Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats

doi:10.1016/S0031-9384(03)00036-2

Physiology & Behavior

Volume 78, Issues 4–5, April 2003, Pages 585-591

https://doi.org/10.1016/S0031-9384(03)00036-2 Get rights and content

Abstract

The effect of angiotensin-converting enzyme (ACE) inhibitor enalapril (EPL) (2 and 4 mg/kg), angiotensin (AT) II receptor antagonist losartan (LRN) (5 and 10 mg/kg), and anxiolytic drug diazepam (DZP) (0.5 mg/kg) on anxiety parameters were evaluated in experimentally induced renal hypertensive rats (RHR). Renal hypertension was induced in Wistar strain male albino rats weighing 200–250 g by following the method of Goldblatt. The animals having systolic blood pressure more than 180–210 mm Hg were subjected to open-field exploratory behaviour, elevated plus maze behaviour, and social interaction tests of anxiety. The RHR showed hyperactivity in open-field behaviour and anxiogenicity in elevated plus maze and social interaction tests. Losartan (5 and 10 mg/kg) and DZP (0.5 mg/kg) significantly attenuated the hyperactivity and anxiogenic behaviour in experimentally induced hypertensive rats and induced anxiolysis in normotensive rats (NTR). Enalapril reversed the hypertension-induced alteration only at higher dose (4 mg/kg) and failed to show any effect in NTR. It can be concluded that renin angiotensin aldosterone system (RAAS) has a significant role on behaviour, and LRN has shown better effect in reversing the hyperactivity and anxiogenicity in the experimentally induced hypertensive rats, indicating a possible role of AT receptor in the mediation of anxiolysis.

Section snippets

Animals

Inbred Wistar strain male albino rats weighing 200–250 g were used in this study. Animals were procured from the Central Animal House of the Institute and housed in groups of five to six in colony cages at an ambient temperature of 25±2 °C and 45–55% relative humidity with 12:12-h light/dark cycle. They had free access to pellet chow (Brook Bond, Lipton, India) and water ad libitum. The project was approved by the Institutional Animal Ethical Committee under the regulation of CPCSEA, New Delhi.

Surgery

Blood pressure

Renal artery occlusion in rats significantly elevated the BP in comparison to NTR. Treatment with EPL [F(2,15)=529.9, P<.001] and LRN [F(2,15)=585.0, P<.001] significantly lowered the BP. DZP slightly decreased the BP in RHR. In NTR, no significant effect on BP was observed with these drugs (Table 3).

Open-field exploratory behaviour

Inducement of hypertension resulted in increased ambulation, rearing, and reduced freezing time, in comparison to NTR, which denote hyperactivity of RHR in open-field behaviour. A decreased central

Discussion

Experimentally induced hypertensive rats showed hyperactivity in open-field exploratory behaviour, an apparatus used to assess motor behaviour and anxiogenicity in elevated plus maze and social interaction tests, which are the standard methods employed to assess anxiety in experimental animals [5], [44], [49]. Treatment with EPL (4 mg/kg) and LRN (5 and 10 mg/kg) significantly decreased the observed hyperactivity and anxiogenicity in RHR which indicates the role of AT in the altered behaviour.

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The brain renin-angiotensin system (RAS) has been implicated in anxiety and depression disorders, but the specific brain sites involved are poorly understood. The medial amygdaloid nucleus (MeA) is involved in expression of behavioral responses. However, despite evidence of the presence of all angiotensinergic receptors in this amygdaloid nucleus, regulation of anxiety- and depressive-like behaviors by angiotensinergic neurotransmissions within the MeA has never been reported. Thus, the present study aimed to investigate the role angiotensin II (AT₁ and AT₂ receptors) and angiotensin-(1–7) (Mas receptor) receptors present within the MeA in behavioral responses in the elevated plus-maze (EPM) and forced swimming test (FST). For this, male Wistar rats had cannula-guide bilaterally implanted into the MeA, and independent sets of animals received bilateral microinjections of either the selective AT₁ receptor antagonist losartan, the selective AT₂ receptor antagonist PD123319, the selective Mas receptor antagonist A-779 or vehicle into the MeA before the EPM and FST. Treatment of the MeA with either PD123319 or A-779 decreased the EPM open arms exploration, while losartan did not affect behavioral responses in this apparatus. However, intra-MeA microinjection of losartan decreased immobility in the FST. Administration of either PD123319 or A-779 into the MeA did not affect the immobility during the FST, but changed the pattern of the active behaviors swimming and climbing. Altogether, these results indicate the presence of different angiotensinergic mechanisms within the MeA controlling behavioral responses in the FST and EPM.
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Emotional disorders like anxiety and depression are responsible for considerable morbidity and mortality all over the world. Several antidepressant and anxiolytic medications are available for the treatment of anxiety and depression. However, a significant number of patients either do not respond to these medications or respond inadequately. Hence, there is a need to identify novel targets for the treatment of anxiety and depression. In this review we focus on the renin angiotensin system (RAS) as a potential target for the treatment of these disorders. We review work that has evaluated the effects of various compounds targeting the RAS on anxiety- and depression-like behaviors. Further, we suggest future work that must be carried out to fully exploit the RAS for the treatment of anxiety and depression. The RAS provides an attractive target for both the identification of novel anxiolytic and antidepressant medications and/or for enhancing the efficacy of currently available medications used for the treatment of anxiety and depression.
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Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some proposed anxiety-modulating factors ⿿ genes, drugs and stressors ⿿ have had discordant effects across different studies. To reconcile the effect sizes of purported anxiety factors, we conducted systematic review and meta-analyses of the literature on ten anxiety-linked interventions, as examined in the elevated plus maze, open field and light-dark box assays. Diazepam, 5-HT1A receptor gene knockout and overexpression, SERT gene knockout and overexpression, pain, restraint, social isolation, corticotropin-releasing hormone and Crhr1 were selected for review. Eight interventions had statistically significant effects on rodent anxiety, while Htr1a overexpression and Crh knockout did not. Evidence for publication bias was found in the diazepam, Htt knockout, and social isolation literatures. The Htr1a and Crhr1 results indicate a disconnect between preclinical science and clinical research. Furthermore, the meta-analytic data confirmed that genetic SERT anxiety effects were paradoxical in the context of the clinical use of SERT inhibitors to reduce anxiety.
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Citation Excerpt :
The long-term losartan treatment after SE decreased motor activity both in the naive rats and in the KA-treated rats. A previous report showed that an acute injection of losartan is able to alleviate hyperactivity in hypertensive rats (Srinivasan et al., 2003). The long-term losartan treatment after SE counteracted most of the deleterious behavioral alterations induced during epileptogenesis in a phase-dependent manner.
Recently, we have shown that the blockade of AT₁ receptor might be useful as an adjuvant treatment strategy for the prevention of oxidative stress and neurotoxicity caused by status epilepticus (SE) in rats. The purpose of the present study was to further assess the efficacy of long-term treatment with losartan (10 mg/kg), the selective AT₁ receptor antagonist, during kainate (KA)-induced epileptogenesis in Wistar rats. Losartan treatment started after onset of SE and continued for 4 weeks. The rats were video- and EEG-recorded for 3 months. Locomotor activity, anxiety and depressive-like behavior were evaluated 9 weeks after SE, when all rats had developed chronic epileptic state. Neuronal damage in hippocampus was analyzed by hematoxylin while serotonin (5-HT) levels in hippocampus by HPLC. AT₁ receptor antagonism increased the latent seizure-free period and decreased the frequency of spontaneous motor seizures. Losartan positively affected epilepsy-provoked behavioral changes, including impulsivity, low anxiety level and depression in a phase-dependent manner and restored the changes in diurnal fluctuation of motor activity. Losartan exerted neuroprotection selectively in the CA1 area of the hippocampus in the KA-treated rats and lowered the 5-HT levels both in normal and abnormal conditions. Our findings suggest that the AT₁ receptor antagonist exerts disease-modifying effects during KA-induced epileptogenesis and neuronal damage in CA1 hippocampal area, attenuated some of the behavioral changes and restored diurnal variability in locomotor activity.

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Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats

Abstract

Section snippets

Animals

Surgery

Blood pressure

Open-field exploratory behaviour

Discussion

Am. J. Surg.

Peptides

Behav. Brain Res.

Gen. Pharmacol.

Behav. Biol.

Brain Res. Bull.

Neuroscience

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuropeptide

Pharmacol. Res.

Brain Res.

Peptides

J. Neurosci. Methods

Peptides

Neurosci. Biobehav. Rev.

Trends Pharmacol. Sci.

Neurosci. Behav. Res.

Regul. Pept.

Pharmacol. Ther.

Behav. Neural Biol.

Brain Res.

Various effects of angiotensin II on amygdaloid neuronal activity in normotensive control and hypertensive transgenic [TGR(mREN-2)27] rats

FASEB J.

Increased mRNA for corticotrophin releasing hormone in the amygdala of fawn-hooded rats: a potential animal model of anxiety

Anxiety

Anxiolytic like action of DUP753, a non peptide angiotensin II receptor antagonist

NeuroReport

Experimental evaluation of psychotropic agents in rodents: 1. Anxiety agents

Indian J. Exp. Biol.

Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats

J. Am. Soc. Nephrol.

Differential effects of social stress on central serotonergic activity and emotional reactivity in Lewis and spontaneously hypertensive rats

Neuroscience

Intelligence and blood pressure in the aged

Science