Does 5, 7-Dihydroxytryptamine injection into nucleus accumbens cause hyperacusis?

Hyperacusis may be defined as diminishing tolerance to moderate and high intensity sounds in people with normal hearing sensitivity. Serotonin plays a critical role in some of auditory tasks including startle reflex and prepulse inhibition. Serotonin deficiency can cause some diseases which can coincide with hyperacusis. The aim of the present study was to investigate the probable influence of serotonergic depletion in nucleus accumbens (NAcc) on the startle reflex. The startle reflexes were examined in Wistar rats (n: 48) in different intensities with and without the background noise. The amplitude of startle reflex significantly increased in NAcc-injected rats without background noise, while this difference disappeared in the presence of background noise in all intensities. These data proposed that the injection of 5, 7-Dihydroxytryptamine (5, 7-DHT) into nucleus accumbens will cause hyperacusis-like behavior, and strengthens the possibility of the role of serotonin and nucleus accumbens in hyperacusis.

p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission.

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT(2A)) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT(2A/2C) receptor antagonist) and MDL100,907 (a selective 5-HT(2A) receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT(2A) receptor.

Effects of single and simultaneous lesions of serotonergic and noradrenergic pathways on open-space and bright-space anxiety-like behavior in two animal models.

The objective of the present study is to investigate the effects of single and simultaneous lesions of the noradrenergic and serotonergic pathways (NA-X, 5-HT-X and XX, respectively) by intracerebroventricular administration of selective neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-HCl (DSP-4) and 5,7-dihydroxytryptamine (5,7-DHT) on anxiety-like behavior in rats. To evaluate the effects of the various lesions, animals were tested in elevated plus-maze (EPM) and light-dark (LD) paradigms. In EPM, single lesions produced strong, statistically significant increase (p<0.001) of both time spent in the open arms (OT) and number of entries into the open arms (OE) compared to sham-lesioned animals. Simultaneous lesion further strengthened this anxiolytic effect causing an approximate 500% elevation of OT compared to sham-lesioned animals. In LD, 5-HT lesion caused a significant (p<0.05) increase in both light movement time and light horizontal activity parameters compared to intact, sham, and NA-lesioned groups. Neither of the lesions caused any change in the spontaneous locomotor activity of the animals up to 15min as measured in activity meter. These findings suggest that single and simultaneous lesions of 5-HT- and NA-pathways modify anxiety-related state of experimental animals to different extents and these modifications alter the behavior of animals differently in the two models used: NA-X and 5-HT-X reduce open space anxiety-like behavior and XX further strengthens this effect in the EPM, while only 5-HT-X is resulting in reduced bright-space anxiety-like behavior leaving the performance of NA-X and XX animals unchanged.

The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats.

It has been proposed that the ascending dorsal raphe (DR)-serotonergic (5-HT) pathway facilitates conditioned avoidance responses to potential or distal threat, while the DR-periventricular 5-HT pathway inhibits unconditioned flight reactions to proximal danger. Dysfunction on these pathways would be, respectively, related to generalized anxiety (GAD) and panic disorder (PD). To investigate this hypothesis, we microinjected into the rat DR the benzodiazepine inverse receptor agonist FG 7142, the 5-HT(1A) receptor agonist 8-OH-DPAT or the GABA(A) receptor agonist muscimol. Animals were evaluated in the elevated T-maze (ETM) and light/dark transition test. These models generate defensive responses that have been related to GAD and PD. Experiments were also conducted in the ETM 14 days after the selective lesion of DR serotonergic neurons by 5,7-dihydroxytriptamine (DHT). In all cases, rats were pre-exposed to one of the open arms of the ETM 1 day before testing. The results showed that FG 7142 facilitated inhibitory avoidance, an anxiogenic effect, while impairing one-way escape, an anxiolytic effect. 8-OH-DPAT, muscimol, and 5,7-DHT-induced lesions acted in the opposite direction, impairing inhibitory avoidance while facilitating one-way escape from the open arm. In the light/dark transition, 8-OH-DPAT and muscimol increased the time spent in the lighted compartment, an anxiolytic effect. The data supports the view that distinct DR-5-HT pathways regulate neural mechanisms underlying GAD and PD.

High and low affinity 5-HT2 and 5-HT1C binding sites: responses to neonatal 5,7-DHT lesions in rat brain.

5-HT receptor denervation supersensitivity has been proposed to explain behavioural supersensitivity to L-5-HTP in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions. No upregulation of 5-HT2 binding sites was found despite supersensitivity to putative 5-HT2,1C drugs. To test the hypothesis that the 5-HT1C properties of these drugs are involved instead, dose-response and time-course studies of 5-HT1C and 5-HT2 receptors were performed using several different radioligands in rat brain after making neonatal 5,7-DHT lesions by intraperitoneal injection. 5-HT1C sites labelled with [3H]-mesulergine showed a distinct regional distribution: brainstem > diencephalon > cortex > hippocampus > cerebellum, constituting 65, 70, 31, 70, and 73% of total sites labelled by [3H]-mesulergine in the absence of 20 nM spiperone to block 5-HT2 sites, respectively. 5,7-DHT lesions did not significantly alter BMAX, KD, or nH of [3H]-mesulergine-labelled 5-HT1C sites in cortex or other regions but did reduce the density of cortical [3H]-paroxetine sites (-55%). Cortical 5-HT1C sites labelled by [3H]-5-HT or [3H]-mianserin, and cortical 5-HT2 sites labelled by [3H]-DOB or [3H]-ketanserin, were also unaffected. These data suggest that although denervation supersensitivity of 5-HT1C or 5-HT2 receptors may occur at the level of the receptor transducer-effector, there is no evidence it occurs at the receptor recognition site.