Head Twitches Research Articles

Effect of magnesium chloride on psychomotor activity, emotional status, and acute behavioural responses to clonidine, d-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan

BackgroundThe beneficial effects of magnesium (Mg) salts on central manifestations of Mg deficiency are well known. Mg replacement therapy can be effective to prevent some of the serious depression-like and anxiety-related behaviour sequelae of Mg deficiency. However, few experimental studies have been undertaken on Mg-deficiency-induced behavioural changes. Even fewer studies have been carried out on acute behavioural responses to clonidine, D-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan (HTP), which might characterize possible neuromediator changes in Mg deficiency. The effects of correcting Mg deficiency by magnesium chloride (MgCl2 · 6H2O) and the combination of this salt with vitamin B6, on the behavioural manifestations of Mg deficiency have never been described as well.ObjectiveThe aims of this study were: to estimate effect of MgCl2 · 6H2O alone and in combination with vitamin B6 on acute behavioural responses to agonists or blockers of the main neurotransmitter systems in CNS, psychomotor activity and emotional status of rats fed with Mg-deficient diet for 49 days. In our study open field test has shown that in Mg-deficient rats locomotor activity and vertical activity, number of visiting and residence time in central squares were decreased significantly. In the elevated plus maze test, the number of visiting open arms and residence time of rats were significantly less as compared with the control group. In the forced swimming test, time immobile was significantly increased by 44.29% and time of swimming was decreased by 52.79% compared to control.ResultsIn our study Mg-deficient rats were more sensitive to d-amphetamine-induced motor stereotypes. Mg deficiency antagonized 5-hydroxytryptophan-induced head-twitch response and arecoline-induced tremor. Supplement of MgCl2 · 6H2O with vitamin B6 administered to a Mg-deficient rat increased the Mg level in plasma and erythrocytes. Furthermore, this increase was in relation to vitamin B6 given to the animal. Mg supplementation alone and in combination with pyridoxine normalized acute behavioural responses to d-amphetamine, 5-hydroxytryptophan, and arecoline in Mg deficient rats with a return to pre-deficient levels observed in the Mg sufficient group.DiscussionCombination of Mg salts and pyridoxine hydrochloride can be effective at treating some behavior form of primary Mg deficiency.

Effect of memantine on lithium chloride induced head twitches in rats.

Effect of memantine on lithium chloride induced head twitches in rats.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 2-{4-[4-(2,5-disubstituted thiazol-4-yl)phenylethyl]piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles as atypical antipsychotic agents

A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT2A/D2 ratio of 1.1286 although the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989.

Synthesis, Computational Studies and Preliminary Pharmacological Evaluation of New Arylpiperazines

A series of novel arylpiperazines were synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced climbing behavior (D2 antagonism), 5‐HTP induced head twitches (5‐HT2A antagonism) and catalepsy studies in albino mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserine and risperidone was assessed by calculating from a set of physiochemical properties using software programs. The test compounds (3a-j) demonstrated good similarity values with respect to the standard drugs. Among them, compound 3d has emerged as an important lead compound showing potential atypical antipsychotic like profile.

Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice

Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin represents a potentially useful alternative to psilocybin for development as a potential therapeutic agent.

Serotonin, But NotN-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling ComplexIn Vivo

Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT(2A)R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT(2A)R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT(2A)R activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT(2A)R signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT(2A)R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.

ChemInform Abstract: Syntheses and 5-HT2 Antagonist Activity of Bicyclic 1,2,4-Triazol-3(2H) -one and 1,3,5-Triazine-2,4(3H)-dione Derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.

Effect of Flavonoids in Scutellariae Radix on Depression-Like Behavior and Brain Rewards: Possible in Dopamine System

A series of animal models are used to investigate the anti-depression mechanism of flavonoids in scutellariae radix (SR) in vivo. Depression-like behavior in mice was studied after intraperitoneal administration of SR. The results showed that SR administered to mice by the intraperitoneal route obviously shortened the duration in the tail suspension test and the forced swimming test, aggravated the symptoms of eyelid ptosis, akinesia, and mortality caused by reserpine, prolonged climbing times, affected the conditioned place preference, and increased sugar consumption in mice. However the SR did not affect the head twitches induced by 5-HTP, locomotor activity in mice, the toxicity of yohimbine, and the body temperature decrease caused by high dosage of apomorphine. The tests show that SR has some anti-depression effect related to the dopamine system. Furthermore another anti-depression mechanism was possible that could affect the mechanism of brain reward, bring positive reinforcement, and increase the sensitivity to euphoria in mice.

P-Hydroxyamphetamine causes prepulse inhibition disruptions in mice: Contribution of dopamine neurotransmission

It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine ( p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D 2 receptor antagonist), L-745,870 (a selective D 4 receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D 1 receptor antagonist), eticlopride (a D 2/D 3 receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D 2 or D 4 receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.

Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF2L/2LCk-cre). A severe impairment specific for the serotonin 2A receptor (5-HT2AR) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT2ARs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered by BDNF depletion. 5-HT2A ([3H]-MDL100907) and 5-HT1A ([3H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT2A receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT1A receptor binding was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT2A and 5-HT1A mRNA expression but normal 5-HT2C content in these brain regions in BDNF2L/2LCk-cre mice. We investigated whether the reduction in frontal 5-HT2AR binding was reflected in reduced functional output in two 5-HT2A-receptor mediated behavioral tests, the head-twitch response (HTR) and the ear-scratch response (ESR). BDNF2L/2LCk-cre mutants treated with the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished ESR but no differences in HTR compared to wildtypes. These findings illustrate the context-dependent effects of deficient BDNF signaling on the 5-HT receptor system and 5-HT2A-receptor functional output.

Synergistic effect of decreased opioid activity and sleep deprivation on head-twitch response in mice

In schizophrenia, an opioidergic understimulation and a decreased sleep duration are found. The pathogenic significance of these factors is unknown. The present study assessed the influence of the combination of the factors on serotonergic 2A (5-HT(2A)) receptors that are possibly related to psychosis development. 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response in mice was used as a model of 5-HT(2A) receptor functioning. Mice underwent sleep deprivation and/or a blockade of opioidergic receptors with naloxone. To evaluate the involvement of 5-HT(2A) receptor in effects observed, animals were pretreated with MDL 100,907, a potent and selective antagonist of 5-HT(2A) receptor. As was found, 4 h of sleep deprivation followed by administration of naloxone significantly increases the frequency of head twitches, with sleep deprivation and naloxone being ineffective alone. The action of the “sleep deprivation–opioid understimulation” combination is antagonized completely by MDL 100,907. Thus, some schizophrenia-associated factors can synergistically enhance the activity of 5-HT(2A) receptors. These results suggest the above factors being pathogenically relevant in schizophrenia.

Functional selectivity at the serotonin 2A receptor: differential signaling by serotonin and dimethylated tryptamines

Serotonin and the hallucinogenic metabolites of tryptamines, dimethylated tryptamines, activate the serotonin 2A receptor (5‐HT2AR), which is implicated in numerous mental health disorders. We have previously demonstrated that the 5‐HT2AR is differentially regulated by βarrestin2 (βarr2) depending upon the agonist; here we utilized βarr2 knockout mice to compare signaling profiles in vivo, by assessing the head twitch response (which serves as a behavioral model for selective 5‐HT2AR activation), and in vitro, by assessing kinase activation. We demonstrate that serotonin leads to 5‐HT2AR‐mediated phosphorylation of the serine/threonine kinase AKT in the mouse frontal cortex and in primary neuronal cultures and that the head twitch response occurs in a βarr2 and AKT dependent manner. In contrast, a metabolism‐resistant dimethylated tryptamine, 5‐MeO‐DMT, does not induce phosphorylation of AKT in frontal cortex or in cortical neurons and induces the head twitch response regardless of βarr2 or inhibition of AKT expression. We also show that in the absence of βarr2, the head twitch response is enhanced in response to 5‐MeO‐DMT, suggesting that while βarr2 mediates serotonin signaling at the 5‐HT2AR, it dampens dimethylated tryptamine signaling at this receptor.Funding: R01 DA025158, NIDA.

Elevation of Endocannabinoids via Inhibition of their Catabolic Enzymes Attenuates the Precipitated Opioid Withdrawal Syndrome

It has long been known that cannabis and its primary active constituent, Δ9‐tetrahydrocannbinol (THC), reduce opioid withdrawal symptoms. The endocannabinoids, anandamide (AEA) and 2‐arachidonyl glycerol (2‐AG), also activate CB1 receptors, but they are rapidly metabolized by their respective enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The objective of this study was to determine whether elevating AEA or 2‐AG, via selective pharmacological inhibition of their metabolizing enzymes, would reduce precipitated morphine withdrawal symptoms. ICR mice were implanted subcutaneously with morphine pellets and challenged 72 h later with the opioid receptor antagonist, naloxone, to precipitate withdrawal. The withdrawal signs included number of jumps, paw tremors, head twitches, body weight loss and the occurrence of diarrhea. Pretreatment with the MAGL inhibitor, JZL184 dose‐dependently reduced the intensity of all naloxone‐precipitated withdrawal signs and these effects were reversed by the CB1R antagonist rimonabant, but not by the CB2R antagonist SR144528, suggesting a CB1 receptor specific mechanism of action. The FAAH inhibitor, PF‐3845 reduced the intensity of naloxone precipitated jumps and paw flutters through a CB1 receptor mechanism, but did not affect other withdrawal signs. The results from the present study are the first to show that the elevation of endocannabinoids ameliorates the expression of opioid withdrawal. Thus, the enzymes responsible for endocannabinoid degradation offer promising targets for possible new treatments for opioid dependence.

Serotonin 2C (5‐HT2C) receptor inverse agonists elicit head bob behavior through a dopamine D1 receptor dependent mechanism

Rabbit head bobs and rodent head twitches are behavioral assays of serotonin (5‐HT)2A receptor activation; each behavior can be elicited by DOI (a 5‐HT2A/2C agonist) and attenuated by ketanserin (a 5‐HT2A antagonist). 5‐HT2A receptor antagonists M100907 (M100) and MDL11939 (MDL) also elicit head bobs; however, these effects are distinguishable from DOI‐elicited responses as they are not blocked by ketanserin, suggesting a mechanism other than 5‐HT2A receptor activation. The current study examined the potential role of 5‐HT2C and dopamine (DA) receptors in inducing head bobs. Pre‐administration of the 5‐HT2C antagonist, SB242084 (1umol/kg, sc, 30 min) reduced head bobs elicited by both M100 (2.5umol/kg) and MDL (3umol/kg). Pretreatment of rabbits with the D1 antagonist SCH23390 (0.05umol/kg) also blocked M100 and MDL elicited head bobs. Moreover, administration of a D1 agonist, SKF38393 (9umol/kg) increased head bobs. To further characterize the role of 5‐HT2C receptors, we tested the response to a 5‐HT2C inverse agonist, SB206553. At a dose of 1umol/kg, we found no effect; however, a higher dose (3umol/kg) significantly increased head bobs. Consequently, head bobs may be considered an in vivo measure of 5‐HT2C inverse agonism. Finally, given the role of 5‐HT in DA release, we conclude that SB206553, M100, and MDL all induce the same behavior through 5‐HT2C inverse agonist‐mediated activation of D1 receptors.

Effect of acute and chronic treatment with QCF-3 (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone, a novel 5-HT3 receptor antagonist, in animal models of depression

The serotonin type 3 (5-HT3) receptor is unique among the seven recognized serotonin receptor “families”. The existence serotonin type 3 receptor (5-HT3) in neuro-anatomical regions stimulated the research interest for novel therapeutic targets such as anxiety, depression, nociception and cognitive function. In the current study, (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone (QCF-3), a novel 5-HT3 receptor antagonist, with an optimal log P (the logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P) and significant pA2 value (is a negative logarithm of the molar concentration of antagonist required to reduce the effect of multiple dose agonist to that of single dose) was screened for its anti-depressant potential using rodent behavioral models of depression. Psycho-pharmacological investigations involved acute and chronic treatment (14days) with QCF-3 and assessment of behavior during the forced swim test (FST) and tail suspension test (TST) in mice and olfactory bulbectomised rats. A dose response study in mice revealed an initial anti-depressant-like effect of QCF-3 (0.5–4mg/kg, ip) in the FST and TST. Interaction studies showed that QCF-3 (1 and 2mg/kg) significantly enhanced the antidepressant action of fluoxetine and bupropion in the FST and TST, respectively. QCF-3 (1 and 2mg/kg) potentiated the 5-hydroxytryptophan (5-HTP) induced head twitches response in mice and reversed reserpine-induced hypothermia in rats. Further, OBX rats exhibited behavioral anomalies in the open field and hyper-emotionality tests that were attenuated by chronic QCF-3 treatment. In conclusion, this behavioral study describes an antidepressant-like effect of QCF-3in rodent behavioral models of depression.

The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen

Hallucinogenic serotonin 2A (5-HT(2A)) receptor partial agonists, such as (+ or -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT(2A) receptor antagonists. In addition to 5-HT(2A) receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT(2C) receptors. We tested for involvement of 5-HT(2C) receptors in the HTR induced by DOI. Comparison of 5-HT(2C) receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT(2C) receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT(2A) receptors in frontal cortex explained the strain difference, including 5-HT(2A) receptor density, Galpha(q) or Galpha(i/o) protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT(2C) receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT(2C) receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. We conclude that the HTR to DOI in mice is strongly modulated by 5-HT(2C) receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT(2) receptors.

Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery

Abstract The anti-serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5-2 mg kg−1) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg−1) that induced depressant-like effects were found to significantly reduce 5-hydroxytrypto-phan-induced head twitch response. Interaction studies revealed that the depressant-like effects of PTL (1 mg kg−1) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg−1) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.

N-Methyl-D-aspartate receptor antagonists enhance the head-twitch response, a 5-hydroxytryptamine2 receptor-mediated behaviour, in reserpine-treated mice.

In this study, N-methyl-D-aspartate (NMDA)-receptor antagonists enhanced the head-twitch response induced by 5-hydroxytryptamine (5-HT) in reserpine-treated mice. To minimize the risk of any indirect involvement of NMDA-receptor antagonists (D(-)-2-amino-5-phosphonopentanoic acid (AP-5), D(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP), (+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-imi ne (MK-801), ketamine, dextrorphan and dextromethorphan) with 5-HT neurones, vesicle stores of monoamines, especially 5-HT, were depleted with reserpine. In addition, the enhancement of 5-HT-induced head-twitch response was inhibited by apomorphine and NMDA as well as ritanserin in reserpine-treated mice. These results support our previous conclusion that NMDA receptors play important roles in the glutamatergic modulation of 5-HTergic function at the postsynaptic 5-HT2 receptors in mice.

Functional interactions between 5‐HT2A and presynaptic 5‐HT1A receptor‐based responses in mice genetically deficient in the serotonin 5‐HT transporter (SERT)

Despite decreased presynaptic 5-HT(1A) and altered 5-HT(2A) receptor function in genetically-deficient serotonin (5-HT) transporter (SERT) mice, the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100635) still induced head twitches in these mice, a well-established 5-HT(2A) receptor-mediated response. Interactions between 5-HT(1A) and 5-HT(2A) receptors were assessed using the head-twitch response following 5-HT(1A) and 5-HT(2A) receptor agonists and antagonists in SERT wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice. The role of brain 5-HT availability in WAY 100635 induced head twitches was also examined. WAY 100635 induced head twitches in a SERT gene-dose dependent manner, inducing 5-fold more head twitches in SERT -/- versus SERT +/+ mice. In SERT -/- mice, inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) markedly depleted tissue 5-HT in all five brain areas examined and abolished WAY 100635 induced head twitches. Further, the selective 5-HT reuptake inhibitor fluvoxamine increased WAY 100635 induced head twitches in SERT +/+ and +/- mice. Head twitches following the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were robust in SERT +/+ and +/- mice but much reduced in SERT -/- mice. DOI-induced head twitches were decreased by the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in SERT +/+ and +/- mice. All drug-induced head twitches were blocked by the 5-HT(2A) receptor antagonist a-Phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939). These data show that indirect activation of 5-HT(2A) receptors via blockade of presynaptic 5-HT(1A) receptors potentiated head-twitch responses, suggesting functional interactions between these receptors, interactions affected by altered 5-HT availability. Our findings strongly support the correlation of WAY 100635 induced head twitches with increased 5-HT availability, induced genetically or pharmacologically.

Hallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Senescence-Accelerated Mice

Many neuropharmacological agents modulate the activity and conformation of heptahelical G protein-coupled receptors and activate ligand-specific signaling pathways. The hallucinogenic chemical 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), a serotonin receptor 2A (5-HT2AR) agonist, evokes extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and head-twitch behavior. We previously reported that the senescence accelerated-prone mouse 6 (SAMP6) exhibited altered emotional behavior and increased levels of a serotonin-biosynthesizing enzyme compared to the senescence accelerated-resistant mouse 1 (SAMR1); however, the mechanism underlying the relationship between specific receptor signaling and behavioral phenotypes was unclear. In this study, we performed head-twitch tests and examined the total and phosphorylated levels of ERK1/2 and cAMP-responsive element-binding protein (CREB) in the bilateral somatosensory cortex to assess the differences between SAMP6 and SAMR1 using DOI. Although DOI dose-dependently increased the head-twitch response in both strains, the responses of SAMP6 given 0.3 and 1.0 mg/kg DOI were significantly greater than those of SAMR1 given DOI at the same doses. Although no dose-dependent increase in total ERK1/2 and total CREB expression was detected in response to DOI, the levels of phospho-ERK1/2 and -CREB increased in both strains. The phospho-ERK1/2 and -CREB levels in SAMP6 given 0.3 and 1.0 mg/kg DOI were significantly higher than those in SAMR1 given DOI at the same doses. These results indicate that SAMP6 increases DOI-dependent ERK1/2-CREB signaling leading to more head-twitch responses than SAMR1, and that SAMP6 could provide a useful model for examining the relationship between 5-HT2AR regulatory signaling and behavioral phenotypes.