 0.03 nmol; M.E.D. for hUcn III = 0.3 nmol). Only mUcn II and CRF appeared to increase anxious behaviors in the elevated plus maze test (M.E.D. = 0.3 and 0.01 nmol, respectively). CRF increased the release of plasma ACTH (M.E.D. of 0.3 nmol), while mUcn II and hUcn III had no effect on ACTH release. These data suggest that the CRF2 receptor subtype plays a primary role in the activation of behavioral, but not neuroendocrine, stress responses.     

Corticotropin-releasing factor (CRF) induced anorexia is not influenced by a melanocortin 4 receptor blockage.

CRF and melanocortin (MSH/ACTH) peptides share a number of central effects including anorexia and grooming. The effects of CRF may be secondary, due to CRF's effects on melanocortin peptide release. We investigated if the newly discovered selective melanocortin 4 receptor antagonist HS014 could influence CRF induced anorexia and grooming. The data show that ICV administration of CRF (3 mg/rat), significantly reduced food intake, feeding time and feeding episodes whereas it increased grooming time and grooming episodes. HS014 (5 mg/rat), that previously has been shown to antagonize the anorectic effect and the excessive grooming induced by alpha-MSH, did however not influence any of the behavioral effects induced by CRF when the peptides were administered together. The data indicate that the anorectic and grooming effects of CRF are independent of pathways involving the MC4 receptors. These data suggest that the anorectic and grooming effect of CRF are not due to a secondary effect caused by increase in release of melanocortins acting on the central MC receptors.     

Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala

Corticotropin-releasing factor receptor CRF1 has been implicated in the neurobiological mechanisms of anxiety and depression. The amygdala plays an important role in affective states and disorders such as anxiety and depression. The amygdala is also emerging as a neural substrate of pain affect. However, the involvement of the amygdala in the interaction of pain and anxiety remains to be determined. This study tested the hypothesis that CRF1 receptors in the amygdala are critically involved in pain-related anxiety. Anxiety-like behavior was determined in adult male rats using the elevated plus maze (EPM) test. The open-arm preference (ratio of open arm entries to the total number of entries) was measured. Nocifensive behavior was assessed by measuring hindlimb withdrawal thresholds for noxious mechanical stimulation of the knee. Measurements were made in normal rats and in rats with arthritis induced in one knee by intraarticular injections of kaolin/carrageenan. A selective CRF1 receptor antagonist (NBI27914) or vehicle was administered systemically (i.p.) or into the central nucleus of the amygdala (CeA, by microdialysis). The arthritis group showed a decreased preference for the open arms in the EPM and decreased hindlimb withdrawal thresholds. Systemic or intraamygdalar (into the CeA) administration of NBI27914, but not vehicle, inhibited anxiety-like behavior and nocifensive pain responses, nearly reversing the arthritis pain-related changes. This study shows for the first time that CRF1 receptors in the amygdala contribute critically to pain-related anxiety-like behavior and nocifensive responses in a model of arthritic pain. The results are a direct demonstration that the clinically well-documented relationship between pain and anxiety involves the amygdala.     

Effects of corticotropin-releasing factor, corticotropin and cortisol on gastrointestinal motility in dogs

Gastrointestinal motor activity following intracerebroventricular (ICV) and intravenous (IV) administration of corticotropin releasing factor (CRF), corticotropin (ACTH) and cortisol was investigated in fasted dogs with strain-gauge transducers chronically implanted on the antrum and proximal jejunum. ICV but not IV administration of CRF (20 to 100 ng/kg) suppressed the gastric cyclic migrating motor complex (MMC) for 3 to 6 hours without affecting the jejunum. Similar disruptive effects on the gastric MMC were observed after ICV administration of ACTH (0.5 U/kg) or cortisol (0.1 micrograms/kg) but not after IV administration of 10 times higher doses. These results suggest that in dog CRF may be involved in the central control of the interdigestive gastric motility, these effects were not probably due to the release of ACTH and cortisol the other hormones of the pituitary adrenocortical system change the gastric motility when centrally administered through a possible feed-back mechanism affecting brain CRF level.     

Corticotropin-releasing factor (CRF) receptor subtypes in mediating neuronal activation of brain areas involved in responses to intracerebroventricular CRF and stress in rats

Corticotropin-releasing factor (CRF) plays an important role in stress responses through activation of its receptor subtypes, CRF1 receptor (CRF₁) and CRF2 receptor (CRF₂). The parvocellular paraventricular nucleus of the hypothalamus (PVNp), the central nucleus of the amygdala (CeA), and the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), which are rich in CRF neurons with equivocal expression of CRF₁ and CRF₂, are involved in stress-related responses. In these areas, Fos expression is induced by various stimuli, although the functions of CRF receptor subtypes in stimuli-induced Fos expression are unknown. To elucidate this issue and to examine whether Fos is expressed in CRF or non-CRF neurons in these areas, the effects of antalarmin and antisauvagine-30 (AS-30), CRF₁- and CRF₂-specific antagonists, respectively, on intracerebroventricular (ICV) CRF- or 60 min-restraint-induced Fos expression were examined in rats. ICV CRF increased the number of Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in CRF and non-CRF neurons and by AS-30 in CRF neurons. Restraint also increased Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in the CRF neurons. ICV CRF also increased Fos-positive non-CRF neurons in the CeA and the BNSTov, which was inhibited by AS-30 in both areas, and inhibited by antalarmin in the BNSTov only. Restraint increased Fos-positive non-CRF neurons in the CeA and BNSTov, with the increases being almost completely inhibited by either antagonist. These results indicate that both ICV CRF and restraint activate both CRF and non-CRF neurons in the PVNp and non-CRF neurons in the CeA and BNSTov, and that the activation is mediated by CRF₁ and/or CRF₂. However, the manner of involvement for CRF₁ and CRF₂ in ICV CRF- and restraint-induced activation of neurons differs with respect to the stimuli and brain areas; being roughly equivalent in the CeA and BNSTov, but different in the PVNp. Furthermore, the non-CRF_1&2-mediated signals seem to primarily play a role in restraint-induced activation of non-CRF neurons in the PVNp since the activation was not inhibited by CRF receptor antagonists.     

Corticotropin-releasing factor (CRF) receptor subtypes in mediating neuronal activation of brain areas involved in responses to intracerebroventricular CRF and stress in rats

Corticotropin-releasing factor (CRF) plays an important role in stress responses through activation of its receptor subtypes, CRF1 receptor (CRF₁) and CRF2 receptor (CRF₂). The parvocellular paraventricular nucleus of the hypothalamus (PVNp), the central nucleus of the amygdala (CeA), and the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), which are rich in CRF neurons with equivocal expression of CRF₁ and CRF₂, are involved in stress-related responses. In these areas, Fos expression is induced by various stimuli, although the functions of CRF receptor subtypes in stimuli-induced Fos expression are unknown. To elucidate this issue and to examine whether Fos is expressed in CRF or non-CRF neurons in these areas, the effects of antalarmin and antisauvagine-30 (AS-30), CRF₁- and CRF₂-specific antagonists, respectively, on intracerebroventricular (ICV) CRF- or 60 min-restraint-induced Fos expression were examined in rats. ICV CRF increased the number of Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in CRF and non-CRF neurons and by AS-30 in CRF neurons. Restraint also increased Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in the CRF neurons. ICV CRF also increased Fos-positive non-CRF neurons in the CeA and the BNSTov, which was inhibited by AS-30 in both areas, and inhibited by antalarmin in the BNSTov only. Restraint increased Fos-positive non-CRF neurons in the CeA and BNSTov, with the increases being almost completely inhibited by either antagonist. These results indicate that both ICV CRF and restraint activate both CRF and non-CRF neurons in the PVNp and non-CRF neurons in the CeA and BNSTov, and that the activation is mediated by CRF₁ and/or CRF₂. However, the manner of involvement for CRF₁ and CRF₂ in ICV CRF- and restraint-induced activation of neurons differs with respect to the stimuli and brain areas; being roughly equivalent in the CeA and BNSTov, but different in the PVNp. Furthermore, the non-CRF_1&2-mediated signals seem to primarily play a role in restraint-induced activation of non-CRF neurons in the PVNp since the activation was not inhibited by CRF receptor antagonists.     

Cardiac actions of central but not peripheral urotensin II are prevented by beta-adrenoceptor blockade

Urotensin II (UII) is a highly conserved peptide that has potent cardiovascular actions following central and systemic administration. To determine whether the cardiovascular actions of UII are mediated via beta-adrenoceptors, we examined the effect of intravenous (IV) propranolol on the responses to intracerebroventricular (ICV) and IV administration of UII in conscious sheep. Sheep were surgically instrumented with ICV guide tubes and flow probes or cardiac sympathetic nerve recording electrodes. ICV UII (0.2 nmol/kg over 1 h) caused prolonged increases in heart rate (HR; 33 +/- 11 beats/min; P < 0.01), dF/dt (581 +/- 83 L/min/s; P < 0.001) and cardiac output (2.3 +/- 0.4 L/min; P < 0.001), accompanied by increases in coronary (19.8 +/- 5.4 mL/min; P < 0.01), mesenteric (211 +/- 50 mL/min; P < 0.05) and iliac (162 +/- 31 mL/min; P < 0.001) blood flows and plasma glucose (7.0 +/- 2.6 mmol/L; P < 0.05). Propranolol (30 mg bolus followed by 0.5 mg/kg/h IV) prevented the cardiac responses to ICV UII and inhibited the mesenteric vasodilatation. At 2 h after ICV UII, when HR and mean arterial pressure (MAP) were increased, cardiac sympathetic nerve activity (CSNA) was unchanged and the relation between CSNA and diastolic pressure was shifted to the right (P < 0.05). The hyperglycemia following ICV UII was abolished by ganglion blockade but not propranolol. IV UII (20 nmol/kg) caused a transient increase in HR and fall in stroke volume; these effects were not blocked by propranolol. These results demonstrate that the cardiac actions of central UII depend on beta-adrenoreceptor stimulation, secondary to increased CSNA and epinephrine release, whereas the cardiac actions of systemic UII are not mediated by beta-adrenoreceptors and probably depend on a direct action of UII on the heart.     

CRF type 1 receptors in the dorsal periaqueductal gray modulate anxiety-induced defensive behaviors

The dorsal periaqueductal gray (dPAG) is involved in defensive coping reactions to threatening stimuli. Corticotropin releasing factor (CRF) is substantially implicated as a direct modulator of physiological, endocrine and behavioral responses to a stressor. Previous findings demonstrate a direct role of the central CRF system in dPAG-mediated defensive reactions toward a threatening stimulus. These include anxiogenic behaviors in the elevated plus maze (EPM) in rats and defensive reactions in both the mouse defense test battery (MDTB) and rat exposure test (RET) paradigms in mice. Furthermore, CRF was shown to directly and dose-dependently excite PAG neurons in vitro. The aim of the present series of experiments was to directly evaluate the role of the CRF1 receptor (CRF1) in dPAG-induced defensive behaviors in the MDTB and the RET paradigms. For this purpose, cortagine, a novel CRF1-selective agonist, was directly infused into the dPAG. In the RET the high dose of cortagine (100 ng) significantly affected spatial avoidance measures and robustly increased burying behavior, an established avoidance activity, while having no effects on behaviors in the MDTB. Collectively, these results implicate CRF1 in the dPAG as a mediator of temporally and spatially dependent avoidance in response to controllable and constant stimuli.     

Effects of ovine CRF injections into the dorsomedial, dorsolateral and lateral columns of the periaqueductal gray: a functional role for the dorsomedial column

Corticotropin-releasing factor (CRF) and its receptor subtypes have been implicated in the regulation of endocrine, behavioral and autonomic responses to stress, fear and anxiety. Ovine CRF (oCRF) is a nonspecific CRF receptor agonist that produces anxiogenic-like effects when injected locally into the dorsal aspects of the periaqueductal gray (PAG). This structure is subdivided into four distinct longitudinal columns but their exact functional role is not fully understood. The purpose of the present study was to characterize the effects of oCRF (0.25, 0.5 and 1 microg/0.2 microL) injections into the dorsomedial (dmPAG), dorsolateral (dlPAG) and lateral (lPAG) columns of the PAG using an analysis of the exploratory behavior of rats in the elevated plus-maze (EPM) test. The results showed that microinjections of oCRF intra-dmPAG reduced entries and time spent in the open arms and decreased end-arm exploration and head-dipping. In contrast, oCRF intra-dlPAG or lPAG did not affect the exploratory behavior of the animals in the EPM. These findings point to a columnar specificity for the oCRF effects in the PAG, that is, it increased spatial avoidance measures of the EPM test only in the dmPAG. The proaversive effects of oCRF in the dmPAG gain further relevance when combined with previous immunohistochemical studies showing that CRF-containing projections from the periventricular hypothalamic system arch dorsomedially to the PAG, which could function as an important relay station in the midbrain tectum for avoidance behaviors.     

C-terminal region of teneurin-1 co-localizes with the dystroglycan complex in adult mouse testes and regulates testicular size and testosterone production

Testicular size is directly proportional to fertility potential and is dependent on the integration of developmental proteins, trophic factors, and sex steroids. The teneurins are transmembrane glycoproteins that function as signaling and cell adhesion molecules in the establishment and maintenance of the somatic gonad, gametogenesis, and basement membrane. Moreover, teneurins are thought to function redundantly to the extracellular matrix protein, dystroglycan. Encoded on the last exon of the teneurin genes is a family of bioactive peptides termed the teneurin C-terminal-associated peptides (TCAPs). One of these peptides, TCAP-1, functionally interacts with β-dystroglycan to act as a neuromodulatory peptide with trophic characteristics independent from the teneurins. However, little is known about the localization and relationship between the teneurin-TCAP-1 system and the dystroglycans in the gonad. In the adult mouse testis, immunoreactive TCAP-1 was localized to spermatogonia and spermatocytes and co-localized with β-dystroglycan. However, teneurin-1 was localized to the peritubular myoid cell layer of seminiferous tubules and tubules within the epididymis, and co-localized with α-dystroglycan and α-smooth muscle actin. TCAP-1-binding sites were identified in the germ cell layers and adluminal compartment of the seminiferous tubules, and epithelial cells of the epididymis. In vivo, TCAP-1 administration to adult mice for 9 days increased testicular size, seminiferous and epididymal tubule short-diameter and elevated testosterone levels. TCAP-1-treated mice also showed increased TCAP-1 immunoreactivity in the caput and corpa epididymis. Our data provide novel evidence of TCAP-1 localization in the testes that is distinct from teneurin-1, but is integrated through an association with the dystroglycan complex.     

Effects of corticotropin releasing factor and sauvagine on social behavior of isolated mice

Corticotropin releasing factor (CRF) and sauvagine (SVG) when injected ICV both reduced aggressive behavior and sociability while increasing defensive behavior in isolated DBA/2 mice interacting with a group-housed intruder. SVG was more effective than CRF in producing such behavioral effects. These results add further evidence to the similarity between CRF and SVG, and are discussed in terms of the involvement of these peptides in emotional reactivity in the laboratory mouse.     

Cardiovascular effects of dynorphin A (1–13) in conscious rats and its modulation of morphine bradycardia over time

The short-term cardiovascular effects of dynorphin A (1–13), as well as its effects upon morphine bradycardia were investigated. In unanesthetized, unrestrained rats, intracerebroventricular (ICV) dynorphin A (1–13) injections (10–20 μg) produced a dose-related pressor effect, whereas intravenous (IV) dynorphin A (1–13) (1.0 mg/kg) produced a depressor effect; these responses persisted less than five min. Heart rate was not significantly altered by these doses or routes of administration. Dynorphin A (1–13) also produced behavioral effects in the unanesthetized animals, such as wet dog shakes in response to IV administration and wet dog shakes accompanied by barrel rolling in response to ICV administration. To evaluate the effects of dynorphin A (1–13) pretreatment on the bradycardic response to IV morphine, rats were pretreated with 10 μg dynorphin A (1–13) ICV four, six or eight hours prior to challenge with morphine sulfate (0.1 mg/kg IV). Four hour pretreatment with dynorphin A (1–13) (tested at 14:00 hr) resulted in a potention of morphine bradycardia, with six hours pretreatment (tested at 16:00 hr) no effect was observed, and eight hours following dynorphin A (1–13) pretreatment (tested at 18:00 hr) morphine bradycardia was attenuated. Additionally, the bradycardic response to IV morphine alone became more exaggerated as rats approached their nocturnal activity cycle. These data further establish that dynorphin A (1–13) exerts a potent, long lasting modulatory effect on morphine bradycardia and emphasize the importance of circadian variables in altering the magnitude of cardiovascular responses to opioid agonists.