5 research outputs found
Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats
Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene–environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene–environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia
Individual expression of conditioned safety but not of conditioned relief is correlated with contextual fear
Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats
Background:
The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.
Aims:
Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats.
Methods:
We designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors.
Results/outcomes:
By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3–1.5 mg/kg/day), attenuates psychotic-like behavior in rats.
Conclusions/interpretation:
These findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action
Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑<i>a</i>]pyridine Substructure
1,4-Disubstituted aromatic piperazines
are privileged structural
motifs recognized by aminergic G protein-coupled receptors. Connection
of a lipophilic moiety to the arylpiperazine core by an appropriate
linker represents a promising concept to increase binding affinity
and to fine-tune functional properties. In particular, incorporation
of a pyrazoloÂ[1,5-<i>a</i>]Âpyridine heterocyclic appendage
led to a series of high-affinity dopamine receptor partial agonists.
Comprehensive pharmacological characterization involving BRET biosensors,
binding studies, electrophysiology, and complementation-based assays
revealed compounds favoring activation of G proteins (preferably G<sub>o</sub>) over β-arrestin recruitment at dopamine D<sub>2</sub> receptors. The feasibility to design G protein-biased partial agonists
as putative novel therapeutics was demonstrated for the representative
2-methoxyphenylpiperazine <b>16c</b>, which unequivocally displayed
antipsychotic activity in vivo. Moreover, combination of the pyrazoloÂ[1,5-<i>a</i>]Âpyridine appendage with a 5-hydroxy-<i>N</i>-propyl-2-aminotetraline unit led to balanced or G protein-biased
dopaminergic ligands depending on the stereochemistry of the headgroup,
illustrating the complex structure–functional selectivity relationships
at dopamine D<sub>2</sub> receptors
Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑<i>a</i>]pyridine Substructure
1,4-Disubstituted aromatic piperazines
are privileged structural
motifs recognized by aminergic G protein-coupled receptors. Connection
of a lipophilic moiety to the arylpiperazine core by an appropriate
linker represents a promising concept to increase binding affinity
and to fine-tune functional properties. In particular, incorporation
of a pyrazoloÂ[1,5-<i>a</i>]Âpyridine heterocyclic appendage
led to a series of high-affinity dopamine receptor partial agonists.
Comprehensive pharmacological characterization involving BRET biosensors,
binding studies, electrophysiology, and complementation-based assays
revealed compounds favoring activation of G proteins (preferably G<sub>o</sub>) over β-arrestin recruitment at dopamine D<sub>2</sub> receptors. The feasibility to design G protein-biased partial agonists
as putative novel therapeutics was demonstrated for the representative
2-methoxyphenylpiperazine <b>16c</b>, which unequivocally displayed
antipsychotic activity in vivo. Moreover, combination of the pyrazoloÂ[1,5-<i>a</i>]Âpyridine appendage with a 5-hydroxy-<i>N</i>-propyl-2-aminotetraline unit led to balanced or G protein-biased
dopaminergic ligands depending on the stereochemistry of the headgroup,
illustrating the complex structure–functional selectivity relationships
at dopamine D<sub>2</sub> receptors