The mediating role of phosphodiesterase type 4 in the dopaminergic modulation of motor impulsivity

• Published in: Behavioural brain research 2018-09, Vol.350, p.16-22
• Main Authors: Heckman, P.R.A., Blokland, A., Van Goethem, N.P., Van Hagen, B.T.J., Prickaerts, J.
• Format: Article
• Language: English
• Subjects: cAMP; Dopamine; Impulsivity; Phosphodiesterase 4; Roflumilast
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2018.05.017

•CSRTT measures impulsivity via premature responding.•Increasing and decreasing dopamine levels resulted in increased premature responding.•Roflumilast increased premature responses in combination with d-amphetamine.•Roflumilast decreased premature responding in a 6-OHDA model.•PDE4 inhibitors could reverse motor impulsivity induced by hypodopaminergia. The current study investigated the mediating role of phosphodiesterase type 4 (PDE4) regulated cAMP in the dopaminergic modulation of premature responding (action restraint) in rats. Response inhibition, which includes action restraint, finds its neurobiological origin in cortico-striatal-thalamic circuitry and can be modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cAMP/PKA signaling cascade. Areas in the prefrontal cortex are very sensitive to their neurochemical environment, including catecholamine levels. As a result, we investigated the effects of intracellular modulation of the dopamine cascade by means of PDE4 inhibition by roflumilast on premature responding in a hypo, normal and hyper dopaminergic state of the brain. As a hypo dopaminergic model we induced a 6-OHDA lesion in the (rat) prefrontal cortex, more specifically the infralimbic cortex. For the hyper dopaminergic state we also turned to a well-established model of impaired action restraint, namely the systemic administration of d-amphetamine. In line with the notion of a U-shaped relation between dopamine and impulsive responding, we found that both increasing and decreasing dopamine levels resulted in an increase in premature responding in the choice serial reaction time task (CSRTT). The PDE4 inhibitor roflumilast increased premature responses in combination with d-amphetamine, whereas a decrease in premature responding after roflumilast treatment was found in the 6-OHDA lesioned animals. As a result, it would be interesting to test the effects of PDE4 inhibition in disorders affected by disrupted impulse control related to cortico-striatal-thalamic hypodopaminergia including attention deficit hyperactivity disorder (ADHD).