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The behavioural response of mice lacking NK₁ receptors to guanfacine resembles its clinical profile in treatment of ADHD

BACKGROUND AND PURPOSE:

Mice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R-/- mice) display behavioural abnormalities resembling those in attention deficit hyperactivity disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviated the hyperactivity and impulsivity/inattention displayed by NK1R-/- mice in the light/dark exploration box (LDEB) and 5-choice serial reaction-time task (5-CSRTT), respectively. Following reports of co-morbid anxiety in ADHD, we also investigated effects of guanfacine on anxiety-like behaviour displayed by NK1R-/- and wild-type (WT) mice in the elevated plus maze (EPM).

EXPERIMENTAL APPROACH:

Mice were treated with guanfacine (0.1, 0.3 or 1.0 mg·kg(-1), i.p.), vehicle or no injection and tested in the 5-CSRTT or the LDEB. Only the lowest dose of guanfacine was used in the EPM assays.

KEY RESULTS:

In the 5-CSRTT, a low dose of guanfacine (0.1 mg·kg(-1)) increased attention in NK1R-/- mice, but not in WT mice. This dose did not affect the total number of trials completed, latencies to respond or locomotor activity in the LDEB. Impulsivity was decreased by the high dose (1.0 mg·kg(-1)) of guanfacine, but this was evident in both genotypes and is likely to be secondary to a generalized blunting of behaviour. Although the NK1R-/- mice displayed marked anxiety-like behaviour, guanfacine did not affect the behaviour of either genotype in the EPM.

CONCLUSIONS AND IMPLICATIONS:

This evidence that guanfacine improves attention at a dose that did not affect arousal or emotionality supports our proposal that NK1R-/- mice express an attention deficit resembling that of ADHD patients.

Ref: Br J Pharmacol 171: 4785-4796, 2014.

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Experimental

Abuse & Dependence

Author

Pillidge K, Porter AJ, Dudley JA, Tsai YC, Heal DJ, Stanford SC