Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders

Abstract

Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. 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. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. 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. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.

Keywords: Augmented relearning; Cognitive enhancer; Drug development; Exposure therapy; Fear extinction; Reconsolidation.

Fig. 1

Different modes of fear alleviation and sites of possible pharmacological intervention. A, Fear alleviation is mediated via different mechanisms leading to acute or sustained fear relief. Sustained fear relief can be obtained either with exposures to the feared cues/situations or, in some instances, also without them For a detailed description of the involved mechanisms, see Riebe et al. (2012). Pharmacological interventions to boost fear relief can target different mechanisms at various levels. Examples are given with numbers 1–4, for detail see text B, Fear conditioning represents a training phase in which a novel conditioned stimulus (CS) is paired with an unconditioned stimulus (US) (redline). Throughout fear training and testing, fear is measured as a conditioned response (y-axis), typically freezing, fear-potentiated startle, increased heart rate, and other quantifiable behavioral measures of fear. Following this training period, mice undergo a consolidation phase which transfers the labile newly formed fear memory into a stable long-term memory. Fear can be extinguished by repeated presentations of the CS (without the US; red line) resulting in fear extinction. Following the extinction training session, and akin to fear learning, consolidation processes are initiated to stabilize this labile fear extinction memory into a long-term memory. Poor extinction is evidenced by high fear responding (red bar), and successful extinction retrieval is shown by reduced fear (green) during a retrieval test. Extinguished fear can recover via three main mechanisms: spontaneous recovery (recovery of extinguished fear responses occurs with the passage of time in the absence of any further training), fear renewal (when the conditioned CS is presented outside the extinction context, for example the conditioning or novel contexts), and fear reinstatement (when un-signaled presentations of the US are interposed between the completion of extinction training and a subsequent retention test). Drugs (green arrows) can be administered either immediately prior to (to induce extinction acquisition also called ‘within-session extinction’ and/or extinction consolidation) or immediately following (to rescue/ boost extinction consolidation processes) the training session to modulate extinction mechanisms. A clinical aim of drug augmentation strategies is to promote good extinction retrieval and to protect against return-of-fear phenomena to provide good ‘longterm extinction’. C, Fear memory can be reactivated (red bar) by presentation of the CS, which transfers the stabilized memory into a labile phase which requires reconsolidation (a process by which previously consolidated memories are stabilized after fear retrieval). The fear memory can then be tested during another retrieval test (red bar) to assess reconsolidation. Drugs (green arrow) can be administered either immediately prior to or after the retrieval session to modulate reconsolidation mechanisms. This effect can then be tested during subsequent retrieval tests. Evidence for successful interference with reconsolidation of the original fear memory is revealed in reduced freezing during the test session. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Anatomy of fear extinction and expression. Fear extinction and expression rely on neuronal processing in an anatomical circuitry centering on the AMY, mPFC, and HPC Glutamatergic and GABAergic neurons, among others, are important components of connectivity and regulation of fear. The AMY is critically involved in the expression of aversive (fear) memories. While fear neurons in the BA send excitatory projections directly to the centromedial AMY (CeM) driving expression of fear (right panel), during extinction (left panel), the infralimbic cortex (IL) inhibits CeM output by driving inhibitory ITC neurons. IL inputs might also synapse directly on “extinction” neurons within the BA. “Extinction” neurons can influence activity within the central AMY (CeA) through several routes, possibly by driving inhibitory ITC or CeL (off, PKC+) neurons that limit CeM activity. There is also a BA-CeL pathway contributing to ultimate inhibition of the CeM. The hippocampus is involved in contextual aspects of extinction via its projections to both the IL and the BA, among other brain regions. Hence, inhibitory memories built following extinction are encoded by the AMY and the mPFC and are modulated by the HPC. It is thought that extinction training and exposure therapy produce long-lasting changes in synaptic plasticity and interneuronal communication in this circuitry ultimately reducing fear responses via output stations including the CeM. For further details, the reader is refered to recent reviews of (Duvarci & Pare, 2014; Orsini & Maren, 2012).

Fig. 3

Overview of pharmacological targets and signaling cascades proposed to be important in mediating synaptic plasticity underlying extinction. The formation of extinction memories requires an intricate regulatory network of signal transduction and gene transcription and translation, leading to a complex pattern of intracellular changes and long-term structural changes. Various pre- and postsynaptic membrane receptors including ionotropic and metabotropic glutamate receptors, cannabinoid receptors, 5-HT, and dopamine receptors have been shown to be important targets. Main downstream mechanisms include calcium entry through NMDAR and VGCC in concert with AMPA receptors initiating synaptic plasticity via calcium-dependent protein kinases (e.g. PKA, PKC, PKM and CamKII, phosphatases (e.g. calcineurin) and activation of the ERK/MAPK pathway. Subsequent interaction with transcription factors, such as CREB and Zif268 within the nucleus results in a wide range of newly synthesized proteins, such as BDNF important for synaptic plasticity including LTP formation. BDNF activated TrkB receptors further regulate the ERK/MAPK pathway. Finally, epigenetic modifications are important in translating neurotransmitter/neuromodulator signaling activity generated at the synapse into activation/repression of the desired genomic response in the cell nucleus. As outlined in the text, boosting these synaptic plasticity mechanisms by pharmacological means may constitute the establishment of novel drug targets to promote fear extinction.

Fig. 4

Overview of research on the role of the serotonergic system in extinction.

Fig. 5

Overview of research on the role of the dopaminergic system in extinction.

Fig. 6

Overview of research on the role of the glutamatergic system in extinction

Fig. 7

Overview of research on the role of the GABAergic system in extinction.

Fig. 8

Overview of research on the role of the cannabinoid system in extinction.

Fig. 9

Schematic representation depicting the epigenetic regulation of fear extinction. DNA methylation is associated with suppression of gene transcription. The precise molecular processes through which this occurs are complex. In brief, methylation of cytosines at CpG dinucleotides recruits methyl-DNA binding proteins, at specific sites in the genome. Proteins that bind to methylated DNA, including methyl CpG-binding protein 2(MeCP2) and methyl CpG-binding domain protein1 (MBD1), have both a methyl-DNA binding domain and a transcription-regulatory domain. The transcription-regulatory domain recruits adapter/scaffolding proteins, which in turn recruit HDACs, including HDAC2, to repress gene transcription [reviewed in (Sweatt, 2009). Following extinction related neuronal activity a number of molecular mechanisms are invoked, ultimately leading to facilitated histone acetylation and subsequent enhancement of gene transcription. These mechanisms include enhancement of HAT activity, such as PCAF (see text) and a reduction in HDAC activity by mechanisms which include nitrosylation (NO) of HDACs, including HDAC2, which facilitates dissociation of HDAC from the chromatin. Moreover, enhanced histone acetylation may also be mediated by the conversion of DNA demethylation which is mediated by the Tet family of methylsytosine dioxygenases. Emerging pharmaceutical evidence is showing that HDAC inhibitors can facilitate gene transcription by enhancing histone acetylation in the promoter region of extinction-relevant genes (see text).

Fig. 10

Strategy for translating research from humans to mice and back, focusing on human disorders of fear dysregulation. Rodent models of enhanced fear and impaired extinction (induced by genetic or environmental manipulations) closely resemble human symptomatology, particularly the fear dysregulation that occurs in PTSD, panic, and phobic disorders. Using these models increases the chances of identifying candidate genes for human anxiety disorders by reducing the problems of genetic heterogeneity and a variable environment. It is also important to study the involvement of these candidate genes in patients, as well as using unbiased genome-wide association studies and genome-wide epigenetic approaches to identify previously unknown genetic pathways contributing to risk in humans. Subsequently, elucidating the function of the identified gene and its epigenetic regulation using rodent models as well as the human population increases our knowledge of the neurobiology of fear disorders, which, at the same time, is necessary to improve the models. It is also necessary to use rodent models to test the ability to pharmacologically enhance extinction of fear and diminish fear expression prior to clinical test phases. Arrows demonstrate how the different levels of understanding, from genetics to epigenetics to neural circuits, can inform each other, as well as how they can be informed across species due to the high level of convergence of shared fear-related processing across mammals.