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Panic disorder is an anxiety disorder that can be treated by long-term administration of tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors such as phenelzine, or the selective serotonin reuptake inhibitor (SSRI) antidepressants. Clinical data also indicate that some benzodiazepines, such as alprazolam, are effective antipanic agents, and that their therapeutic onset is faster than that of antidepressants. Benzodiazepines are well known for their action at GABAA receptors, and preclinical data indicate that imipramine and phenelzine also interfere with the GABAergic system. In addition some clinical data lend support to decreased benzodiazepine-sensitive receptor function in panic disorder patients. Using imipramine, phenelzine and alprazolam, we investigated, in rats, the possibility that the therapeutic efficacy of antipanic agents stems from the remodeling of GABAergic transmission in the pons-medulla region. Of the 12 GABA[sub A] receptor subunit (α1-6, β1-3, γ1-3) steady-state mRNA levels investigated, we observed an increase in the levels of the α3-, β1- and γ2-subunit transcripts with all three antipanic agents tested. The effects of imipramine and phenelzine on these subunits occurred after 21 days of treatment, while alprazolam effects were observed after 3 days of administration. Histochemical data suggest that the α3β1γ2 subunits comprise a receptor subtype in the pons-medulla region. Therefore, we conclude that these molecular events parallel the therapeutic profile of the drugs examined. We further propose that these events may correspond to a remodeling of the GABA[sub A] receptor population, and may be useful markers for investigation of the antipanic properties of drugs. [ABSTRACT FROM AUTHOR]

Abstract: Accumulated evidence suggests that the single transmembrane domain insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-II/M6P or IGF-II receptor) plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of insulin like growth factor (IGF-II). However, the role of this receptor in signal transduction following IGF-II binding remains controversial. In the present study, we revealed that Leu27IGF-II, an analog which binds preferentially to the IGF-II receptor, can attenuate K+-as well as veratridine-evoked GABA release from the adult rat hippocampal formation. Tetrodotoxin failed to alter the effects of Leu27IGF-II on GABA release, thus suggesting the lack of involvement of voltage-dependent Na+ channels. Interestingly, the effect is found to be sensitive to pertussis toxin (PTX), indicating the possible involvement of a Gi/o protein-dependent pathway in mediating the release of GABA from the hippocampal slices. Additionally, Leu27IGF-II was found to attenuate GABA release from frontal cortex but not from striatum. These results, together with the evidence that IGF-II receptors are localized on GABAergic neurons, raised the possibility that this receptor, apart from mediating intracellular trafficking, may also be involved in the regulation of endogenous GABA release by acting directly on GABAergic terminals. [Copyright &y& Elsevier]

Highlights: [•] Multiphoton imaging was done in co-cultures of fetal human cortex. [•] Ca2+ and mitochondrial dynamics were imaged in neurons and astrocytes for ⩾5h. [•] Ca2+ response patterns to some neuro/glio-transmitters differed for both cell types. [•] Anoxia and FCCP raised Ca2+ in neurons, but not astrocytes. [•] Anoxia and FCCP depolarized mitochondrial membrane potential in both cell types. [ABSTRACT FROM AUTHOR]