Effect of antagonism of angiotensin II (AT1 or AT2) receptors on locomotor hyperactivity of NK1 receptor knockout mice

EM Grabowska1, AJ Grimme1, A Hindocha1, TC Yan1, SP Hunt2, SC Stanford1. 1UCL, Department of Neuroscience, Physiology & Pharmacology, London, WC1E 6BT, United Kingdom, 2UCL, Department of Cell & Developmental Biology, London, WC1E 6BT, United Kingdom.

We have previously reported that a functional deficit of substance P-preferring receptors (NK1R) in NK1R-/- (‘knockout’) mice induces locomotor hyperactivity (see: Yan et al. 2009), suggesting that activation of NK1R prevents this abnormal behaviour. There is also evidence that release of substance P is increased by angiotensin II (Diz et al., 1998). It follows that indirect activation of NK1R by angiotensin II might reduce locomotor activity. Here, we tested the ensuing prediction that disruption of this functional coupling between angiotensin II and NK1R, by blocking angiotensin II receptors, increases locomotor activity. Specifically, we compared the effects of an acute challenge with a preferential antagonist of either angiotensin II type 1 (AT1) receptors (losartan), or angiotensin II type 2 (AT2) receptors (PD123319; 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c] pyridine-6 -carboxylic acid), on the locomotor activity of NK1R-/- and wildtype mice in a light/dark exploration box (LDEB).

Male NK1R+/+ and NK1R-/- mice were used (25-35g; 129/Sv X C57BL/6 crossed with an outbred MF1 strain). Mice were randomly assigned to groups given an i.p. injection of saline (10 ml/kg) or losartan (10 or 25 mg/kg (N = 4)) or PD123319 (1 or 3 mg/kg) (N = 6 or 7/group). One hour later, the behaviour of the mice in a LDEB was monitored for 30 min and scored blind. Data were analysed by multifactorial ANOVA, followed by the LSD test (post hoc).

The effect of both antagonists on animals’ locomotor activity depended on genotype (genotype*drug: (losartan) F2,23 = 4.5, P<0.05; (PD123319) F2,37 = 3.6, P<0.05). The activity of NK1R-/- mice was increased by both doses of losartan (+47%, +69%) or PD123319 (+30%, +60%) (P<0.05 in all cases). Neither drug affected the activity of wildtype mice.

The results indicate that antagonism of either AT1 or AT2 receptors increases locomotor activity in NK1R-/- mice. Whereas this finding is consistent with our prediction that angiotensin II blunts locomotor activity, contrary to our proposal, this action must be independent of any indirect activation of NK1R because these receptors are lacking in NK1R-/- mice. Our results further indicate that neither losartan nor PD123319 affected the locomotor activity of wildtype mice. This leads us to conclude that activation of NK1R in wildtype mice can compensate for a deficit in AT1 or AT2 receptor function. Such a compensatory process could be mediated through an interaction in the neuronal network that governs locomotor activity and/or convergence on a common intracellular messenger.

Diz DI et al, (1998) Hypertension, 31:473-9.

Yan TC et al, (2009). Neuropharmacology, 57: 627-635.

This work was funded, in part, by the Medical Research Council (UK).