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ABSTRACT: Local infusion of the GABA(A) receptor agonist muscimol is used for reversible inactivation of septohippocampal brain structures associated with cognitive functions. However, information on the effective duration, affected processes and site(s) of action of muscimol in the hippocampus is lacking. Therefore, the dose- and time-dependent effects of bilateral dorsohippocampal infusion of muscimol (0.01 - 2.0μg/mouse) below the CA1 area were examined on processing of fear memory in male C57BL/6J mice. Infusion of muscimol 15min - 6h but not 9h or 24h before training impaired conditioned context-dependent fear tested 24h or 48h after training. Post-training infusion of muscimol also impaired context-dependent fear when applied either 4h or 6h after training, although with lower efficacy. Muscimol was ineffective when administered immediately, 1h or 24h after training. Infusion of muscimol 15min before training impaired context-dependent fear 4-6h after training indicating preserved short-term but impaired long-term memory. Regardless of infusion time and dose, muscimol had no effect on tone-dependent (cued) fear memory. The impairment by the fluorescently-labeled muscimol-bodipy (5.3μg/mouse) were similar to those of an equimolar dose of muscimol (1μg/mouse). The distribution profile after local infusion indicated that muscimol-bodipy (5.3μg/mouse) was confined to the CA1 area of the dorsal hippocampus. These results demonstrated that GABA(A) receptor activation in the CA1 area of the dorsal hippocampus causes a long-term memory impairment of conditioned context-dependent fear mediated by a long-lasting (≥6h) muscimol action most likely affecting consolidation processes.
Behavioural brain research 10/2012; · 3.22 Impact Factor
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ABSTRACT: 5-HT(1A) receptors are implicated in the modulation of cognitive processes including encoding of fear learning. However, their exact role has remained unclear due to contrasting contributions of pre- vs. postsynaptic 5-HT(1A) receptors. Therefore, their role in fear conditioning was studied in mice using the selective ligand S15535, which fully activates 5-HT(1A) autoreceptors, yet only weakly stimulates their postsynaptic counterparts. The effects of S15535 were compared to those of the full agonist 8-OH-DPAT and the selective antagonist NAD-299. 8-OH-DPAT dose-dependently (0.01-0.5 mg/kg) and markedly impaired both context- and tone-dependent fear conditioning, as determined by complementary measures of inactivity and freezing. 8-OH-DPAT-mediated impairments were blocked by pre-injection of the selective 5-HT(1A) antagonist WAY100635. S15535 (0.01-5.0 mg/kg) mimicked 8-OH-DPAT in predominantly impairing conditioned contextual fear, though with smaller effect size than 8-OH-DPAT, consistent with lower efficacy at postsynaptic 5-HT(1A) receptors. Furthermore, S15535 (1.0 mg/kg) tended to attenuate the impairment of fear conditioning by 8-OH-DPAT (0.3 mg/kg). In contrast, NAD-299 (0.3 and 1 mg/kg) facilitated contextual freezing. WAY100635 (0.3 mg/kg) prevented the impairment of contextual fear by S15535 (1 and 5 mg/kg), underpinning the role of 5-HT(1A) receptors in the actions of S15535. Collectively, these data indicate that 5-HT(1A) receptor ligands modulate fear conditioning in a bidirectional manner: activation of postsynaptic 5-HT(1A) sites exerts an inhibitory influence, whereas their blockade promote facilitation of fear conditioning. The results with S15535 underscore the importance of ligand efficacy in determining the actions of 5-HT(1A) receptor ligands in fear conditioning and other models of cognitive function.
Neuropharmacology 08/2009; 57(5-6):567-76. · 4.81 Impact Factor
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ABSTRACT: The present study evaluated whether hypolocomotion elicited by subcutaneous administration of the non-specific 5-HT/preferential 5-HT(2C) receptor agonist mCPP during novelty exposure was due to an enhanced anxiety-like state. The effects of mCPP on exploratory behavior during exposure to a new environment (novelty) were studied in male C57BL/6N mice. Subcutaneous injection of mCPP (1 and 3mg/kg) and the preferential 5-HT(2C) receptor agonist MK212 (0.7 and 1mg/kg) induced hypolocomotion during novelty exposure. The selective 5-HT(2C) receptor antagonist SB242084 (0.3mg/kg) reversed the mCPP-induced hypolocomotion into hyperlocomotion. In contrast, MK212 induced hypolocomotion that was blocked by SB242084, indicating a specific 5-HT(2C) receptor involvement. When injected intracerebroventricularly, mCPP (30microg) elicited hypolocomotion, whereas the same dose mildly increased locomotion when injected into the dorsal hippocampus. Since anxiety affects autonomic functions, effects of mCPP on cardiovascular function were studied by radio-telemetry in the home cage of unrestrained mice. Subcutaneous injection of mCPP (3mg/kg) had no significant effect on heart rate and mean arterial blood pressure. In summary, in view of lack of autonomic effects, and the lack of hypoactivity upon forebrain stimulation, the hypolocomotion induced by systemic mCPP cannot be explained by an enhanced anxiety-like state.
Neuropharmacology 04/2007; 52(3):949-57. · 4.81 Impact Factor
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ABSTRACT: Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.
Hippocampus 02/2005; 15(4):418-26. · 5.18 Impact Factor
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ABSTRACT: Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT(1A) receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1). a functional 5-HT(1A) receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2). the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT(1A) receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease.
Neuropsychopharmacology 03/2003; 28(2):253-64. · 7.99 Impact Factor
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ABSTRACT: Galanin (3 nmol/rat), 2 h after its intracerebroventricular (i.c.v.) administration to male rats, attenuated the passive avoidance (PA) retention deficit induced by the 5-hydroxytryptamine (HT)1A receptor agonist 8-hydroxy-2-(di-N-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg) The reduction in the postjunctional 5-HT1A receptor-mediated response after i.c.v. galanin was not associated with changes in the mRNA levels and agonist binding properties of cortical limbic 5-HT1A receptors, believed to be the target receptors mediating the PA deficit caused by 8-OH-DPAT. These results suggest that acute increases of galanin transmission in vivo even after 2 h can counteract limbic 5-HT1A receptor-mediated responses of relevance for affective disorders without significantly affecting gene expression and binding characteristics of cortical limbic 5-HT1A receptors.
Neuroscience Letters.
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ABSTRACT: 5-HT1A receptors are implicated in the modulation of cognitive processes including encoding of fear learning. However, their exact role has remained unclear due to contrasting contributions of pre- vs. postsynaptic 5-HT1A receptors. Therefore, their role in fear conditioning was studied in mice using the selective ligand S15535, which fully activates 5-HT1A autoreceptors, yet only weakly stimulates their postsynaptic counterparts. The effects of S15535 were compared to those of the full agonist 8-OH-DPAT and the selective antagonist NAD-299. 8-OH-DPAT dose-dependently (0.01–0.5 mg/kg) and markedly impaired both context- and tone-dependent fear conditioning, as determined by complementary measures of inactivity and freezing. 8-OH-DPAT-mediated impairments were blocked by pre-injection of the selective 5-HT1A antagonist WAY100635. S15535 (0.01–5.0 mg/kg) mimicked 8-OH-DPAT in predominantly impairing conditioned contextual fear, though with smaller effect size than 8-OH-DPAT, consistent with lower efficacy at postsynaptic 5-HT1A receptors. Furthermore, S15535 (1.0 mg/kg) tended to attenuate the impairment of fear conditioning by 8-OH-DPAT (0.3 mg/kg). In contrast, NAD-299 (0.3 and 1 mg/kg) facilitated contextual freezing. WAY100635 (0.3 mg/kg) prevented the impairment of contextual fear by S15535 (1 and 5 mg/kg), underpinning the role of 5-HT1A receptors in the actions of S15535. Collectively, these data indicate that 5-HT1A receptor ligands modulate fear conditioning in a bidirectional manner: activation of postsynaptic 5-HT1A sites exerts an inhibitory influence, whereas their blockade promote facilitation of fear conditioning. The results with S15535 underscore the importance of ligand efficacy in determining the actions of 5-HT1A receptor ligands in fear conditioning and other models of cognitive function.
Neuropharmacology.
