5-HT1A Receptor Agonist Research Articles

5-HT1A receptor agonism in the basolateral amygdala increases mutual-reward choices in rats

Rats show mutual-reward preferences, i.e., they prefer options that result in a reward for both themselves and a conspecific partner to options that result in a reward for themselves, but not for the partner. In a previous study, we have shown that lesions of the basolateral amygdala (BLA) reduced choices for mutual rewards. Here, we aimed to explore the role of 5-HT1A receptors within the BLA in mutual-reward choices. Rats received daily injections of either 50 or 25 ng of the 5-HT1A receptor agonist 8-OH-DPAT or a vehicle solution into the BLA and mutual-reward choices were measured in a rodent prosocial choice task. Compared to vehicle injections, 8-OH-DPAT significantly increased mutual-reward choices when a conspecific was present. By contrast, mutual-reward choices were significantly reduced by 8-OH-DPAT injections in the presence of a toy rat. The effect of 8-OH-DPAT injections was statistically significant during the expression, but not during learning of mutual-reward behavior, although an influence of 8-OH-DPAT injections on learning could not be excluded. There were no differences between 8-OH-DPAT-treated and vehicle-treated rats in general reward learning, behavioral flexibility, locomotion or anxiety. In this study, we have shown that repeated injections of the 5-HT1A receptor agonist 8-OH-DPAT have the potential to increase mutual-reward choices in a social setting without affecting other behavioral parameters.

Combination of Stressors in the Critical Periods of Development Increases Resistance to Inflammatory Pain Stress in Adult Rats

We report here studies of the long-term effects of combined stress in the prenatal and prepubertal periods of development on measures of tonic inflammatory pain in the formalin test and the severity of depression-like behavior, and also the stress reactivity of the hormonal response in adult rats. In addition, the effects of the serotonin (5-HT) reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone, given chronically to stressed mothers during pregnancy, on various types of adaptive behavior impaired by prenatal stress were assessed in rats of both sexes. The results showed that in rats of both sexes prenatal stress increased the pain response organized at the spinal and supraspinal levels of the central nervous system and that fluoxetine and buspirone normalized responses. Stress during the prepuberal period of development eliminated the effects of prenatal stress on the inflammatory pain responses integrated at the supraspinal level in adult rats; in these conditions, fluoxetine and buspirone had no effects, in contrast to their antinociceptive actions on the pain response integrated at the spinal level. Stress at prepubertal age eliminated sex-related differences seen in depression-like behavior in prenatally unstressed and prenatally stressed rats given physiological saline. Control adult females and adult females exposed to prenatal stress in the prepubertal period showed increases in the plasma corticosterone level after forced swimming as compared with the basal hormone level, though there were no significant differences in the level of stress reactivity of the hormonal response after forced swimming. Thus, the conditions for stress actions increasing stress resistance in adult rats were identified. Stress in the critical period of development formed a phenotype with increased stress resistance to inflammatory pain, which was seen in responses organized at the supraspinal level in adult individuals.

Activation of 5-HT1A and 5-HT7 receptors enhanced a positively reinforced long-term memory

Memory is one of the most important capabilities of our mind since it determines our individuality. Memory formation involves different stages: acquisition, consolidation and retrieval. There are many studies about early stages, however little is known about memory retrieval. Retrieval is the use of learned information and represents a big problem in patients with memory deficits where the main issue is that they can learn but cannot remember. Previous findings have demonstrated that 5-hydroxytryptamine (5-HT) is a neurotransmitter involved in memory process. Hence, here we are exploring the role of 5-HT in memory retrieval by using its metabolic precursor l-tryptophan and several ligands at 5-HT1A and 5-HT7 receptors. Experimental protocol consisted of evaluating conditioned responses (%CR) after one week of interruption following autoshaping sessions for memory formation; a decrease of %CR was interpreted as memory decay. Systemic administration of: (1) l-tryptophan (50 and 100 mg/kg), (2) 5-HT1A receptor agonist 8-OH-DPAT (0.031 and 0.062 mg/kg), (3) the selective antagonist 5-HT1A receptor WAY 100635 (0.3 and 0.6 mg/kg), (4) the 5-HT7 receptor agonist, LP 211, in a dose-dependent manner (1, 2.5, 5.0 and 10.0 mg/kg) enhanced memory retrieval. Further, the 5-HT7 receptor antagonist, SB 269970 (10.0 mg/kg), had no effect. Finally, SB 269970 (10.0 mg/kg) significantly blocked memory retrieval enhancement produced by 10.0 mg/kg LP 211, but not that induced by 2.5 mg/kg LP 211.These results, taken together, suggest that activation of 5-HT1A and 5-HT7 receptors enhanced memory retrieval and these receptors may be therapeutic targets to improve long-term memory retrieval.

Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment

Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI–induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.

Involvement of noradrenergic and serotonergic systems in risk-based decisions between options of equivalent expected value in rats

Risk perception is an important factor that may mediate risk-based decision-making processes regulated by noradrenergic (NA) and serotonergic (5-HT) systems. Most risk-based decision-making models involve complex factors, such as risk perception or reward value, such that the final decision is the result of the interactions among these factors. However, the contribution of risk perception per se in risk decisions has remained unclear. Therefore, in the present study, we made some modifications to the classical probabilistic discounting task (PDT) to focus on the impact of risk perception and noradrenergic/serotonergic systems on decision-making behavior. Meanwhile, we conducted an elevated plus-maze (EPM) test to detect the correlation between anxiety and choice behavior. In the current study, rats had to choose between a “certain” lever that delivered a certain number of pellets and a “risky” lever that delivered eight pellets in a probabilistic manner (descending: 50%, 25%, 12.5% or ascending 12.5%, 25%, 50% of the time). The long-term rewarding values of the two levers were always identical in each block within each session. According to their baseline performances in choosing the risky lever, rats were divided into the risk-prefer group and risk-averse group. The results showed that there was a significant correlation between open arm time in EPM and risky choice for both descending order and ascending order, indicating that highly anxious rats more often preferred the safe option under risk. Pharmacological stimulation of α2-adrenergic receptors via dexmedetomidine (0.01 mg/kg) decreased the preference of probabilistic rewards in the risk-prefer group, while blocking α2 receptors by atipamezole (0.3 mg/kg) also reduced risky choices. The NA reuptake inhibitor, atomoxetine, increased the preference for risky choices in the risk-prefer group, the effect of which was attained via multiple superimposed doses. Administration of the 5-HT2A receptor agonist, DOI (0.1 mg/kg), increased risk-taking behavior in the risk-prefer group. Taken together, these results suggest that NA may be more inclined to process negative information such as loss or uncertainty in the regulation of risk-related decision making, whereas 5-HT may function primarily to increase risk-taking behavior. Our findings may help to further elucidate how noradrenergic and serotonergic systems differentially affect individuals with different risk preferences in terms of regulating risk perception in risk-related decision making.

Differential signaling signatures evoked by DOI versus lisuride stimulation of the 5-HT2A receptor

The 5-HT2A receptor is a target for hallucinogenic and non-hallucinogenic ligands that evoke unique behavioral, electrophysiological and molecular consequences. Here, we explored the differential effects of distinct 5-HT2A receptor ligands on signaling pathways downstream to the 5-HT2A receptor. The hallucinogenic 5-HT2A receptor agonist DOI evoked an enhanced signaling response compared to the non-hallucinogenic 5-HT2A receptor agonist lisuride in human/rat 5-HT2AR-EGFP receptor expressing HEK293 cell lines and cortical neuronal cultures. We noted higher levels of phospho-PLC, pPKC, pERK, pCaMKII, pCREB, as well as higher levels of IP3 and DAG production following 5-HT2A receptor stimulation with DOI. Our study reveals distinct signaling signatures, differing in magnitude and kinetics at the 5-HT2A receptor in response to DOI versus lisuride.

The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques

BackgroundLong-term treatment of Parkinson's disease (PD) with l-DOPA typically leads to development of l-DOPA induced dyskinesia (LID). Amantadine, an NMDA antagonist, attenuates LID, but with limited efficacy and considerable side-effects. NLX-112 (also known as befiradol or F13640), a highly selective and efficacious 5-HT1A receptor agonist, reduced LID when tested in rodent and marmoset models of PD. MethodsThe effects of NLX-112 (0.03, 0.1 and 0.3 mg/kg PO) on established LID evoked by acute challenge with l-DOPA (27.5 ± 3.8 mg/kg PO) were assessed in MPTP-treated cynomolgus macaques. Amantadine (10 mg/kg PO) was tested as a positive control. Plasma exposure of NLX-112 (0.1 mg/kg PO) was determined. ResultsNLX-112 significantly and dose-dependently reduced median LID levels by up to 96% during the first hour post-administration (0.3 mg/kg). Moreover, NLX-112 reduced the duration of ‘bad on-time’ associated with disabling LID by up to 48% (0.3 mg/kg). In contrast, NLX-112 had negligible impact on the anti-parkinsonian benefit of l-DOPA. NLX-112 exposure peaked at ~50 ng/ml at 30 min post-administration but decreased to ~15 ng/ml at 2h. Amantadine reduced by 42% ‘bad on-time’ associated with l-DOPA, thereby validating the model. ConclusionThese data show that, in MPTP-lesioned cynomolgus macaques, NLX-112 exerts robust anti-dyskinetic effects, without reducing the anti-parkinsonian benefit of l-DOPA. These observations complement previous findings and suggest that selective and high efficacy activation of 5-HT1A receptors by NLX-112 may constitute a promising approach to combat LID in PD, providing an alternative for patients in whom amantadine is poorly tolerated or without useful effect.

Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore.

Psychedelic drugs can exert potent anti-inflammatory effects. However, anti-inflammatory effects do not appear to correlate with behavioral activity, suggesting different underlying mechanisms. We hypothesized that the distinct structural features of psychedelics underlie functionally selective mechanisms at the target 5-HT2A receptor to elicit maximal anti-inflammatory effects. In order to test this hypothesis, we developed a new rat-based screening platform for allergic asthma. Next, we investigated 21 agonists at the 5-HT2A receptor from the three primary chemotypes (phenylalkylamine, ergoline, and tryptamine) for their ability to prevent airways hyperresponsiveness as a measure of pulmonary inflammation. Furthermore, we assessed each drug for in vitro activation of the canonical signaling pathway, calcium mobilization, from the 5-HT2A receptor. We find that the drug 2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity and identify structural modifications that are either permissive or detrimental to anti-inflammatory activity. Additionally, there is no correlation between the ability of a particular psychedelic to activate intracellular calcium mobilization and to prevent the symptoms of asthma or with behavioral potencies. Our results support the notions that specific structural features mediate functional selectivity underlying anti-inflammatory activity and that relevant receptor activated pathways necessary for anti-inflammatory activity are different from canonical signaling pathways. Our results inform on the nature of interactions between ligands at the 5-HT2A receptor as they relate to anti-inflammatory activity and are crucial for the development of new 5-HT2A receptor agonists for anti-inflammatory therapeutics in the clinic that may be devoid of behavioral activity.

Effects of Stress Exposure during Adolescent Period on Inflammatory Pain Response, Psychoemotional Behavior, and Action of Antidepressants in Prenatally Stressed Adult Male Rats.

We studied the effects of stress exposure during the adolescent period of development (SAPD) on the parameters of inflammatory painful response and the level of depression-like behavior in prenatally stressed adult male rats. In addition, we analyzed the effects of selective serotonin (5-HT) reuptake inhibitor fluoxetine and 5-HT1A receptor agonist buspirone injected chronically to pregnant mothers for correction of behavioral disturbances caused by prenatal stress in their adult male progeny. In the formalin test, SAPD decreased integrated at the supraspinal level pain-like response that was increased by prenatal stress; under these conditions, buspirone and fluoxetine were ineffective in contrast to their antinociceptive action on spinally integrated pain-like response increased by SAPD. In the forced swimming test, SAPD had no effect on the level of depression-like behavior in prenatally stressed males; no differences in plasma corticosterone level were found in these animals.

Do Cheyne and Stokes have an important message for modern‐day patients with heart failure? Yes, they do

Do <scp>C</scp>heyne and <scp>S</scp>tokes have an important message for modern‐day patients with heart failure? <scp>Y</scp>es, they do

Improvement of lower urinary tract function by a selective serotonin 5-HT1A receptor agonist, NLX-112, after chronic spinal cord injury

Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. NLX-112 is a very potent, highly-selective, and fully efficacious 5-HT1A receptor agonist, which has been developed for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease patients. We performed urodynamics tests and external urethral sphincter electromyogram recordings to assess lower urinary tract function while NLX-112 was infused through the femoral vein in rats with chronic complete SCI or contusive SCI. The dose response studies indicated that NLX-112 was able to improve voiding behavior by regulating both detrusor and EUS activity. These included improvements in voiding efficiency, reduction of detrusor hyperactivity, and phasic activity of EUS during the micturition period. In addition, the application of a selective 5-HT1A receptor antagonist, WAY100635, reversed the improved detrusor and EUS activity elicited by NLX-112. In summary, the current data suggest that pharmacological activation of 5-HT1A receptors by NLX-112 may constitute a novel therapeutic strategy to treat neurogenic bladder after SCI.

Down-regulation of Spinal 5-HT2A and 5-HT2C Receptors Contributes to Somatic Hyperalgesia induced by Orofacial Inflammation Combined with Stress

Patients suffering with functional somatic pain syndromes such as temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) have some similar symptoms, but the underlying cause is still unclear. The purpose of this study was to investigate whether 5-HT2A and 5-HT2C receptors in the spinal cord contribute to somatic hyperalgesia induced by orofacial inflammation combined with different modes of stress. Ovariectomized rats were injected subcutaneously with estradiol and bilateral masseter muscles were injected with complete Freund’s adjuvant followed by stress. Somatic sensitivity was assessed with thermal and mechanical stimulation. The anxiety- and depression-like behaviors were measured by immobility time, sucrose preference, elevated plus maze and open field tests. The expression of 5-HT2A and 5-HT2C receptors in the spinal cord was examined by Western blot. Orofacial inflammation combined with 11 day forced swim stress (FSS) induced persistent mechanical allodynia for 15 days and thermal hyperalgesia for 2 days. The mechanical and thermal hyperalgesia lasted for 43 days and 30 days respectively following orofacial inflammation combined with 11 day heterotypic stress. Orofacial inflammation combined with stress induced anxiety- and depression-like behaviors. The expression of 5-HT2A and 5-HT2C receptors significantly decreased in the orofacial inflammation combined with stress groups. Intrathecal injection of 5-HT2A or 5-HT2C receptor agonist reversed somatic hyperalgesia. The results suggest that down-regulation of 5-HT2A and 5-HT2C receptors in the spinal cord contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress, indicating that 5-HT2A and 5-HT2C receptors may be potential targets in the treatment of TMD comorbid with FMS.

Key role of 5-HT1A receptors in the modulation of the neuronal network underlying the respiratory rhythm generation in lampreys.

In mammals, 5-HTexcitatory respiratory effects imply 5-HT1A receptor-mediated disinhibition of pre-Bötzinger complex neurons. In the lamprey, 5-HT1A receptors are involved in the neural control of locomotion, but their role in the respiratory regulation, particularly at the level of the putative respiratory rhythm generator, the paratrigeminal respiratory group (pTRG), is not known. We here investigate the respiratory function of inhibitory 5-HT1A receptors within the pTRG of the isolated brainstem of the adult lamprey. The 5-HT1A receptor agonists either bath applied or microinjected into the pTRG did not cause significant effects. However, the selective 5-HT1A receptor antagonist (S)-WAY 100135 bath applied or microinjected into the pTRG induced depressing respiratory effects or even apnoea, thus revealing that 5-HT exerts a 5-HT1A receptor-mediated potent tonic influence on respiration and contributes to maintain baseline levels of respiratory activity. Microinjections of strychnine or bicuculline, either alone or in combination, into the pTRG prevented (S)-WAY 100135-induced apnoea. In addition, immunohistochemical studies corroborate the present findings suggesting that 5-HT1A receptors are widely expressed in close apposition to the soma of glycine-immunoreactive cells located within the pTRG region. The results show that in the lamprey respiratory network, 5-HT exerts a tonic influence on respiration by a potent inhibitory control on both GABAergic and glycinergic mechanisms. The observed disinhibitory effects resemble the excitatory respiratory modulation exerted by 5-HT1A receptor-mediated inhibition of glycinergic and/or GABAergic neurons present in mammals, supporting the notion that some features of the neuronal network subserving respiratory rhythm generation are highly conserved throughout phylogeny.

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial.

Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF. The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate-severe CA [nocturnal apnoea-hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1week, with a crossover design (1week of wash-out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14-73%, P=0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P=0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone-related serious adverse events. Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF.

Denial of food to the hungry rat: A novel paradigm for induction and evaluation of anger-like emotion

BackgroundAnger is one of the primary emotions that profoundly impacts our daily life. Although the neural basis of anger needs to be explored on high priority, the field has not sufficiently advanced, perhaps due to the lack of a suitable animal model. New methodWe fabricated arenas in which the hungry rat can see and smell food but can not consume it. These animals seemed hyperactive and we monitored the (a) motor activity to access food, (b) biting behaviour, (c) blood pressure, heart rate and nor-epinephrine (NE) in plasma, (d) 5-HT and its metabolite in CSF, (e) effect of diazepam, 5-HT agonist, and antagonist on the behaviour, and (f) expression of immediate early gene in discrete areas of the brain. ResultsThe fasted animal frantically tries to acquire food. It engages in intense biting of the separator plate; the behaviour was considered as an expression of anger-like emotion. These behaviours were attenuated following pre-treatment with diazepam, fluoxetine (both ip) or 5-HT1A receptor agonist (icv), but potentiated by 5-HT1A antagonist (icv). Concomitantly, an increase in the blood pressure, heart rate and NE in plasma, but a decrease in 5-HT and 5-HIAA in the CSF was noted. The animals showed activation of neuronal c-Fos in different brain areas compared to fasted or refed controls. Comparison with existing methodsA novel animal paradigm for assessment of anger. ConclusionsThe protocol enables us to generate and evaluate anger-like responses in rat and permits insights into the neurological basis of anger.

The serotonin reuptake blocker citalopram destabilizes fictive locomotor activity in salamander axial circuits through 5-HT1A receptors.

Serotoninergic (5-HT) neurons are powerful modulators of spinal locomotor circuits. Most studies on 5-HT modulation focused on the effect of exogenous 5-HT and these studies provided key information about the cellular mechanisms involved. Less is known about the effects of increased release of endogenous 5-HT with selective serotonin reuptake inhibitors. In mammals, such molecules were shown to destabilize the fictive locomotor output of spinal limb networks through 5-HT1A receptors. However, in tetrapods little is known about the effects of increased 5-HT release on the locomotor output of axial networks, which are coordinated with limb circuits during locomotion from basal vertebrates to mammals. Here, we examined the effect of citalopram on fictive locomotion generated in axial segments of isolated spinal cords in salamanders, a tetrapod where raphe 5-HT reticulospinal neurons and intraspinal 5-HT neurons are present as in other vertebrates. Using electrophysiological recordings of ventral roots, we show that fictive locomotion generated by bath-applied glutamatergic agonists is destabilized by citalopram. Citalopram-induced destabilization was prevented by a 5-HT1A receptor antagonist, whereas a 5-HT1A receptor agonist destabilized fictive locomotion. Using immunofluorescence experiments, we found 5-HT-positive fibers and varicosities in proximity with motoneurons and glutamatergic interneurons that are likely involved in rhythmogenesis. Our results show that increasing 5-HT release has a deleterious effect on axial locomotor activity through 5-HT1A receptors. This is consistent with studies in limb networks of turtle and mouse, suggesting that this part of the complex 5-HT modulation of spinal locomotor circuits is common to limb and axial networks in limbed vertebrates.NEW & NOTEWORTHY Little is known about the modulation exerted by endogenous serotonin on axial locomotor circuits in tetrapods. Using axial ventral root recordings in salamanders, we found that a serotonin reuptake blocker destabilized fictive locomotor activity through 5-HT1A receptors. Our anatomical results suggest that serotonin is released on motoneurons and glutamatergic interneurons possibly involved in rhythmogenesis. Our study suggests that common serotoninergic mechanisms modulate axial motor circuits in amphibians and limb motor circuits in reptiles and mammals.

Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation.

We previously reported that the serotonergic system is important for the antidepressant-like effects of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, which produces rapid and long-lasting antidepressant effects in patients with major depressive disorder (MDD). In particular, selective stimulation of the 5-HT1A receptor in the medial prefrontal cortex (mPFC), as opposed to the somatic 5-HT1A autoreceptor, has been shown to play a critical role in the antidepressant-like actions of ketamine. However, the detailed mechanisms underlying mPFC 5-HT1A receptor-mediated antidepressant-like effects are not fully understood. Here we examined the involvement of the glutamate AMPA receptor and brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of 5-HT1A receptor activation in the mPFC. The results show that intra-mPFC infusion of the 5-HT1A receptor agonist 8-OH-DPAT induces rapid and long-lasting antidepressant-like effects in the forced swim, novelty-suppressed feeding, female urine sniffing, and chronic unpredictable stress tests. In addition, the results demonstrate that the antidepressant-like effects of intra-mPFC infusion of 8-OH-DPAT are blocked by co-infusion of an AMPA receptor antagonist or an anti-BDNF neutralizing antibody. In addition, mPFC infusion of 8-OH-DPAT increased the phosphorylation of signaling proteins downstream of BDNF, including mTOR, ERK, 4EBP1, and p70S6K. Finally, selective stimulation of the 5-HT1A receptor increased levels of synaptic proteins and synaptic function in the mPFC. Collectively, these results indicate that selective stimulation of 5-HT1A receptor in the mPFC exerts rapid and sustained antidepressant-like effects via activation of AMPA receptor/BDNF/mTOR signaling in mice, which subsequently increase synaptic function in the mPFC, and provide evidence for the 5-HT1A receptor as a target for the treatment of MDD.

Administration of low doses of the 5-HT1A receptor agonist 8-OH-DPAT attenuates the discriminative signal of amphetamine in the conditioned taste aversion procedure

Several studies have reported that low doses of the 5-HT1A receptor agonist 8-OH-DPAT reduce cocaine-induced locomotor activity. However, it has also been reported that high doses of 8-OH-DPAT do not substitute for or alter the discriminative signal of cocaine (COC) or amphetamine (AMPH). This study aimed to evaluate the effects of low and high doses of the 5-HT1A agonist 8-OH-DPAT on the discriminative signal of AMPH using conditioned taste aversion as a drug discrimination procedure. Additionally, to establish a correlation between the behavioral effects in drug discrimination and changes in dopamine (DA) and gamma-aminobutyric acid (GABA) concentrations, we evaluated the effect of systemic administration of low or high doses of the 5-HT1A receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100135 on DA and GABA extracellular concentrations in the nucleus accumbens (nAcc) and ventral tegmental area (VTA), respectively, using cerebral microdialysis. The behavioral results showed that low but not high doses of 8-OH-DPAT produced a reduction in the AMPH-induced discriminative signal, while WAY100135 administration prevented such effects. The microdialysis results showed that a low dose of 8-OH-DPAT decreased extracellular DA concentrations in the nAcc and increased GABA concentrations in the VTA. Pretreatment with WAY100135 prevented these effects. These data support the hypothesis that 5-HT1A receptors modulate the behavioral effects of psychostimulant drugs, such as AMPH, through somatodendritic 5-HT1A autoreceptors in the raphe nucleus indicating that 5-HT1A receptors may be an important target for the development of pharmacological treatments for psychostimulant addiction.

The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2′ and 3′ positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3′-methyl, 2′,3′-chroman, 2′,3′-dihydrofuran and 2′,3′-furan analogs, the 3′-methoxy and 3′-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2′,3′-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.

Acute and Chronic Laryngeal Deficits Following Cervical Spinal Cord Injury

Laryngeal dysfunction is a common symptom following cervical spinal cord injury (cSCI) and currently there are no effective pharmacological interventions or behavioral treatments. The larynx is the primary valve controlling entrance into the trachea and lungs via opening and closing of the vocal folds. Although not well studied following cSCI, it is understood that laryngeal deficits during swallow often produce aspiration of food/liquid, significantly increasing risk of pneumonia. Our previous terminal electrophysiology experiments using freely breathing sodium pentobarbital anesthetized cats with acute hemisections at the 3rd cervical spinal level (C3) showed immediate alterations in laryngeal activity. These alterations persisted for 4 hours (testing duration). The serotonin (5‐HT1A) receptor agonist 8‐OH‐DPAT was delivered via the vertebral artery at low (3 □g/kg) and/or high (30 □g/kg) doses. This agonist altered behavior‐specific muscle recruitment patterns. In particular, the high dose restored laryngeal activity across breathing and swallow, which could be reversed with the competitive antagonist WAY100635 (0.5 mg/kg). In the current study, we tested if alterations seen acutely in laryngeal activity persist chronically, and if the 8‐OH‐DPAT clinical‐correlate buspirone (Buspar) would produce similar therapeutic results. Adult female cats underwent C3 hemisections and recovered for 4 or 8 weeks. Laryngeal endoscopy was performed weekly under isofluorane (3%) during normocapnia and hypercapnia (5% CO2). Asynchronous vocal fold movement was seen in all animals, defined by unilateral movement delays, and the extent of opening and closing of the glottis became variable. In a subset of animals, oral buspirone (5 mg) was given with food. One hour later, repeat endoscopic evaluation revealed full resolution of laryngeal function with synchronized movements during normocapnia and hypercapnia. Most importantly, with termination of buspirone dosing, laryngeal dysfunction returned. This work shows that the anesthetized preparation effectively identifies upper airway dysfunction early and chronically after C3 SCI, and that it can be used as a pre‐clinical model for novel therapeutic interventions. Results also indicate that buspirone is a high‐priority target for additional investigation as a therapeutic intervention after cSCI.Support or Funding InformationThis work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Veterans Affairs Rehabilitation, Research and Development RCSB9249S (DRH), Kentucky Spinal Cord and Head Injury Research Trust, Rebecca F. Hammond Endowment (DRH), and the Commonwealth of Kentucky Challenge for Excellence.