Cortico-striatal cyclic AMP-phosphodiesterase-4 signalling and stereotypy in the deer mouse: attenuation after chronic fluoxetine treatment

Abstract

Motor stereotypies, described as repetitive, topographically invariant and seemingly purposeless behaviours, are common to several developmental and neuropsychiatric disorders. While drug induced stereotypy has been extensively studied, the neurobiology of spontaneous stereotypy is poorly understood. Deer mice present with naturalistic stereotypic behaviours that are selectively suppressed by fluoxetine. We studied basal cyclic adenosine monophosphate (cAMP) levels and phosphodiesterase (PDE) type 4 activity in prefrontal cortex and striatum of high, low and non-stereotypic deer mice, as well as response in high stereotypic mice to chronic fluoxetine treatment (20 mg/kg/day × 21 days intraperitoneally). Cortical cAMP levels were associated with stereotypic behaviour, being significantly elevated in low and high stereotypic mice compared to non-stereotypic animals, with a similar trend in the striatum. In both brain regions, there was a significant inverse correlation between PDE4 activity and stereotypic behaviour. In the prefrontal cortex, PDE4 activity was significantly reduced in both low and high stereotypic mice compared to their non-stereotypic controls, while in the striatum, only high stereotypic mice showed a significant reduction in PDE4 activity. Fluoxetine significantly attenuated stereotypies in high stereotypic animals, together with a reduction in cortical cAMP levels and PDE4 activity, without noteworthy effects in the striatum. Spontaneous stereotypy in deer mice is thus characterized by raised cAMP and reduced PDE4 enzyme activity, particularly in the prefrontal cortex, and is modified by chronic treatment with fluoxetine.