Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder that primarily affects the cortico-basal ganglia-thalamo-cortical (CBGTC) circuitry and is characterized by motor and vocal tics. Previous studies have found enhancement in procedural memory, which depends on the CBGTC circuitry and plays an important role in the learning and processing of numerous motor, social, and cognitive skills and habits. Based on these studies, procedural hyperfunctioning in TS has been proposed. However, the neurocognitive mechanism underlying such hyperfunctioning is poorly understood. Here, we investigated how two aspects of procedural learning, namely 1) frequency-based statistical learning and 2) order-based sequence learning, are affected in TS. Twenty-one children with TS between the ages of ten and fifteen as well as 21 typically developing controls were tested on a probabilistic sequence learning task that enables the parallel assessment of these two aspects. We found that children with TS showed enhanced sensitivity to statistical information but impaired sequence learning compared to typically developing children. The deconstruction of procedural memory suggests that procedural hyperfunctioning in TS may be supported by enhanced sensitivity to statistical information. These results can provide a potential path for improving therapy methods and skilloriented educational programs for TS.
Introduction: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.
Cariprazine is an approved antipsychotic and antidepressant which is a dopamine (DA) D 3 -preferring D 3 /D 2 receptor partial agonist, serotonin (5-HT) 5-HT 1A receptor partial agonist, and 5-HT 2B and 5-HT 2A receptor antagonist, a profile unique for atypical antipsychotic drugs. The purpose of this study was to clarify the effects of cariprazine and selective D 3 receptor ligands on neurotransmitter efflux in the rat nucleus accumbens (NAC) and ventral hippocampus (HIP), brain regions important for reality testing, rewarded behavior, and cognition. In vivo microdialysis was performed in awake, freely moving rats after administration of cariprazine; (1)-PD-128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a D 3 receptor-preferring agonist; and SB-277011A [trans- N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride], a selective D 3 receptor antagonist, alone or combined, and extracellular levels of multiple neurotransmitters and metabolites were measured in the NAC and HIP by ultraperformance liquid chromatography with tandem mass spectrometry. Cariprazine increased DA, norepinephrine (NE), and 5-HT efflux in both regions, whereas it increased glycine (Gly) and glutamate efflux only in the NAC and efflux of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) only in the HIP. Similarly, SB-277011A increased DA, NE, DOPAC, and HVA, but not 5-HT, efflux in the NAC and HIP, and acetylcholine efflux in the HIP. Most of these effects of cariprazine and SB-277011A were fully or partially attenuated by the D 3 receptor agonist (1)-PD-128907, suggesting these effects of cariprazine are related to its D 3 receptor partial agonism, and that this mechanism, leading to diminished stimulation of D 3 receptors, may contribute to its efficacy in both schizophrenia and bipolar disorder. The possible role of Gly in the action of cariprazine is discussed. SIGNIFICANCE STATEMENTThe novel atypical antipsychotic drug cariprazine increased nucleus accumbens and hippocampal neurotransmitter efflux, similar to the actions of the D 3 receptor antagonist SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide hydrochloride]. The D 3 receptor-preferring agonist (1)-PD-128907 [(4aR, 10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4oxazin-9-ol hydrochloride], diminished the effects of both compounds on neurotransmitter efflux in both regions. These results suggested D3 receptor partial agonist activity of cariprazine, producing functional antagonism, may contribute to its efficacy in schizophrenia and bipolar disorder. This study was supported by grants from Allergan, Plc. and Gedeon Richter, Plc. H.Y.M. has been consulting for and receives research funding from Allergan. B.K. and B.F. are employees of Gedeon Richter Plc. N.A. is an employee of Allergan. M.H. and W.H. have no conflicts of interest to declare.This work w...
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