Cerebral tryptophan hydroxylase activity, and 5-HT1A receptor, 5-HT2A receptor, and 5-HT transporter binding in grouped and isolated Roman RHA and RLA rats: relationships with behaviours in two models of anxiety (original) (raw)
Related papers
Journal of Neurochemistry, 2004
The selective breeding of Roman high-(RHA/Verh) and lowavoidance (RLA/Verh) rats for rapid versus poor acquisition of active avoidant behaviour has produced two behavioural phenotypes with different performances in a variety of animal models of anxiety, in which RLA/Verh rats are consistently more fearful than RHA/Verh rats. In addition, these two lines display different functional properties of brain neurotransmitters like serotonin (5-HT), known to be involved in the expression of anxiety-and depression-related behaviours. Therefore, we used brain microdialysis and [ 3 H]-citalopram binding autoradiography to characterize further the neurochemical properties of 5-HTergic transmission in the two lines. No significant line-related differences were detected in the basal 5-HT output in the frontoparietal cortex (FPCx). In contrast, the increase in the cortical 5-HT output elicited by the systemic administration or the local application, via reverse dialysis, of chlorimipramine and fluoxetine was more robust in RHA/Verh than in RLA/Verh rats. Moreover, the binding signal of [ 3 H]-citalopram to 5-HT re-uptake sites was more intense in the FPCx of RHA/Verh rats than in their RLA/Verh counterparts. These findings suggest that the functional tone of the 5-HTergic projection to the FPCx is stronger in the RHA/Verh line relative to the RLA/Verh line. It is proposed that RLA/Verh rats may be used as a model with heuristic value for studying the role of 5-HTergic transmission in anxiety and in the anxiolytic effects of monoamine re-uptake inhibitors.
1996
The purpose of this study was to determine the roles of the presynaptic 5-hydroxytryptamine 1A (5-HT 1A ) receptors in the median raphé nucleus (MRN) and of the postsynaptic 5-HT 1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT 1A receptor agonist (Ϯ)-8hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN had significant anxiolytic effects in all three test situations examined (social interaction, plus-maze trials 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT 1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT 1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-OH-DPAT (100 ng) had significant anxiogenic effects in the social interaction test and in plus-maze trial 2. These anxiogenic effects were antagonized by silent doses of 5-HT 1A receptor antagonists [(ϩ)WAY 100135, 10 mg/kg s.c., and intrahippocampal (Ϯ)tertatolol, 3 g, respectively], confirming mediation by 5-HT 1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT 1A receptor antagonist (Ϯ)tertatolol (3 g) had any significant effect when administered to the dorsal hippocampus. This demonstrates that previous experience of a rat in the plus-maze has a major effect on the sensitivity of dorsal hippocampal 5-HT 1A receptors, as we have demonstrated previously for the 5-HT 1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT 1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT 1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT 1A receptor agonists are given systemically.
European Journal of Pharmacology, 1994
The behavioural response of rats in the high light unfamiliar condition of the social interaction test of anxiety was observed following direct administration of the 5-HT1A receptor agonist, (+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 50, 100 or 200 ng) or antagonist tertatolol (3 /zg) into the median raphe nucleus or dorsal hippocampus. In the median raphe nucleus, 8-OH-DPAT (200 ng) significantly increased social interaction without changing locomotor activity; lower doses were inactive. In the dorsal hippocampus, bilateral injection of 8-OH-DPAT (100 ng) significantly decreased social interaction, without effect on locomotor activity; both 50 and 100 ng significantly changed grooming. Tertatolol had no effect on social interaction following administration to the median raphe nucleus, but significantly increased locomotor activity. Bilateral injection of tertatolol into the dorsal hippocampus decreased social interaction and changed grooming. These effects are similar to those of 8-OH-DPAT suggesting tertatolol may have 5-HT1A receptor agonist properties. In conclusion, the findings of this study demonstrate that 5-HTIA somatodendritic autoreceptors and post-synaptic receptors mediate anxiolytic and anxiogenic effects, respectively, in the social interaction test.
Behavioural Brain Research, 2010
Altered activity of brain serotonergic (5HT) system has been implicated in a wide range of behaviours and behavioural disorders, including anxiety. Functioning of 5HT-1A receptor has been suggested as a modulator of emotional balance in both, normal and pathological forms of anxiety. Here, we studied serotonergic modulation of anxiety-like behaviour using a genetic rat model with constitutional differences in 5HT homeostasis, named Wistar-Zagreb 5HT (WZ-5HT) rats. The model, consisting of high-5HT and low-5HT sublines, was developed by selective breeding of animals for extreme activities of peripheral (platelet) 5HT transporter, but selection process had affected also central 5HT homeostasis, as evidenced from neurochemical and behavioural studies.
Behavioural Brain Research, 2011
Previous evidence has shown that facilitation of GABA/benzodiazepine-mediated neurotransmission in the ventromedial hypothalamus (VMH) inhibits both escape and inhibitory avoidance responses generated in the elevated T-maze test of anxiety (ETM). These defensive behaviors have been associated with panic and generalized anxiety, respectively. Aside from GABA/benzodiazepine receptors, the VMH also contains a significant number of serotonin (5-HT) receptors, including 1A, 2A and 2C subtypes. The purpose of the present study was to investigate the effect of the activation of 5-HT 1A and 5-HT 2A/2C receptors in the VMH on defensive behavioral responses in rats submitted to the ETM. For that, male Wistar rats were treated intra-VMH with the 5-HT 1A agonist 8-OH-DPAT, with the 5-HT 2A/2C agonist DOI, with the 5-HT 2C selective agonist MK-212, or with the 5-HT 2A/2C antagonist ketanserin and 10 min after were submitted to the ETM. Results showed that both DOI and MK-212 significantly decreased avoidance measurements, an anxiolytic-like effect, without altering escape. 8-OH-DPAT and ketanserin were without effect, although the last drug attenuated the effects of DOI. None of the drugs altered locomotor activity in an open field. These results suggest that 5-HT 2A/2C receptors of the VMH are involved in the regulation of inhibitory avoidance and might be of relevance to the physiopathology of generalized anxiety.
Domestication alters 5-HT 1A receptor binding in rat brain
Serotonin-1A receptor binding density was compared in the brains of wild and domesticated adult male Rattus norvegicus using in vitro receptor autoradiography of [3H]8-hydroxy-2-[n-dipropylamino]tetraline (DPAT). While both groups exhibited similar patterns of labeling, [3H]DPAT binding density was significantly (p less than or equal to 0.05) lower in the median raphe nucleus and greater in superficial entorhinal cortex and rostral dentate gyrus of domesticated compared to wild rats. The results suggest that specific serotonergic circuits from the median raphe nucleus to the entorhinal and hippocampal regions might be involved in regulation of the defensive behaviors that differ profoundly between wild and domesticated rats. The relationship of these putative differences to behavioral disorders such as anxiety and depression in humans is discussed.
Journal of Neurochemistry, 2007
We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20-40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram's ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram , particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP's effect remains to be elucidated.
Brain Research, 1995
Recent studies have shown that arthritis-susceptible Lewis female rats display a marked hypoactivity of the hypothalamo-pituitaryadrenal (HPA) axis and decreased concentrations of hippocampal serotonin receptors (5-HTIA) , when compared with arthritis-resistant Fischer 344 female rats. Although previous studies have suggested that these inter-strain differences may extend to several behaviours, the hypothesis that Fischer 344 and Lewis differ in their anxiety and locomotor scores when placed in novel environments has been only scarcely tested. The present study has thus analysed the behaviours of male Fischer 344 and Lewis rats placed successively in activity cages, in an open field (low and high aversive conditions), and in two animal models of anxiety (the elevated plus-maze, the black/white box). Moreover, because the present study was conducted with male rats, we have also checked whether the HPA axis-and 5-HTIA receptor-related differences previously described between female Fischer 344 and Lewis rats extended to males. Under basal conditions: (i) activity of the HPA axis; and (ii) hippocampal 5-HT1A receptor binding and activity of tryptophan hydroxylase (the rate-limiting enzyme in 5-HT biosynthesis) were decreased in Lewis rats, compared with Fischer 344 rats. In addition, the response of the HPA axis to a mild stress (10 min in a novel environment) was lower in Lewis rats than in Fischer 344. When placed in activity cages, Lewis rats displayed a lower locomotor activity, compared with Fischer 344 rats. In the open-field, Lewis rats crossed a lower number of inner squares and groomed less than Fischer 344 rats. In the elevated plus-maze and in the black/white box, Fischer 344 and Lewis rats exhibited similar 'anxious' profiles as none of the rats visited the open arms (elevated plus-maze) and the white compartment (black/white box). This study, which extends earlier neurochemical and neuroendocrine findings in females, suggests that both strains display high levels of anxiety but markedly differ in their locomotor activities. Whether the latter strain difference is due to alterations in the HPA axis and/or the central serotonergic systems is an issue that remains to be explored. * Corresponding author. Fax: (33) 5757-1087. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0006-8993(95)00733-4
Anxiety in the rat is associated with decreased release of 5-HT and glycine from the hippocampus
Neuroscience Letters, 1987
Rats, implanted with dialysis loops in the dorsal hippocampus, were injected with subconvulsant doses of pentylenetetrazole (PTZ 15 and 30 mg/kg) and a 30-rain sample collected for high-performance liquid chromatography (HPLC) analysis of amines and amino acids. Immediately after the sampling period they. were given a 5-rain test in the elevated plus-maze. On the basis of their performance in this test. they were divided into an "anxious" and a "non-anxious' group. The anxious group had significantly lower levels of glycine and serotonin (5-HT) release. Although PTZ decreased the release of noradrenaline, this was not corrclated with behavioural differences in the elevated plus-maze.