Attention Deficits and Hyperactivity Following Inhibition of cAMP-Dependent Protein Kinase Within the Medial Prefrontal Cortex of Rats

Author(s): Tracie A. Paine, Rachael L. Neve and William A. Carlezon Jr
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA


Previous work demonstrates that microinjections of dopamine D1 receptor agonists and antagonists directly into the medial prefrontal cortex (mPFC) of rats can affect attention in the 5-choice serial reaction time task (5CSRTT), a rodent test analogous to the continuous performance task used to study attention in humans. These studies were designed to determine if intra-mPFC modulation of cAMP-dependent protein kinase (PKA), an intracellular target of D1 receptor stimulation, also affects attention. We examined the effects of localized microinfusions of the cAMP analog Sp-cAMPS (to activate PKA) or Rp-cAMPS (to inhibit PKA) in the 5CSRTT. In parallel, we examined the effects of these manipulations on activity levels in an open field, as well as on motivation and the capacity to make complex operant responses using the intracranial self-stimulation (ICSS) test. Inhibition of PKA reduced accuracy in the 5CSRTT and caused substantial increases in locomotor activity without affecting motivation or the capacity to emit operant responses at high rates. Stimulation of PKA also affected some measures of performance in the 5CSRTT, but this effect was associated with reduced capacity to respond at high rates. Viral vector-mediated disruption of cAMP response element-binding protein (CREB), a transcription factor directly activated by PKA, also reduced accuracy in the 5CSRTT, raising the possibility that acute inhibition of PKA and sustained inhibition of CREB affect attention through common mechanisms. These studies indicate that PKA inhibition within the mPFC of rats produces inattention and hyperactivity, and thus might be useful in modeling human attention disorders.


by William A. Carlezon Jr.

This work is designed to understand the intracellular signaling pathways that contribute to attention behavior using animal models.  Attention was measured in rodents using the 5-choice serial reaction time task, which is modeled after the continuous performance task used to study attention in humans.  The data show that disruption of PKA (cAMP-dependent protein kinase) within the prefrontal cortex of rats produces both inattention and hyperactivity, two hallmark symptoms of attention deficit-hyperactivity disorder (ADHD).  Mimicking one specific consequence of PKA disruption (reduced activation of the transcription factor CREB) produced inattention but not hyperactivity, raising the possibility that these signs are produced by different downstream targets of PKA.  Surprisingly, activation of PKA tended to produce increases in impulsivity behavior, another hallmark sign of ADHD, although the effect did not reach statistical significance.  One way to interpret these data is that the three key signs of ADHD (inattention, hyperactivity, impulsivity) are separable, each reflecting dysregulation of a different molecular process within a common signaling pathway.  An important question for future work is whether treatment of the signs individually with highly selective agents can result in meaningful improvements in performance.

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