América A. Scopinho

Acute reversible inactivation of the ventral medial prefrontal cortex induces antidepressant-like effects in rats.

The ventral medial prefrontal cortex (vMPFC) has direct connections to subcortical, diencephalic and brainstem structures that have been closely related to depression. However, studies aimed at investigating the role of the vMPFC in the neurobiology of depression have produced contradictory results. Moreover, the precise involvement of vMPFC anatomic subdivisions, the prelimbic (PL) and the infralimbic (IL) cortices, in regulating depressive-like behavior have been poorly investigated. The forced swimming test (FST) is a widely employed animal model aimed at detecting antidepressant-like effects. Therefore, to further investigate a possible involvement of the vMFPC in depressive-like behavior, rats bilaterally implanted with cannulae aimed at the PL or IL prefrontal cortices were submitted to 15 min of forced swimming (pre-test) followed, 24h later, by a 5-min swimming session (test), where immobility time was registered. Synaptic transmission in these regions was temporarily inhibited using local microinjection of cobalt chloride at different periods of the experimental procedure (before or after the pre-test or before the test). PL inactivation decreased immobility time independently of the time of the injection. In the IL, inactivation induced a significant antidepressant-like effect when performed immediately before the pre-test or before the test, but not after the pre-test. These results suggest that activation of the vMPFC is important for the behavioral changes observed in rats submitted to the FST. They further indicate that, although both the PL and IL cortices are involved in these effects, they may play different roles.

The lateral septal area modulates the baroreflex in unanesthetized rats

The septal lateral area (LSA) is a limbic structure that is involved with autonomic and behavioral responses. In the present study we report the effect of acute and reversible LSA synaptic inhibition on the parasympathetic and the sympathetic components of baroreflex in unanesthetized rats. Neurotransmission was temporarily inhibited by bilateral microinjection of the nonselective synapse blocker CoCl(2) in the LSA. Bilateral microinjection of 100 nL of 1 mM CoCl(2) into the LSA did not affect blood pressure or heart rate baseline, suggesting no tonic LSA influence on resting cardiovascular parameters. However, 10 min after CoCl(2) microinjections, maximum tachycardiac responses to blood pressure decreases caused by intravenous infusion of sodium nitroprusside and bradycardiac responses evoked by blood pressure increases caused by intravenous infusion of phenylephrine were enhanced when compared with control values. These enhancement of both the tachycardiac and bradycardiac reflex evoked increase of baroreflex gain. Baroreflex activity returned to control values 60 min after CoCl(2) microinjections, confirming the reversible blockade. The present results indicate an involvement of the LSA in baroreflex modulation. Data suggest that synapses in the LSA play a tonic inhibitory influence on both the sympathetic and the parasympathetic components of the baroreflex in unanesthetized rats.

Pressor effects of noradrenaline injected into the lateral septal area of unanesthetized rats.

The lateral septal area (LSA) is involved in central cardiovascular control. In the present study, we report on the cardiovascular effects of noradrenaline (NA) injection into the LSA of unanesthetized rats, as well as on local receptors and peripheral mechanisms involved in their mediation. Microinjections of NA (9, 15, 21, 27 or 45 nmol) caused long-lasting, dose-related pressor and bradycardic responses in unanesthetized rats. No responses were observed when the dose of 21 nmol of NA was microinjected into medial septal area or lateral ventricle suggesting a main action at the LSA. No changes were observed in arterial pressure and heart rate when NA was injected in the LSA of anesthetized rats. The effects of 21 nmol of NA were abolished by local pretreatment with 10 nmol of the specific alpha1-receptor antagonist WB 4101, but were not affected by pretreatment with 10 nmol of the specific alpha2-receptor antagonist RX 821002. The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V1-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 microg/kg). No pressor response to NA was observed in hypophysectomized rats. The present observation of alpha1-adrenoceptor-mediated pressor responses after local injection of NA confirms earlier evidence of a LSA involvement in central cardiovascular control. Pretreatment with the alpha1-adrenoceptor antagonist WB-4101 did not affect baseline blood pressure or heart rate suggesting no tonic involvement of septal adrenergic mechanisms suggesting a modulatory LSA influence on cardiovascular control. Additionally, the blockade of the pressor response by the i.v. pretreatment with a V1-vasopressin antagonist indicates that noradrenergic LSA mechanisms modulate vasopressin release.

Behavioral and Autonomic Responses to Acute Restraint Stress Are Segregated within the Lateral Septal Area of Rats

Background The Lateral Septal Area (LSA) is involved with autonomic and behavior responses associated to stress. In rats, acute restraint (RS) is an unavoidable stress situation that causes autonomic (body temperature, mean arterial pressure (MAP) and heart rate (HR) increases) and behavioral (increased anxiety-like behavior) changes in rats. The LSA is one of several brain regions that have been involved in stress responses. The aim of the present study was to investigate if the neurotransmission blockade in the LSA would interfere in the autonomic and behavioral changes induced by RS. Methodology/Principal Findings Male Wistar rats with bilateral cannulae aimed at the LSA, an intra-abdominal datalogger (for recording internal body temperature), and an implanted catheter into the femoral artery (for recording and cardiovascular parameters) were used. They received bilateral microinjections of the non-selective synapse blocker cobalt chloride (CoCl2, 1 mM/ 100 nL) or vehicle 10 min before RS session. The tail temperature was measured by an infrared thermal imager during the session. Twenty-four h after the RS session the rats were tested in the elevated plus maze (EPM). Conclusions/Significance Inhibition of LSA neurotransmission reduced the MAP and HR increases observed during RS. However, no changes were observed in the decrease in skin temperature and increase in internal body temperature observed during this period. Also, LSA inhibition did not change the anxiogenic effect induced by RS observed 24 h later in the EPM. The present results suggest that LSA neurotransmission is involved in the cardiovascular but not the temperature and behavioral changes induced by restraint stress.

α1‐Adrenoceptors in the lateral septal area modulate food intake behaviour in rats

Control of food intake is a complex behaviour which involves many interconnected brain structures. The present work assessed if the noradrenergic system in the lateral septum (LS) was involved in the feeding behaviour of rats.

Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists

Δ9-THC is a component of Cannabis sativa that increases food intake in animals and humans, an effect prevented by selective CB1 receptor antagonists. Cannabidiol (CBD) is another constituent of this plant that promotes several opposite neuropharmacological effects compared to Δ9-THC. CBD mechanisms of action are still not clear, but under specific experimental conditions it can antagonize the effects of cannabinoid agonists, block the reuptake of anandamide and act as an agonist of 5-HT1A receptors. Since both the cannabinoid and serotoninergic systems have been implicated in food intake control, the aim of the present work was to investigate the effects caused by CBD on hyperphagia induced by agonists of CB1 or 5-HT1A receptors. Fed or fasted Wistar rats received intraperitoneal (i.p.) injections of CBD (1, 10 and 20 mg/kg) and food intake was measured 30 min later for 1 h. Moreover, additional fed or fasted groups received, after pretreatment with CBD (20 mg/kg) or vehicle, i.p. administration of vehicle, a CB1 receptor agonist WIN55,212-2 (2 mg/kg) or a 5-HT1A receptor agonist 8-OH-DPAT (1 mg/kg) and were submitted to the food intake test for 1 h. CBD by itself did not change food intake in fed or fasted rats. However, it prevented the hyperphagic effects induced by WIN55,212-2 or 8-OH-DPAT. These results show that CBD can interfere with food intake changes induced by a CB1 or 5-HT1A receptor agonist, suggesting that its role as a possible food intake regulator should be further investigate.

Involvement of the lateral septal area in the expression of fear conditioning to context

Considering the evidence that the lateral septal area (LSA) modulates defensive responses, the aim of the present study is to verify if this structure is also involved in contextual fear conditioning responses. Neurotransmission in the LSA was reversibly inhibited by bilateral microinjections of cobalt chloride (CoCl(2), 1 mM) 10 min before or after conditioning or 10 min before re-exposure to the aversively conditioned chamber. Only those animals that received CoCl(2) before re-exposure showed a decrease in both cardiovascular and behavioral conditioned responses. These results suggest that the LSA participates in the expression, but not acquisition or consolidation, of contextual fear conditioning.

Non-N-methyl-D-aspartate glutamate receptors in the paraventricular nucleus of hypothalamus mediate the pressor response evoked by noradrenaline microinjected into the lateral septal area in rats.

The lateral septal area (LSA) is a part of the limbic system and is involved in cardiovascular modulation. We previously reported that microinjection of noradrenaline (NA) into the LSA of unanesthetized rats caused pressor responses that are mediated by acute vasopressin release. Magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) of the hypothalamus synthesize vasopressin. In the present work, we studied which of these nuclei is involved in the pressor pathway activated by unilateral NA injection into the LSA as well as the local neurotransmitter involved. Chemical ablation of the SON by unilateral injection of the nonspecific synapses blocker cobalt chloride (1 mM/100 nl) did not affect the pressor response evoked by NA (21 nmol/200 nl) microinjection into the LSA. However, the response to NA was blocked when cobalt chloride (1 mM/100 nl) was microinjected into the PVN, indicating that this hypothalamic nucleus is responsible for the mediation of the pressor response. There is evidence in the literature pointing to glutamate as a putative neurotransmitter activating magnocellular neurons. Pretreatment of the PVN with the selective non‐N‐methyl‐D‐asparate (NMDA) antagonist NBQX (2 nmol/100 nl) blocked the pressor response to NA microinjected into the LSA, whereas pretreatment with the selective NMDA antagonist LY235959 (2 nmol/100 nl) did not affect the response to NA. Our results implicate the PVN as the final structure in the pressor pathway activated by the microinjection of NA into the LSA. They also indicate that local glutamatergic synapses and non‐NMDA glutamatergic receptors mediate the response in the PVN.

Increased Circulating Vasopressin May Account for Ethanol-induced Hypertension in Rats

BACKGROUND Long-term ethanol intake has been reported to evoke both hypertension and increase of systemic vasopressin levels in rats. METHODS In this work, we investigated the involvement of systemic vasopressin in the hypertension evoked in rats by long-term ethanol (20% vol/vol) intake for 2 weeks, by systemic treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50 microg/kg). Moreover, plasma arginine-vasopressin (AVP) content was quantified using an AVP radioimmunoassay and the expression of vasopressin mRNA in the supraoptic (SON) and paraventricular (PVN) nuclei was measured using real-time PCR. RESULTS Mild hypertension was observed after 2 weeks of ethanol treatment when compared with control animals. Moreover, an increase in both the expression of vasopressin mRNA and the vasopressin blood content was observed in ethanol-treated rats in comparison to the control group. Basal blood pressure levels of ethanol-treated animals were significantly reduced by IV treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP. However, dTyr(CH2)5(Me)AVP had no effect on the blood pressure of control animals. CONCLUSIONS The results indicate that mild hypertension is already observed at an early phase of ethanol consumption in rats. Because the content of circulating vasopressin was increased in ethanol-treated rats and their basal blood pressure returned to control levels after IV treatment with a V1-vasopressin receptor antagonist, it is proposed that increased circulating vasopressin content may mediate the hypertension observed in ethanol-treated rats.

Dorsal and ventral hippocampus modulate autonomic responses but not behavioral consequences associated to acute restraint stress in rats.

Recent evidence has suggested that the dorsal (DH) and the ventral (VH) poles of the hippocampus are structurally, molecularly and functionally different regions. While the DH is preferentially involved in the modulation of spatial learning and memory, the VH modulates defensive behaviors related to anxiety. Acute restraint is an unavoidable stress situation that evokes marked and sustained autonomic changes, which are characterized by elevated blood pressure (BP), intense heart rate (HR) increases, skeletal muscle vasodilatation and cutaneous vasoconstriction, which are accompanied by a rapid skin temperature drop followed by body temperature increases. In addition to those autonomic responses, animals submitted to restraint also present behavioral changes, such as reduced exploration of the open arms of an elevated plus-maze (EPM), an anxiogenic-like effect. In the present work, we report a comparison between the effects of pharmacological inhibition of DH and VH neurotransmission on autonomic and behavioral responses evoked by acute restraint stress in rats. Bilateral microinjection of the unspecific synaptic blocker cobalt chloride (CoCl2, 1mM) into the DH or VH attenuated BP and HR responses, as well as the decrease in the skin temperature, elicited by restraint stress exposure. Moreover, DH or VH inhibition before restraint did not change the delayed increased anxiety behavior observed 24 h later in the EPM. The present results demonstrate for the first time that both DH and VH mediate stress-induced autonomic responses to restraint but they are not involved in the modulation of the delayed emotional consequences elicited by such stress.