Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.
aDipartimento di Psicologia, University ‘La Sapienza’, Rome, Italy
bIstituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, Rome, Italy
cIstituto di Ricovero e Cura a Carattere Scientifico OASI Maria SS, Troina (EN), Italy
dIstituto di Scienze Neurologiche, Consiglio Nazionale delle Ricerche, Sezione Catania, Catania, Italy
Sponsorship: This work was supported by a Grant ‘Giovani Ricercatori’, Ateneo 2002 to R.V.
Correspondence and requests for reprints to Stefano Puglisi-Allegra, Dipartimento di Psicologia, Università ‘La Sapienza’, via dei Marsi n. 78, 00185 Rome, Italy
Received 7 April 2004 Accepted as revised 24 June 2004