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Propranolol can induce PTSD-like memory impairments in rats.

ABSTRACT: Introduction:One hallmark symptom of post-traumatic stress disorder (PTSD) is an inability to restrict fear responses to the appropriate predictor. An infusion of glucocorticoids (GCs) after a high-intensity shock has been shown to induce PTSD-like memory impairments. In addition to GCs, noradrenergic signalling is also recognized as a key biomarker underlying PTSD symptomatology. Methods:To explore the role of the noradrenergic system in PTSD-like memory impairments, in this study, various doses of the ?-adrenoceptor antagonist propranolol were systemically or bilaterally injected into the dorsal hippocampus immediately after unpaired cue-shock contextual fear conditioning, and then the rats were tested 24 h later. Results:Interestingly, we found that only low-dose propranolol could induce PTSD-like memory impairments, as rats showed reduced freezing to the correct predictor and generalized fear responses to the safe cues, accompanied by increased NE levels in the hippocampus and altered neural activity within the frontal-subcortical circuit. Conclusion:These findings demonstrate that the noradrenergic system is involved in regulating the consolidation of contextual fear memory and that propranolol can dose-dependently induce PTSD-like memory impairments.

SUBMITTER: Zhu RT

PROVIDER: S-EPMC5822589 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Propranolol can induce PTSD-like memory impairments in rats.

Zhu Rong-Ting RT Liu Xiang-Hui XH Shi Yan-Wei YW Wang Xiao-Guang XG Xue Li L Zhao Hu H

Brain and behavior 20180118 2

<h4>Introduction</h4>One hallmark symptom of post-traumatic stress disorder (PTSD) is an inability to restrict fear responses to the appropriate predictor. An infusion of glucocorticoids (GCs) after a high-intensity shock has been shown to induce PTSD-like memory impairments. In addition to GCs, noradrenergic signalling is also recognized as a key biomarker underlying PTSD symptomatology.<h4>Methods</h4>To explore the role of the noradrenergic system in PTSD-like memory impairments, in this stud ...[more]

PMID: 29484264

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Project description:BACKGROUND:Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. METHODS:A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 ?L per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. RESULTS:DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. CONCLUSION:Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.

Project description:Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28-49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABA(A) receptors with open Cl(-) channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.

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Propranolol can induce PTSD-like memory impairments in rats.

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Propranolol can induce PTSD-like memory impairments in rats.

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