Table 1.

Effects of specific PDE inhibitors and genetic deletion on striatal function and related behavioural measures

PDE	Substrate	Selective Inhibitors	Effects of specific PDE manipulations	Refs
PDE 1 PDE1B	cGMP>cAMP	Vinpocetine/IC224	Striatal PDE1B mRNA declines in R6/1 and R6/2 HD mouse model prior to motor symptom onset. Knock-out mice exhibit hypersensitivity, impaired spatial learning, and DARPP-32 phosphorylation in response to dopamine agonists	[99–102]
PDE 2 PDE2A	cGMP/cAMP	EHNA/BAY 60-7550	EHNA increases NO-mediated cGMP accumulation in striatal slices. EHNA increases the responsiveness of cultured striatal neurons to dopamine D1 receptor agonism.	[103–105]
PDE 3 PDE3A,B	cAMP	Milrinone/Cilostamide	Decreased striatal PDE3A expression following electroconvulsive shock	[12–16, 106]
PDE 4 PDE4D	cAMP	Rolipram	The PDE4 inhibitor rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals that was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Reverse dialysis of rolipram increases striatal dopamine efflux in vivo. Rolipram augments adenosine A2A receptor-mediated phosphorylation of DARPP-32 preferentially in the indirect pathway MSNs. Rolipram mimics the biological effects of dopamine D2 receptor antagonists, and to a lesser degree, D1 receptor agonists. Rolipram decreases conditioned avoidance responding and amphetamine and PCP-induced locomotor activity. Rolipram rescues amphetamine-induced reductions in auditory-evoked potentials and prepulse inhibition. PDE4B KO mice exhibit decreased prepulse inhibition, enhanced responsiveness to amphetamine, decreased baseline motor activity, and anxiogenic behavior.	[12–16, 45, 107, 116, 119]
PDE 7 PDE7B	cAMP	–	Decreased PDE7B transcript and decreased corticostriatal LTD in A53T Syn OVX	[108, 109]
PDE 8 PDE8B	cAMP	–	ADSD–PD-like disorder caused by frameshift mutation in PDE8B leading to decreased PDE8B function.	[12–16, 110]
PDE 9 PDE9A	cGMP	BAY 73-6691/PF-4447943	Regulates tonic levels of striatal cGMP	[14, 111, 112]
PDE 10 PDE10A	cGMP/cAMP	Papaverine/TP-10 (PF-545920)/PQ-10/MP-10/THPP-1	Papaverine and more specific PDE10A inhibitors increase cfos expression and CREB, ERK, and GluR1 phosphorylation via PKA activation. Papaverine, MP-10, PQ-10 increase expression of neurotensin, enkephalin, and substance P in WT and NOS KO mice. Papaverine increases DARPP-32 phosphorylation more robustly in striatopallidal MSNs. Papaverine and TP-10 increased responsiveness of striatopallidal MSNs to corticostriatal transmission and induced an increase in axonal excitability in striatonigral MSNs. PDE10 inhibitors and genetic deletion induce decreases in spontaneous and psychostimulant-driven locomotion, and delayed acquisition or decreases in conditioned avoidance responding. PDE10 inhibitors inhibit NMDA receptor antagonist-induced locomotion and deficits in prepulse inhibition of acoustic startle in rats and improve baseline sensory gating in mice. TP-10 reduced the disruption of auditory gating induced by amphetamine. PDE10 inhibitors induce catalepsy in a dose-dependent manner and potentiate catalepsy induced by antipsychotic drugs. THPP-1 increased object recognition memory in rats and attenuated a ketamine-induced deficits in the object retrieval detour task in monkeys. KO mice exhibit increased social interaction. mRNA and protein levels decline in the striatum of R6/1 and R6/2 HD mice prior to motor symptom development. TP-10 ameliorates striatal and cortical pathology in R6/2 mouse model of HD. Chronic TP-10 may provide neuroprotective effects in models of HD through complex changes in signalling and gene expression.	[13, 25, 41–46, 74, 76, 93, 113–115, 117–119]