Inhibitory Avoidance Extinction Research Articles

Fear extinction can be made state-dependent on peripheral epinephrine: Role of norepinephrine in the nucleus tractus solitarius

We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.

MGlu5 as a potential therapeutic target for the treatment of fragile X syndrome

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most common known cause of autism. It is caused by the expansion of a CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, which encodes the fragile X mental retardation protein (FMRP). FMRP negatively regulates group 1 (Grp 1) metabotropic glutamate receptor (mGlu a.k.a. mGluR) activity, and many FXS phenotypes are thought to be due to the over activity of the Grp 1 mGlu, mGlu5. This review evaluates the evidence for mGlu5 as a potential therapeutic target in the treatment of FXS. A 50% reduction in mGlu5 expression in Fmr1 knockout (KO) mice has been shown to reverse many FXS-relevant phenotypes including alterations in synaptic plasticity, increased dendritic spine density, increased basal hippocampal protein synthesis, inhibitory avoidance extinction and susceptibility to audiogenic seizures. A negative modulator of mGlu5 may, therefore, be expected to have the same effect. In Fmr1 KO mice, Grp 1 mGlu antagonists, such as 2-methyl6-(phenylethynyl)pyridine (MPEP), fenobam and AFQ056, have been shown to reduce audiogenic seizures, reverse altered dendritic spine morphology, reduce excessive protein synthesis and improve behavioural abnormalities. MPEP, however, has failed to reverse altered long-term potentiation in the sensory neocortex or reduce machroorchidism. Clinical trials of mGlu5negative modulators have had some positive outcomes but have had too few participants and were not performed over a long enough period to detect significant effects. Nevertheless, the prospects for development of mGlu5-negative modulators as FXS therapeutics are good and most research supports mGlu5 as a potential therapeutic target.

Modulation of the extinction of two different fear-motivated tasks in three distinct brain areas

The hippocampus, basolateral amygdala and ventromedial prefrontal cortex participate in the extinction of inhibitory avoidance and contextual fear conditioning. We studied the effect of drugs acting on receptors involved in synaptic modulation on extinction of both tasks. The drugs were given bilaterally right after the first of two sessions of extinction in each task through cannulae implanted into the mentioned areas. The doses used are known to influence memory consolidation of the original tasks. Their effects were evaluated on a second extinction session 24h later, and assumed to result from influences on the consolidation of extinction. The glutamate NMDA receptor stimulant d-serine (50μg/side) and the histamine methyl-transferase inhibitor SKF9188 (12.5μg/side) enhanced, and the NMDA antagonist amino-phosphonopentanoate (5μg/side) and the H2 histamine receptor antagonist ranitidine (17.5μg/side) inhibited, extinction of both tasks regardless of the region into which they were administered. Thus, glutamate NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Norepinephrine (1μg/side), the β-adrenoceptor antagonist timolol (1μg/side), the D1 dopamine receptor agonist SKF38393 (12.5μg/side) and the D1 antagonist SCH23390 (1.5μg/side) also affected extinction of both tasks, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by β- and D1 receptors is more complex. In conclusion, extinction of two different aversive tasks is modulatable by various systems, which bears upon the behavioral and pharmacological treatment of fear-motivated brain disorders.

Extinction procedure induces pruning of dendritic spines in CA1 hippocampal field depending on strength of training in rats.

Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training.

Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the acquisition and extinction of inhibitory avoidance

Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the acquisition and extinction of inhibitory avoidance