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Background: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear., Methods: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory., Results: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist., Conclusions: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.

Escape from fear (EFF) is a controversial paradigm according to which animals learn to actively escape a fear-eliciting conditioned stimulus (CS) if the escape response (R-sub(e)) is paired with CS termination. Some theories posit that EFF learning is responsible for instrumental avoidance conditioning. However, EFF learning has typically been weaker than avoidance learning and difficult to reproduce. The authors examined EFF learning and memory with 2 atypical R-sub(e)s: rearing and nose-poking. The data suggest that rearing, but not nose-poking, can be learned as an instrumental EFF response. Further, EFF memory was response specific, aversively motivated, and controlled by the CS. Successful EFF learning also resulted in better long-term elimination of a passive fear reaction (freezing). Factors important for EFF experiments and theoretical considerations are discussed., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

In the standard model of pavlovian fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of fear conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs fear memory consolidation. These findings indicate that CE is not only involved in fear expression but, like LA, is also involved in the learning and consolidation of pavlovian fear conditioning.

In the present study, we examined the role of the auditory thalamus [medial division of the medial geniculate nucleus and the adjacent posterior intralaminar nucleus (MGm/PIN)] in auditory pavlovian fear conditioning using pharmacological manipulation of intracellular signaling pathways. In the first experiment, rats were given intrathalamic infusions of the MEK (mitogen-activated protein kinase-kinase) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126) before fear conditioning. Findings revealed that long-term memory (assessed at 24 h) was impaired, whereas short-term memory (assessed at 1-3 h) of fear conditioning was intact. In the second experiment, rats received immediate posttraining intrathalamic infusion of U0126, the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), or infusion of the protein synthesis inhibitor anisomycin. Posttraining infusion of either U0126 or DRB significantly impaired long-term retention of fear conditioning, whereas infusion of anisomycin had no effect. In the final experiment, rats received intrathalamic infusion of U0126 before long-term potentiation (LTP)-inducing stimulation of thalamic inputs to the lateral nucleus of the amygdala (LA). Findings revealed that thalamic infusion of U0126 impaired LTP in the LA. Together, these results suggest the possibility that MGm/PIN cells that project to the LA contribute to memory formation via ERK (extracellular signal-regulated kinase)-mediated transcription, but that they do so by promoting protein synthesis-dependent plasticity locally in the LA.

Reactivation of consolidated memories returns them to a protein synthesis-dependent state. One interpretation of these findings is that the memory reconsolidates after use. Two alternative interpretations are that protein synthesis inhibition facilitates extinction and that postreactivation protein synthesis inhibition leads to an inability to retrieve the consolidated memory. First, using two different approaches, we report that reconsolidation cannot be reduced down to facilitated extinction. We show that the reconsolidation deficit does not show renewal after a contextual shift, whereas an extinguished auditory fear memory does under the same conditions and the deficit occurs regardless of whether the memory is reactivated with an extinction [conditioned stimulus (CS) alone] or a reinforced trial (CS-unconditioned stimulus). To address the issue of whether postreactivation anisomycin leads to an inability to retrieve the consolidated memory, we used two traditional assays for retrieval deficits. First, we demonstrate that the amnesia induced by blockade of reconsolidation does not show any spontaneous recovery. Second, we show that application of reminder shock does not result in the reinstatement of the memory. These findings support the idea that reactivation of consolidated memories initiates a second time-dependent memory formation process.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in synaptic plasticity and memory formation in a variety of learning systems and species. The present experiments examined the role of CaMKII in the circuitry underlying pavlovian fear conditioning. First, we reveal by immunocytochemical and tract-tracing methods that alphaCaMKII is postsynaptic to auditory thalamic inputs and colocalized with the NR2B subunit of the NMDA receptor. Furthermore, we show that fear conditioning results in an increase of the autophosphorylated (active) form of alphaCaMKII in lateral amygdala (LA) spines. Next, we demonstrate that intra-amygdala infusion of a CaMK inhibitor, 1-[NO-bis-1,5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl-4-phenylpiperazine, KN-62, dose-dependently impairs the acquisition, but not the expression, of auditory and contextual fear conditioning. Finally, in electrophysiological experiments, we demonstrate that an NMDA receptor-dependent form of long-term potentiation at thalamic input synapses to the LA is impaired by bath application of KN-62 in vitro. Together, the results of these experiments provide the first comprehensive view of the role of CaMKII in the amygdala during fear conditioning.

Consolidation is a process through which labile memories are made persistent [Science 287 (2000) 248]; [Annu Rev Psychol 55 (2004) 51]. When retrieved, a consolidated memory is rendered labile again and undergoes reconsolidation [Learn Mem 7 (2000) 73]; [Trends Neurosci 26 (2003) 65]). Reconsolidation thus offers the opportunity to manipulate memory after it is formed, and may therefore provide a means of treating intrusive memories associated with post-traumatic stress disorder (PTSD). Reconsolidation is most usually studied using protein synthesis inhibitors, which is not practical in humans. However, the beta adrenergic receptor antagonist propranolol impairs consolidation of declarative memory in humans [Science 287 (2000) 248]; [Nature 371 (1994) 702] and consolidation and reconsolidation of inhibitory avoidance learning in rats [Brain Res 368 (1986) 125]; [J Neurosci 19 (1999) 6623]. Here, we show that systemic or intra-amygdala infused propranolol blocks reconsolidation but not consolidation. If the effects on reconsolidation are verified in humans, the results would suggest the possibility that propranolol after memory retrieval might be an effective way of treatment of intrusive memories in PTSD. That the systemic effects of propranolol on reconsolidation are achieved via an action in the amygdala is especially important in light of the fact that PTSD involves alterations in the amygdala [Arch Gen Psychiatry 53 (1996) 380].

A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that bind the regulatory subunits of protein kinase A (PKA). AKAP binding to PKA regulates the phosphorylation of various proteins, some of which have been implicated in synaptic plasticity and memory consolidation. Here we show that the regulatory subunits of PKA are colocalized with AKAP150 (an AKAP isoform that is expressed in the brain) in the lateral amygdala (LA) and that infusion to the LA of the peptide St-Ht31, which blocks PKA anchoring onto AKAPs, impairs memory consolidation of auditory fear conditioning.

The group I metabotropic glutamate receptor subtype mGluR5 has been shown to play a key role in the modulation of synaptic plasticity. The present experiments examined the function of mGluR5 in the circuitry underlying Pavlovian fear conditioning using neuroanatomical, electrophysiological, and behavioral techniques. First, we show using immunocytochemical and tract-tracing methods that mGluR5 is localized to dendritic shafts and spines in the lateral nucleus of the amygdala (LA) and is postsynaptic to auditory thalamic inputs. In electrophysiological experiments, we show that long-term potentiation at thalamic input synapses to the LA is impaired by bath application of a specific mGluR5 antagonist, 2-methyl-6-(phenyle-thynyl)-pyridine (MPEP), in vitro. Finally, we show that intra-amygdala administration of MPEP dose-dependently impairs the acquisition, but not expression or consolidation, of auditory and contextual fear conditioning. Collectively, the results of this study indicate that mGluR5 in the LA plays a crucial role in fear conditioning and in plasticity at synapses involved in fear conditioning.

Long-term potentiation (LTP) at sensory input synapses to the lateral amygdala (LA) is a candidate mechanism for memory storage during fear conditioning. We evaluated the effect of L-type voltage-gated calcium channel (VGCC) and NMDA receptor (NMDAR) blockade in LA on LTP at thalamic input synapses induced by two different protocols in vitro and on fear memory in vivo. When induced in vitro by pairing weak presynaptic stimulation with strong (spike eliciting) postsynaptic depolarization, LTP was dependent on VGCCs and not on NMDARs, but, when induced by a form of tetanic stimulation that produced prolonged postsynaptic depolarization (but not spikes), LTP was dependent on NMDARs and not on VGCCs. In behavioral studies, bilateral infusions of NMDAR antagonists into the LA impaired both short-term and long-term memory of fear conditioning, whereas VGCC blockade selectively impaired long-term memory formation. Collectively, the results suggest that two pharmacologically distinct forms of LTP can be isolated in the LA in vitro and that a combination of both contribute to the formation of fear memories in vivo at the cellular level.

The lateral nucleus of the amygdala (LA) is an essential component of the neural circuitry underlying Pavlovian fear conditioning. Although blockade of NMDA receptors in LA and adjacent areas before training disrupts the acquisition of fear conditioning, blockade before testing also often disrupts the expression of fear responses. With this pattern of results, it is not possible to distinguish a contribution of NMDA receptors to plasticity from a role in synaptic transmission. In past studies, NMDA blockade has been achieved using the antagonist d,l-2-amino-5-phosphovalerate, which blocks the entire heteromeric receptor complex. The present experiments examined the effects of selective blockade of the NR2B subunit of the NMDA receptor in LA using the selective antagonist ifenprodil. Systemic injections of ifenprodil before training led to a dose-dependent impairment in the acquisition of auditory and contextual fear conditioning, whereas injections before testing had no effect. Intra-amygdala infusions of ifenprodil mirrored these results and, in addition, showed that the effects are attributable to a disruption of fear learning rather than a disruption of memory consolidation. NMDA receptors in LA are thus involved in fear conditioning, and the NR2B subunit appears to make unique contributions to the underlying plasticity.

Although much has been learned about the neurobiological mechanisms underlying Pavlovian fear conditioning at the systems and cellular levels, relatively little is known about the molecular mechanisms underlying fear memory consolidation. The present experiments evaluated the role of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the amygdala during Pavlovian fear conditioning. We first show that ERK/MAPK is transiently activated-phosphorylated in the amygdala, specifically the lateral nucleus (LA), at 60 min, but not 15, 30, or 180 min, after conditioning, and that this activation is attributable to paired presentations of tone and shock rather than to nonassociative auditory stimulation, foot shock sensitization, or unpaired tone-shock presentations. We next show that infusions of U0126, an inhibitor of ERK/MAPK activation, aimed at the LA, dose-dependently impair long-term memory of Pavlovian fear conditioning but leaves short-term memory intact. Finally, we show that bath application of U0126 impairs long-term potentiation in the LA in vitro. Collectively, these results demonstrate that ERK/MAPK activation is necessary for both memory consolidation of Pavlovian fear conditioning and synaptic plasticity in the amygdala.

Previous studies have shown that long-term potentiation (LTP) can be induced in the lateral nucleus of the amygdala (LA) after stimulation of central auditory pathways and that auditory fear conditioning modifies neural activity in the LA in a manner similar to LTP. The present experiments examined whether intra-LA administration of inhibitors of protein synthesis or protein kinase A (PKA) activity, treatments that block LTP in hippocampus, interfere with memory consolidation of fear conditioning. In the first series of experiments, rats received a single conditioning trial followed immediately by intra-LA infusions of anisomycin (a protein synthesis inhibitor) or Rp-cAMPS (an inhibitor of PKA activity) and were tested 24 hr later. Results indicated that immediate post-training infusion of either drug dose-dependently impaired fear memory retention, whereas infusions 6 hr after conditioning had no effect. Additional experiments showed that anisomycin and Rp-cAMPS interfered with long-term memory (LTM), but not short-term memory (STM), of fear and that the effect on LTM was specific to memory consolidation processes rather than to deficits in sensory or performance processes. Findings suggest that the LA is essential for memory consolidation of auditory fear conditioning and that this process is PKA and protein-synthesis dependent.

Although the lateral and basal nuclei of the amygdala are believed to be essential for the acquisition of Pavlovian fear conditioning, studies using post-training manipulations of the amygdala in the inhibitory avoidance learning paradigm have recently called this view into question. We used the GABA(A) agonist muscimol to functionally inactivate these nuclei immediately after single-trial Pavlovian fear conditioning or single-trial inhibitory avoidance learning. Immediate post-training infusions of muscimol had no effect on Pavlovian conditioning but produced a dose-dependent effect on inhibitory avoidance. However, pre-training infusions dose-dependently disrupted Pavlovian conditioning. These findings indicate that the amygdala plays an essential role in the acquisition of Pavlovian fear conditioning and contributes to the modulation of memory consolidation of inhibitory avoidance but not of Pavlovian fear conditioning.

The induction of c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) has been shown to be correlated with behavioral expression of a conditioned taste aversion (CTA). However, because this cellular response is also dependent on an intact amygdala, it may represent the activation of a stress-related autonomic response. The present experiments addressed this possibility by evaluating the correlation between c-FLI in the intermediate division of the NTS (iNTS) and 2 measures of conditioned fear: freezing and changes in mean arterial pressure (MAP) and heart rate (HR). Exposure to the taste conditioned stimulus (CS) resulted in a marked induction of c-FLI in the iNTS, whereas exposure to a fear CS did not. Further, exposure to a taste CS did not selectively lead to increases in MAP or HR. Results suggest that induction of c-FLI in the iNTS may reflect the activation of a cell population whose function is unique to the CTA paradigm.

Two competing theories predict different effects on memory consolidation when the amygdala is inactivated after fear conditioning. One theory, based on studies using inhibitory avoidance training, proposes that the amygdala modulates the strength of fear learning, and post-training amygdala manipulations interfere with memory consolidation. The other, based on studies using Pavlovian fear conditioning, hypothesizes that fear learning occurs in the amygdala, and post-training manipulations after acquisition will not affect memory consolidation. We infused the GABAA agonist muscimol (4.4 nmol/side) or vehicle into lateral and basal amygdala (LBA) of rats either before or immediately after tone-foot shock Pavlovian fear conditioning. Pre-training infusions eliminated acquisition, whereas post-training infusions had no effect. These findings indicate that synaptic activity in LBA is necessary during learning, but that amygdala inactivation directly after training does not affect memory consolidation. Results suggest that essential aspects of plasticity underlying auditory fear conditioning take place within LBA during learning.