Valproate improves prepulse inhibition deficits induced by corticotropin-releasing factor independent of GABA(A) and GABA(B) receptor activation.

Corticotropin-releasing factor (CRF) is implicated in the pathogenesis of bipolar disorder, an illness associated with deficits in prepulse inhibition (PPI) of the acoustic startle response. Valproate is used in the treatment of bipolar disorder and may alter CRF activity via a GABA(A)-ergic mechanism. This study determined the effect of valproate on CRF-disrupted PPI and examined the role of the hypothalamic-pituitary-adrenal axis and GABA-ergic signaling in the effect of valproate. Valproate (60-240 mg/kg) dose-dependently reversed PPI deficits displayed by transgenic mice overexpressing CRF (CRFtg), and normalized PPI deficits induced by CRF i.c.v. infusion in 129Sv mice. Valproate enhanced corticosterone secretion more effectively in CRFtg than in wild-type mice. The effect of valproate on PPI was not blocked by the GABA(A) receptor antagonist bicuculline, the GABA(B) receptor antagonists phaclofen and SCH 50911 or combined administration of a GABA(A) and GABA(B) receptor antagonist. The beneficial effect of valproate on PPI was not mimicked by the GABA(A) receptor agonist muscimol, the GABA transaminase inhibitor vigabatrin, the histone deacetylase (HDAC) inhibitor sodium butyrate or by the mood stabilizers lithium, carbamazepine, lamotrigine or topiramate. Thus, we showed that valproate improves CRF-induced PPI deficits, albeit via a so far unknown mechanism. These marked beneficial effects of valproate on CRF-induced sensorimotor gating deficits suggest that valproate may be of particular value in specific subgroups of bipolar patients that are characterized by alterations in the CRF system.

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents.

RATIONALE: As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF1 receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating. OBJECTIVES: To determine the effects of CRF1 receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs. METHODS: CP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of D-amphetamine (2.5-5 mg/kg) and MK801 (0.3-1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on D-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis. RESULTS: No CRF1-antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not D-amphetamine. Further, D-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526. CONCLUSION: The inability of CRF1 receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.

Activation of the septohippocampal system differentiates anxiety from fear in startle paradigms.

It has been suggested that different brain areas are involved in the modulation and expression of fear and anxiety. In the present study we investigated these potential differences by using the fear-potentiated-startle (FPS) and light-enhanced-startle (LES) paradigms to differentiate between fear and anxiety, respectively. Male Wistar rats were tested in the FPS and LES paradigm and perfused 1 h after the test session. Fos immunoreactivity (IR) was quantified in 21 brain areas and compared between FPS, LES and four control conditions. Both FPS and LES procedures significantly enhanced the acoustic startle response. A principal component analysis of Fos-IR-data showed that 70% of the changes in Fos-IR could be explained by three independent components: an arousal-component, identifying brain areas known to be activated under conditions of vigilance, arousal and stress, a LES- and an FPS-component. The LES component comprised the septohippocampal system and functionally interrelated areas including nucleus accumbens, anterior cingulate cortex, lateral habenula and supramammillary areas, but not the dorsolateral part of the bed nucleus of the stria terminalis. The central amygdaloid nucleus and the dorsolateral part of the bed nucleus of the stria terminalis loaded exclusively on the FPS component. Analysis of the separate brain areas revealed significantly higher Fos-IR in LES relative to FPS in the anterior cingulate cortex, nucleus accumbens shell, lateral septum, lateral habenula and area postrema. We conclude that the neural circuitry activated during FPS and LES shows clear differences. In anxiety as induced by LES, activation of the septohippocampal system and related areas seems to play a major role. In fear as induced by FPS, the central amygdaloid nucleus and the dorsolateral part of the bed nucleus of the stria terminalis loaded on the same component, but Fos-IR observed in these brain regions did not differentiate between anxiety and fear. Furthermore, principal-component analysis appears a useful tool in detecting and describing correlated changes in patterns of neuronal activity.

The anxiolytic effects of flesinoxan, a 5-HT1A receptor agonist, are not related to its neuroendocrine effects.

The effects of flesinoxan, a selective 5-HT1A receptor agonist, were studied under basal non-stress conditions and in the shock-probe burying paradigm. Flesinoxan (1 and 3 mg/kg s.c.) significantly reduced burying and freezing behaviour, indicating clear anxiolytic properties. Under non-stress conditions, injection of 3 mg/kg flesinoxan significantly enhanced plasma corticosterone and glucose levels, whereas prolactin secretion was significantly enhanced after both 1 mg/kg and 3 mg/kg flesinoxan. Flesinoxan (1 and 3 mg/kg) did not suppress shock-probe stress-induced rises in plasma corticosterone and glucose levels. The enhanced plasma prolactin levels induced by flesinoxan were not further affected by shock-probe exposure. Our data show that the anxiolytic effects of flesinoxan in the shock-probe burying paradigm are not related to increases in plasma corticosterone and glucose levels.