Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders.
Bottom Line: Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success.Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear.We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA.
Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: email@example.com.Show MeSH
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Mentions: GABA is the main inhibitory neurotransmitter in the adult mammalian brain. Because extinction largely reflects the promotion of active inhibitory processes, it is not surprising that GABA serves as an important source of such inhibition. GABA signaling occurs largely via binding to ionotropic GABAA and metabotropic GABAB receptors (former GABAC receptors have been reclassified and are now termed GABAA rho-subclass receptors). GABAA receptors are pentameric, ligand-gated Cl− channels which, upon activation induce hyperpolarization of cells and hence reduce neuronal excitability. Seven classes of GABAA subunits (α1–6, β1–3, γ1–3, ρ1–3, δ, ε, ) have been identified so far, permitting the assembly of highly variable GABAA receptors with distinct functions and signaling properties. Furthermore, several allosteric binding sites, in addition to the GABA binding pocket located at the α/β-subunit interface, allow nuanced modifications of GABAA receptor signaling. The allosteric benzodiazepine (BZD) binding site is localized at the interface of α-and -γ-subunits and when activated, facilitates GABAergic transmission by promoting GABA binding to the receptor and increasing the opening probability of the Cl− channel. The binding sites of other allosteric modulators of GABAA signaling including barbiturates and neurosteroids among others are not yet fully characterized [see Fig. 7 and (Gunn et al., 2014; Makkar et al., 2010)].
Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: firstname.lastname@example.org.