Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents.
Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.
Pałucha-Poniewiera
A
A
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
Kłodzińska
A
A
Stachowicz
K
K
Tokarski
K
K
Hess
G
G
Schann
S
S
Frauli
M
M
Neuville
P
P
Pilc
A
A
D000661:Amphetamine; D000662:Amphetamines / Q000008:administration & dosage; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D003517:Cyclopentanes / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005625:Frontal Lobe / Q000166:cytology; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D014233:Tricarboxylic Acids / Q000008:administration & dosage*
C409063:1-aminocyclopentane-1,2,4-tricarboxylic acid; D000662:Amphetamines; D014150:Antipsychotic Agents; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D014233:Tricarboxylic Acids; C102718:metabotropic glutamate receptor 3; D016291:Dizocilpine Maleate; D000661:Amphetamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine