Abstract
PAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA’s therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for 7 days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioral tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioral paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioral indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA’s prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP—while phenotypically similar—are mechanistically different and that PAOPA’s effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia.
Highlights
Prolyl-leucyl-glycinamide (PLG), a cleaved tripeptide of the oxytocin molecule and a dopamine allosteric modulator, has shown therapeutic promise in clinical studies of neuropsychiatric illnesses, including major depressive disorder (Ehrensing and Kastin, 1978; Kastin et al, 1980; Ehrensing et al, 1994)
We examined the effects of PAOPA on acute and longer-term PCP-induced effects, including pre-pulse inhibition (PPI) deficits, hyperlocomotion, heightened brain neuronal activity, impaired novel object recognition and social interaction deficits
Following baseline locomotor activity and PPI testing, the animals were separated into four different treatment groups that did not differ in PPI and locomotor activity: Group (A) vehicle (n = 12); Group (B) PCP–saline (n = 15); Group (C) PCP–PAOPA to test the preventative effects of PAOPA (n = 15), and; Group (D) one-time reversal group to test the ability of PAOPA to reverse PCP-induced abnormalities (n = 12) (Table 1)
Summary
Prolyl-leucyl-glycinamide (PLG), a cleaved tripeptide of the oxytocin molecule and a dopamine allosteric modulator, has shown therapeutic promise in clinical studies of neuropsychiatric illnesses, including major depressive disorder (Ehrensing and Kastin, 1978; Kastin et al, 1980; Ehrensing et al, 1994). The Therapeutic Potential of Dopaminergic Allostery (3R)-2-Oxo-3-[[(2S)-2-Pyrrolidinylcarbonyl]amino]-1-pyrrolidineacetamide (PAOPA) has demonstrated more potent positive allosteric activity for the dopamine D2/D4 receptors compared to PLG (Verma et al, 2005). As a unique dopaminergic agent, PAOPA has been investigated for its treatment efficacy in animal models of Parkinson’s disease, movement disorders such as tardive dyskinesia, and schizophrenia. In the 6-hydroxydopamine lesioned rat model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease, PAOPA modulated rotational behavior and showed neuroprotective effects, respectively (Mishra et al, 1997; Marcotte et al, 1998). PAOPA prevented haloperidolinduced movement abnormalities in rats displaying a tardive dyskinesia-like state (Sharma et al, 2003)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
