ABSTRACT
Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.
Subject(s)
Biogenic Amines/metabolism , Carbamates/pharmacology , Cholinesterase Inhibitors/chemistry , Administration, Oral , Amnesia/drug therapy , Amphetamines/chemistry , Animals , Carbamates/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Cholinesterase Inhibitors/pharmacology , Drug Evaluation, Preclinical , Phenylcarbamates/chemistry , Rats , RivastigmineABSTRACT
RATIONALE: Phosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. Four separate PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. PDE4 has been reported to be involved in various central nervous system (CNS) functions including depression, memory, and schizophrenia, although the specific subtype mediating these effects remains unclear. OBJECTIVE: To investigate the role of PDE4B in the CNS, PDE4B wild-type and knockout mice (C57BL/6N background) were assessed in a variety of well-characterized behavioral tasks, and their brains were assayed for monoamine content. RESULTS: Knockout mice showed a significant reduction in prepulse inhibition. Spontaneous locomotor activity was decreased (16%) in knockout mice. Furthermore, when challenged with amphetamine, both groups of mice responded similarly to a low dose of d-amphetamine (1.0 mg/kg), but knockout mice showed an enhanced response to a higher dose (1.78 mg/kg). Decreases in baseline levels of monoamines and their metabolites within the striatum of knockout mice were also observed. PDE4B knockout mice showed a modest decrease in immobility time in the forced swim test that approached significance. In several other tests, including the elevated plus maze, hot plate, passive avoidance, and Morris water maze, wild-type and knockout mice performed similarly. CONCLUSION: The present studies demonstrate decreased striatal DA and 5-HT activity in the PDE4B knockout mice associated with decreased prepulse inhibition, decreased baseline motor activity, and an exaggerated locomotor response to amphetamine. These data further support a role for PDE4B in psychiatric diseases and striatal function.
Subject(s)
Behavior, Animal/physiology , Brain/physiopathology , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Dopamine/metabolism , Serotonin/metabolism , Animals , Arousal/drug effects , Arousal/physiology , Behavior, Animal/drug effects , Brain/drug effects , Dextroamphetamine/pharmacology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motivation , Motor Activity/drug effects , Motor Activity/physiology , Reflex, Startle/drug effects , Reflex, Startle/physiologyABSTRACT
The phenotype of genetically modified animals is strongly influenced by both the genetic background of the animal as well as environmental factors. We have previously reported the behavioral and neurochemical characterization of PDE10A knockout mice maintained on a DBA1LacJ (PDE10A(DBA)) genetic background. The aim of the present studies was to assess the behavioral and neurochemical phenotype of PDE10A knockout mice on an alternative congenic C57BL/6N (PDE10A(C57)) genetic background. Consistent with our previous results, PDE10A(C57) knockout mice showed a decrease in exploratory locomotor activity and a delay in the acquisition of conditioned avoidance responding. Also consistent with previous studies, the elimination of PDE10A did not alter basal levels of striatal cGMP or cAMP or affect behavior in several other well-characterized behavioral assays. PDE10A(C57) knockout mice showed a blunted response to MK-801, although to a lesser degree than previously observed in the PDE10A(DBA) knockout mice, and no differences were observed following a PCP challenge. PDE10A(C57) knockout mice showed a significant change in striatal dopamine turnover, which was accompanied by an enhanced locomotor response to AMPH, These studies demonstrate that while many of the behavioral effects of the PDE10A gene deletion appear to be independent of genetic background, the impact of the deletion on behavior can vary in magnitude. Furthermore, the effects on the dopaminergic system appear to be background-dependent, with significant effects observed only in knockout mice on the C57BL6N genetic background.
Subject(s)
Behavior, Animal/physiology , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/physiology , Amphetamine/pharmacology , Animals , Anxiety/psychology , Avoidance Learning/drug effects , Avoidance Learning/physiology , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Brain Chemistry/drug effects , Brain Chemistry/genetics , Chromatography, High Pressure Liquid , Depression/psychology , Dizocilpine Maleate/pharmacology , Dopamine/metabolism , Dopamine Uptake Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hot Temperature , Methamphetamine/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Nucleotides, Cyclic/metabolism , Pain Measurement/drug effects , Phencyclidine/pharmacology , Phosphoproteins/metabolism , Serotonin/metabolism , Swimming/psychologyABSTRACT
RATIONALE: Recent studies provide evidence for reduced phosphodiesterase-4B (PDE4B) as a genetic susceptibility factor as well as suggesting an association of several single nucleotide polymorphisms (SNPs) in PDE4B that are associated with an increased incidence of schizophrenia. OBJECTIVES: The aim of the current study was to assess the activity of rolipram, a nonsubtype-selective PDE4 inhibitor, in several animal models predictive of antipsychotic-like efficacy and side-effect liability and to use PDE4B wild-type and knockout mice to begin to understand the subtypes involved in the activity of rolipram. RESULTS: In rats, rolipram antagonized both phencyclidine hydrochloride- and D-amphetamine-induced hyperactivity and inhibited conditioned avoidance responding (CAR). In PDE4B wild-type mice, rolipram dose-dependently suppressed CAR (ED(50) = 2.4 mg/kg); however, in knockout mice, their sensitivity to rolipram at the higher doses (1.0 and 3.2 mg/kg) was reduced, resulting in a threefold shift in the ED(50) (7.3 mg/kg), suggesting PDE4B is involved, at least in part, with the activity of rolipram. Only the highest dose of rolipram (3.2 mg/kg) produced a modest but significant degree of catalepsy. CONCLUSIONS: Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability. These results suggest that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis.
