Clozapine decreases exploratory activity and increases anxiety-like behaviour in the Wistar–Kyoto rat but not the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

The spontaneously hypertensive rat (SHR) is the most widely used animal model of ADHD. SHR has been found to have increased glutamate-stimulated noradrenaline release from varicosities in several brain areas. Besides its effects on dopamine D4 receptors, clozapine, an atypical antipsychotic with antagonistic effects on α1-adrenoceptors, may reduce activation of α1-adrenoceptors in SHR and thereby attenuate their hyperactivity. The aims of the study were to determine the effect of clozapine (post-natal day (P) 21–P35, 10 mg/kg/day) on SHR and Wistar-Kyoto (WKY), SHR's normotensive control, and a standard laboratory strain, Sprague Dawley (SD). Rat behaviour was assessed in the open field (P32), novel object (P33) and elevated plus maze (P34) tests that measured locomotor and anxiety-related behaviour. An in vitro superfusion technique was used to measure [3H]noradrenaline release in prefrontal cortex (PFC) and hippocampal slices (P35 or P36). Clozapine decreased exploratory activity in WKY, consistent with antagonism of dopamine D4 and α1-adrenoceptors reducing the behavioural response to novelty. Clozapine also increased anxiety-related behaviour of WKY. However, clozapine did not affect SHR, suggesting that genetic predisposition may play a role in determining clozapine's behavioural effects. WKY have been shown to have higher levels of dopamine D4 receptor expression in the PFC than SHR, which may be a reason for their elevated response to clozapine. SHR released more [3H]noradrenaline from PFC and hippocampal slices in response to glutamate- and elevated potassium-stimulation, compared to WKY and SD rats. However clozapine treatment did not affect glutamate-, GABA- or depolarization-evoked release of [3H]noradrenaline.

► Clozapine reduced exploratory activity in WKY but not in SHR or SD.
► Clozapine increased neophobia and anxiety in WKY but not in SHR or SD
► Clozapine had no effect on the glutamate, GABA or depolarisation evoked noradrenaline release.
► Glutamate evoked greater release of noradrenaline in PFC and hippocampus in SHR.