Functional inactivation of the orbitofrontal cortex disrupts context-induced reinstatement of alcohol seeking in rats.

BACKGROUND: The high rate of relapse to drug use remains a central challenge to treating drug addiction. In human and rat models of addiction, environmental stimuli in contexts associated with previous drug use can provoke a relapse of drug seeking. Pre-clinical studies have used the ABA renewal procedure to study context-induced reinstatement of drug seeking. In the current study, we studied the role of the orbitofrontal cortex (OFC) in context-induced reinstatement to alcohol. METHODS: We trained male and female rats to self-administer alcohol in context A, extinguished drug-reinforced responding in a distinct context B, and assessed context-induced reinstatement in context A or B (control group). Next, we determined the effect of context-induced renewal of alcohol-seeking behavior on the expression of Fos (a neuronal activity marker) in the OFC. Finally, we determined the effect of reversible inactivation by GABAa and GABAb receptor agonists (i.e., muscimol and baclofen, respectively) in the OFC. RESULTS AND CONCLUSIONS: There were no differences between male and female rats in context-induced reinstatement of alcohol-seeking behavior. Re-exposure to Context A, but not Context B, reinstated alcohol-seeking behavior and increased expression of the neural activity marker Fos in the OFC. Reversible inactivation of the OFC with muscimol and baclofen attenuated context-induced reinstatement. Our data indicated that the OFC mediates context-induced reinstatement of alcohol-seeking behavior.

Cooperative regulation of Gja1 expression by members of the AP-1 family cJun and cFos in TM3 Leydig and TM4 Sertoli cells.

Within the testis, connexin43 encoded by Gja1 plays an important role in cell-to-cell communication between Leydig cells as well as between Sertoli cells and spermatogonia. In the adult male, Leydig cells are the principal producers of testosterone sustaining spermatogenesis, while Sertoli cells nourish, protect and support the differentiating germ cells. It has been shown previously that members of the AP-1 family regulate Gja1 expression in myometrial cells, suggesting that such regulatory mechanism may also be relevant within the testis. Thus, we performed cotransfections of AP-1 expression plasmids with different mouse Gja1 promoter/luciferase reporter constructs within TM3 Leydig and TM4 Sertoli cells. We showed that a functional cooperation between cJun and cFos activates Gja1 expression and requires an AP-1 DNA regulatory element located between -132 and -26 bp. In addition, such synergy relies on the recruitment of cFos to this region of the mouse Gja1 promoter. Hence, our data indicate that AP-1 members are important for optimal expression of Gja1 within Sertoli and Leydig cells from the testis.

Mimicking the tumour microenvironment of chronic lymphocytic leukaemia in vitro critically depends on the type of B-cell receptor stimulation.

BACKGROUND: The B-cell receptor (BCR) has a key role in the cross-talk between chronic lymphocytic leukaemia (CLL) cells and the tissue microenvironment, which favours disease progression by promoting proliferation and drug resistance. In vitro studies on downstream signalling and functional effects of CLL BCR ligation often report contradictory results, in part owing to the lack of a standardised stimulation protocol. Our aim was to define a biologically relevant and robust in vitro stimulation method with regard to cellular phenotypic and transcriptional responses. METHODS: We evaluated mRNA (FOS, MYC, LPL) and protein (CD54, CD19, CD62L, CD184) expression of genes modulated by BCR triggering in immunoglobulin heavy-chain variable region genes (IGHV)-mutated and -unmutated CLL cells, after stimulation using soluble or immobilised anti-IgM antibodies from different suppliers. RESULTS: The effect of BCR stimulation on gene and protein expression was comparable in all CLL patients, irrespective of IGHV mutation status. However, immobilised anti-IgM stimulation elicited clear and robust changes in gene and protein expression, whereas the response to soluble anti-IgM was far less obvious. CONCLUSIONS: These data indicate that the method of BCR stimulation is of major importance regarding responsiveness of CLL cells in the context of the tumour microenvironment, whereas genetic differences in the BCR pathway are less critical.

Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis.

Increased bone fracture is one of the health risk factors in patients with bone loss related disorders such as osteoporosis and breast cancer metastasis to bone. Over activity of osteoclasts leads to uncoupling of bone remodeling favoring bone loss over bone formation. Receptor activator of nuclear factor-κß ligand (RANKL) triggers the differentiation pathway leading to multinucleated osteoclast formation. Modulation of RANKL or its downstream signaling pathways involved in osteoclast formation is of significant interest in the development of anti-resorptive agents. In this study, the effects of piperine, an alkaloid present in Piper nigrum L. on osteoclast formation was investigated. Piperine inhibited tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation in murine RAW264.7 macrophages and human CD14+ monocytes induced by RANKL and breast cancer cells. Piperine attenuated the p38-mitogen activated protein kinase pathway activation, while the extracellular-signal-regulated kinase, c-Jun N-terminal kinase, or NF-κß pathways downstream of RANKL remained unaffected. Concomitantly, expression of c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key transcription factors involved in osteoclastogenesis were remarkably inhibited by piperine. Furthermore, piperine disrupted the actin ring structure and bone resorption, a characteristic hallmark of osteoclasts. Collectively, these results suggested that piperine inhibited osteoclast differentiation by suppressing the p38/NFATc1/c-Fos signaling axis..

Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.

Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.

Acute restraint differently alters defensive responses and fos immunoreactivity in the rat brain.

Results from a previous study show that rats exposed to acute restraint display anxiogenic-like behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. In contrast, escape responses were unaltered by stress exposure. Since ETM avoidance and escape tasks seem to activate distinct sets of brain structures, it is possible that the differences observed with acute restraint are due to particularities in the neurobiological mechanisms which modulate these responses. In the present study, analysis of fos protein immunoreactivity (fos-ir) was used to map areas activated by exposure of male Wistar rats to restraint stress (30 min) previously (30 min) to the ETM. Corticosterone levels were also measured in stressed and non-stressed animals. Confirming previous observations restraint facilitated avoidance performance, an anxiogenic result, while leaving escape unaltered. Performance of the avoidance task increased fos-ir in the frontal cortex, intermediate lateral septum, basolateral amygdala, basomedial amygdala, lateral amygdala, anterior hypothalamus and dorsal raphe nucleus. In contrast, performance of escape increased fos-ir in the ventromedial hypothalamus, dorsolateral periaqueductal gray and locus ceruleus. Both behavioral tasks also increased fos-ir in the dorsomedial hypothalamus. Restraint significantly raised corticosterone levels. Additionally after restraint, fos-ir was predominantly seen in the basolateral amygdala and dorsal raphe of animals submitted to the avoidance task. This data confirms that different sets of brain structures are activated by ETM avoidance and escape tasks and suggests that acute restraint differently alters ETM behavior and the pattern of fos activation in the brain.

Mating increases male's interest in other females: a cognitive study in socially monogamous prairie voles (Microtus ochrogaster).

To determine whether socio-sexual interactions with females influence the male prairie vole's cognitive processing, three groups of males were simultaneously exposed to sensory stimuli of a control and a focal female then tested for their behavioral and neuronal responsiveness to the female cues. From the control female, all males received distal cues. From the focal female, the Unmated males received distal cues, the Unmated-Contact males received all cues but did not mate with her, and the Mated-Contact males received all cues and mated with her. Males were tested for their attentiveness to enclosures holding each female and for their memory of the females' previous location. Males' brains were then examined to localize activated regions following exposure to the odor of familiar versus unfamiliar focal females. The Mated-Contact males spent more time in the cage of the control female attending to her enclosure than in the cage of the focal female. Exposure to odors of unfamiliar focal females activated the cingulate cortex of Unmated-Contact males. There was a negative correlation between the level of neuronal activation in the retrosplenial cortex of males that were exposed to the odors of a familiar focal female and their attentiveness to the enclosure of the control female. The data suggest that the effect of socio-sexual interactions with a female on males' cognition depends on the type of sensory signals males receive from females and how individual males perceive those signals.

A synthetic cell-penetrating peptide antagonizing TrkA function suppresses neuropathic pain in mice.

Nerve growth factor (NGF) and its high-affinity receptor, TrkA, are one of the targets in the production of new drugs for the treatment of neuropathic pain. NGF contributes to both the initiation and maintenance of sensory abnormalities after peripheral nerve injury. This study examined the effects of IPTRK3, a new synthetic cell-penetrating peptide that antagonizes TrkA function, on neuropathic pain in mice. Partial sciatic nerve ligation (PSNL) was used to generate neuropathic pain, and we injected IPTRK3 (2 or 10 mg/kg) intraperitoneally on day 7 after PSNL. Effects of the peptide on hyperalgesia, allodynia, and expression of Fos in the spinal cord were examined. Single administration of the peptide on day 7 significantly suppressed both thermal hyperalgesia and mechanical allodynia. Gentle touch stimuli-evoked Fos expression in the lumbar spinal cord was also significantly reduced. Intraperitoneal injection of a cell-penetrating peptide antagonizing TrkA function appears effective for treatment of neuropathic pain in a mouse pain model.

Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia.

Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.

Induction of Fos proteins in regions of the nucleus accumbens and ventrolateral striatum correlates with catalepsy and stereotypic behaviours induced by morphine.

A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the micro-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves long-term neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.

Noradrenergic neurons expressing Fos during waking and paradoxical sleep deprivation in the rat.

Noradrenaline is known to induce waking (W) and to inhibit paradoxical sleep (PS or REM). Both roles have been exclusively attributed to the noradrenergic neurons of the locus coeruleus (LC, A6), shown to be active during W and inactive during PS. However, the A1, A2, A5 and A7 noradrenergic neurons could also be responsible. Therefore, to determine the contribution of each of the noradrenergic groups in W and in PS inhibition, rats were maintained in continuous W for 3h in a novel environment or specifically deprived of PS for 3 days, with some of them allowed to recover from this deprivation. A double immunohistochemical labeling with Fos and tyrosine hydroxylase was then performed. Thirty percent of the LC noradrenergic cells were found to be Fos-positive after exposure to the novel environment and less than 2% after PS deprivation. In contrast, a significant number of double-labeled neurons (up to 40% of the noradrenergic neurons) were observed in the A1/C1, A2 and A5 groups, after both novel environment and PS deprivation. After PS recovery and in control condition, less than 1% of the noradrenergic neurons were Fos-immunoreactive, regardless of the noradrenergic group. These results indicate that the brainstem noradrenergic cell groups are activated during W and silent during PS. They further suggest that the inhibitory effect of noradrenaline on PS may be due to the A1/C1, A2 and to a lesser degree to A5 neurons but not from those of the LC as previously hypothesized.

Locomotor activity to nicotine and Fos immunoreactivity in the paraventricular nucleus of the hypothalamus in adolescent socially-stressed rats.

We reported previously that social stressors in adolescence (SS: one-hour isolation and new cage partners daily for 16 days) increased locomotor activity to nicotine and to amphetamine in females, but not in males, when tested as adults. Here, we investigated whether effects of stressors in adolescence on locomotor responses to nicotine would be observed in both sexes if tested closer in time to the stressor exposure. We also tested whether social instability was necessary to alter nicotine's effects on locomotor activity by including a group that underwent daily isolation but was housed with the same partner (ISO). The locomotor-activating effects of nicotine were lower in SS rats compared to ISO and non-stressed control rats. In males, but not in females, there were effects of nicotine treatment and of stress condition on Fos immunoreactive (Fos-ir) cell counts in the paraventricular nucleus (PVN) of the hypothalamus: SS males had higher Fos-ir counts than did ISO and non-stressed control males, and higher Fos-ir counts in the PVN were found in repeated-nicotine groups than in acute-nicotine and saline groups. These results add to evidence that adolescents are uniquely vulnerable to stressors due to ongoing brain development, and also indicate that effects are sex- and stressor-specific.

Atropine methyl nitrate increases myenteric but not dorsal vagal complex Fos-like immunoreactivity in the rat.

Atropine methyl nitrate (AMN, 0.05, 0.5 and 25 mg/kg) intraperitoneally increased Fos-like immunoreactivity (Fos-LI) in the myenteric plexus, but not the dorsal vagal complex (DVC, the area postrema (AP), nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMV)) in adult, male Sprague-Dawley rats. A 3 mg/kg AMN dose decreased intake of 15% sucrose, but failed to increase Fos-LI in both locations. In conclusion, the myenteric plexus may play a local role in the behavioral response evoked by AMN.

Vagus nerve stimulation preferentially induces Fos expression in nitrergic neurons of rat esophagus.

To identify neurochemical phenotypes of esophageal myenteric neurons synaptically activated by vagal preganglionic efferents, we immunohistochemically detected the expression of Fos, an immediate early gene product, in whole-mount preparations of the entire esophagus of rats following electrical stimulation of the vagus nerves. When electrical stimulation was applied to either the cervical left (LVN) or right vagus nerve (RVN), neurons with nuclei showing Fos immunoreactivity (IR) were found to comprise approximately 10% of the total myenteric neurons in the entire esophagus. These neurons increased from the oral toward the gastric end of the esophagus, with the highest frequency in the abdominal portion of the esophagus. A significant difference was not found in the number of Fos neurons between the LVN-stimulated and RVN-stimulated esophagus. Double-immunolabeling showed that nitric oxide synthase (NOS)-IR occurred in most (86% and 84% in the LVN-stimulated and RVN-stimulated esophagus, respectively) of the Fos neurons in the entire esophagus. Furthermore, the stimulation of either of the vagus nerves resulted in high proportions (71%-90%) of Fos neurons with NOS-IR, with respect to the total Fos neurons in each segment, in the entire esophagus. However, a small proportion (8% and 7% in the LVN-stimulated and RVN-stimulated esophagus, respectively) of the Fos neurons in the esophagus exhibited choline acetyltransferase (ChAT)-IR. The occurrence-frequency of Fos neurons with ChAT-IR was less than 4% of the total Fos neurons in any segment of the LVN-stimulated and RVN-stimulated esophagus. Some of the Fos neurons with ChAT-IR appeared to be innervated by numerous varicose ChAT-positive nerve terminals. The present results showing that electrical stimulation of the vagus nerves induces a high proportion of Fos neurons with NOS-IR suggests the preferential activation of NOS neurons in the esophagus by vagal preganglionic efferents. This connectivity between the vagal efferents and intrinsic nitrergic neurons might be involved in inhibitory actions on esophageal motility.

Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models.

The novel antipsychotic aripiprazole requires high (>90%) striatal D2 receptor occupancy (D2RO) to be clinically active, but despite its high D2RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D2RO, they show motor side effects when D2RO exceeds 80%. We investigated this discrepancy between D2RO, 5HT2 receptor occupancy (5-HT2RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D2RO. While risperidone clearly showed higher 5-HT2RO than D2RO, aripiprazole and haloperidol showed higher D2RO than 5-HT2RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing >80% D2RO, while aripiprazole despite higher D2RO (>90%) induced no catalepsy. Haloperidol and risperidone's ED50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to approximately 60% D2RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D2RO, a 23-fold higher dose (86% D2RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D2ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D2RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D2 agonist antipsychotics.

Stereoselective and region-specific induction of immediate early gene expression in rat parietal cortex by blockade of neurokinin 1 receptors.

Antagonists at neurokinin 1 (NK1) receptors are attracting attention as potential treatments for depressive states in light of their actions in behavioural models predictive of antidepressant properties, their modulation of corticolimbic monoaminergic transmission, and their influence upon neural plasticity. Here, we evaluated the influence of NK1 receptor blockade upon two immediate early genes, Arc and c-fos, implicated in mechanisms of synaptic plasticity. Administration of the selective NK1 receptor antagonist, GR 205,171 (40, but not 1, 5 or 10 mg/kg i.p.), elicited a pronounced elevation in mRNA encoding Arc in both outer and inner layers of the parietal cortex of rat brain. This action was region-specific inasmuch as Arc expression did not change in other cortical territories examined including frontal cortex, nor in CA1, CA3 and the dentate gyrus of the hippocampus. In comparison to GR 205,171, its less active isomer GR 226,206 (1-40 mg/kg) did not significantly modify Arc gene expression in parietal cortex or other cortical areas. GR 205,171 (40 mg/kg) also increased the abundance of c-fos mRNA in outer and inner parietal cortex and caused a corresponding increase in c-fos immunoreactivity in this region. GR 226,206 (40 mg/kg i.p.) had no effect on either c-fos mRNA or protein in parietal cortex. In conclusion, administration of GR 205,171 elicits a stereospecific increase in Arc and c-fos expression in rat parietal cortex but not in other cortical regions. These data suggest that the parietal cortex plays a role in the central actions of NK1 receptor antagonists.

A semi-quantitative analysis of Fos expression by mustard oil.

In the present study, a semi-quantitative analysis of Fos expression by mustard oil was performed. For this purpose, mustard oil was applied to the skin of the right hind foot of Wistar rats at various concentrations: 5%, 10%, 30%, 50%, 80% and 100% in liquid paraffin. The distribution and number of activated Fos-positive cells in the stimulated side (ipsilateral) and contralateral side of the spinal cord were investigated following the application. The ED50 of the response was also determined. The number of Fos-labelled cells gradually increased in a dose dependent manner in both sides of superficial layers (laminae I-II) of the spinal cord with increasing concentration of mustard oil. The increase between the doses was found significant in the ipsilateral superficial layers. The increase was significant in the contralateral superficial layers at concentrations above 50%. Very few Fos-labelled cells were observed around the central canal region in all concentrations. Higher doses of the mustard oil did not increase the number of activated cells in the deeper layers. However, the expression in the deeper layers (laminae III-X) does not show a consistent trend. Also, none of the concentrations used produced labelling in neurons of the deep ventral horn neurons or in motor neurons. Forty percent (40%) of mustard oil gave an approximately 1/2 maximum response i.e. an approximate ED 50. This may be important for studies using intrathecal application of antagonist following the mustard oil activation of skin nerve fibres.

Enhanced cardiovascular alteration and Fos expression induced by central salt loading in a conscious rat transgenic for the metallothionein-vasopressin fusion gene.

The present study is an investigation of the responses of the cardiovascular system and Fos expression to intracerebroventricular (i.c.v.) administration of hypertonic saline (HS) in conscious arginine vasopressin (AVP)-overexpressing transgenic (Tg) and control rats. Central HS (0.3, 0.67, or 1.0M NaCl, 1 microl/min for 20 min) significantly increased the mean arterial blood pressure (MABP) and Fos-like immunoreactivity (FLI) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, the area postrema (AP), the median preoptic nucleus (MnPO), and the organum vasculosum laminae terminalis (OVLT) in both Tg and control rats. The changes in MABP and FLI were significantly larger in Tg rats than in control rats. i.c.v. pretreatment with the AVP V1 receptor antagonist, OPC-21268, blocked the increase in MABP and significantly decreased the Fos expression in the PVN (posterior magnocellular (pm) component) induced by 0.3 M HS in the Tg rats. The present study demonstrates an increased responsiveness to i.c.v. administration of HS in AVP Tg rats, suggesting the relationship between the vasopressinergic drive and central cardiovascular response via, at least in part, the V1 receptor in the PVN magnocellular neurons.