Effects of single and repeated electroconvulsive shock on the social and agonistic behaviour of resident rats

The aim of this study was to determine whether electroconvulsive shock (ECS, an established antidepressant treatment), like acute and chronic antidepressant drug treatments, produces similar differential effects on the behavioural profile of resident rats expressed during social encounters with unfamiliar intruder conspecifics (resident-intruder paradigm). Thirty minute pretreatment with a single ECS suppressed both investigation and aggression directed at intruders concomitant with increased flight behaviour and marked sedation. Behavioural disruption subsided over the following 24 h. In contrast, resident rats subjected to bi-daily ECS treatment expressed elevated aggression at days 7 (four shocks) and 14 (eight shocks). Eight days after the last ECS treatment the behaviour of the resident rats had returned to pretreatment values. Additional studies showed that bi-daily ECS treatment nearly abolished 5-HT(2C) receptor-mediated hypolocomotion induced by acute m-chlorophenylpiperazine (mCPP, 2.5 mg/kg sc) challenge 24 h following 2 ECSs, while 4 ECSs only enhanced 5-HT(2A) receptor-mediated head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 2.0 mg/kg sc). These studies demonstrate that repeated ECS treatment increases the aggressive behaviour of resident rats which may be associated with adaptive changes in 5-HT(2C) and 5-HT(2A) receptor-mediated function. It remains to be seen whether adaptive changes in 5-HT(2C) receptor function represent a common mechanism of clinical antidepressant efficacy.     

Swim stress inhibits 5-HT2A receptor-mediated head twitch behaviour in mice

Rationale. Several studies have shown that swim stress lowers the convulsant potency of different convulsants. The involvement of α₂-adrenoceptors has been proposed. Drugs active at α₂-adrenoceptors are known to modulate the head twitch response, the behaviour supposedly mediated by 5-HT_2A receptors. Objectives. We tested whether swim stress modulates head twitch behaviour in mice and whether α₂-adrenoceptors interfere with this effect. Methods. The mice were stressed (10 min swimming at 18–19°C), and the head twitch response was produced by 5-hydroxytryptophan (5-HTP, the precursor of serotonin) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, a selective 5-HT₂ receptor agonist) administered IP before or after swimming. Yohimbine (a non-selective α₂-adrenoceptor antagonist), idazoxan (a selective α₂-adrenoceptor antagonist) and diazepam were also used. Results. Swim stress inhibited profoundly the 5-HTP-induced head twitch behaviour in mice. α₂-Adrenoceptor antagonists and diazepam failed to counteract this effect. The head twitch behaviour produced by DOI given before or after stress was also inhibited. Repeatedly stressed mice had only a mild inhibition of the head twitch response. Conclusions. The results demonstrate that swim stress inhibits, by an α₂-adrenoceptor unrelated mechanism, 5-HT_2A receptor-mediated head twitch behaviour in mice, suggesting that this effect and the swim stress-induced anticonvulsant effect are produced by two separate and independent mechanisms. Electronic Publication     

Effects of fluoxetine and buspirone on the panicolytic-like response induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

Rationale Administration of 5-hydroxytryptamine (5-HT)_1A and 5-HT_2A receptor agonists into the dorsal periaqueductal gray (DPAG) inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with the antipanic compound imipramine enhances the DPAG 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of escape, implicating these receptors in the mode of action of panicolytic drugs. Objectives In the present study, we investigated whether the inhibitory effect on escape elicited by the intra-DPAG injection of 5-HT_1A and 5-HT_2A receptor agonists is also enhanced after treatment with fluoxetine, another widely used antipanic drug. The effects of fluoxetine were compared to those of buspirone, an anxiolytic drug without major effect on panic disorder. Methods Male Wistar rats, subchronically (3–6 days) or chronically (21–24 days) treated with fluoxetine (10 mg/kg i.p.) or chronically treated with buspirone (0.3 mg/kg i.p.), were intra-DPAG injected with 5-HT (20 nmol), the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 8 nmol) or the preferential 5-HT_2A receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI; 16 nmol). The intensity of electrical current that applied to the DPAG-evoked escape behavior was measured before and after the microinjection of these agonists. Results The electrical current necessary to produce escape was increased after the microinjection of the three 5-HT receptor agonists in all groups of animals tested. However, this panicolytic-like effect was significantly higher in animals receiving long-term treatment with fluoxetine. Conclusions The results suggest that facilitation of the 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of DPAG neuronal activity is implicated in the beneficial effect of antidepressants in panic disorder.     

Ethopharmacological studies differentiate the effects of various serotonergic compounds on aggression in rats

A series of experiments was performed to investigate the effects on aggression of various drugs affecting serotonergic transmission in rats. Using ethologically derived behavioural categories, the behaviour of treated animals was described. Drug effects were observed in two aggression models: resident–intruder aggression (RI) in male rats, and maternal aggression in lactating females during the postpartum period (MA). The 5-HT_1A agonists, buspirone, iosapirone, and 8-OH-DPAT, decreased aggression in RI and MA but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific anti-aggressive profile. Nonselective 5-HT agonists, such as RU 24969, eltoprazine (DU 28853), and TEMPP, reduced aggression quite specifically and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA, the behavioural effects of these drugs were roughly similar. By contrast, MA was more sensitive to the treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression only nonspecifically at the highest dose. DOI, a 5-HT₂ and 5-HT_1C agonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by “wet dog shaking,” characteristic of 5-HT₂-receptor stimulation. The nonspecific 5-HT agonist (and 5-HT₃ antagonist) quipazine also induced “wet dog shaking” at doses that suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5-HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5-HT in different forms of aggression. © 1992 wiley-Liss, Inc.     

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerts an anorexic action that is blocked by 5-HT2 antagonists in rats

Previous literature suggests that the anorexic action of peripherally administered serotonin (5-HT) is mediated by 5-HT₂ receptors. This study, therefore, examined the effect of DOI, a non-indole 5-HT₂ agonist, on deprivation-induced feeding. Rats were first adapted to a schedule in which a milk diet was presented for 6 h daily. Intraperitoneal (IP) administration of DOI (1.0–11.2 mol/kg) inhibited feeding in a dose-related fashion (ID₅₀=2.6 mol/kg). One hour pretreatment with 6.0 mol/kg of the 5-HT₂ antagonists ketanserin and LY53857 completely reversed the anorexic action of an equimolar dose of DOI. Neither ketanserin nor LY53857, alone, altered baseline feeding. Further testing demonstrated the antagonistic effect of LY53857 (0.047–6.0 mol/kg, IP) to be dose related, with an ID₅₀ of 0.14 mol/kg. Ten minute pretreatment with 1-(1-naphthyl)-piperazine (1-NP; 2.0 or 4.0 mol/kg), a mixed-acting agent with 5HT₂ blocking actions, also attenuated the anorexic effect of 6.0 mol/kg DOI. Unlike ketanserin and LY53857, however, 1-NP did reduce food intake by itself. By contrast with ketanserin, LY53857 and 1-NP, the peripherally-acting 5-HT₂ antagonist xylamidine failed to alter the anorexic effect of DOI. Taken together, these results suggest that central 5-HT₂ receptors are important in the control of ingestive behavior.A portion of these results were presented in a preliminary report at the Annual Meeting of the Society for Neuroscience in November 1987.     

5-HT2 modulation of AY-9944 induced atypical absence seizures

We investigated the role of 5-HT(2A) and 5-HT(2C) receptors in atypical absence seizures (AAS) induced by trans-1,4-bis[2-chloro-benzylaminomethyl] cyclohexane, dihydrocholoride (AY-9944). The total duration and number and mean duration of the spontaneous bursts of slow spike-and-wave discharges (SSWD) that characterize the AY model were measured using electrocorticographic (ECoG) recordings in freely moving animals. In a randomized counterbalanced dose response design, rats were treated with either the 5-HT(2A) agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI, 0.5, 1 or 2 mg/kg), the 5-HT(2C) preferring agonist m-chlorophenylpiperazine (mCPP, 1, 2, or 4 mg/kg), the 5-HT(2A) antagonist ketanserin (2.5 or 5 mg/kg), or vehicle. DOI significantly reduced the total duration and number of SSWD. In contrast, mCPP had no effect on total duration or number of SSWD. Ketanserin exacerbated the number of SSWD at 2.5 mg/kg but produced mixed results at 5.0 mg/kg. However, none of the treatments affected the mean SSWD duration. These data support the hypothesis that 5HT(2A) receptors are involved in the pathology of experimental atypical absence seizures.     

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.     

小动物正电子发射断层成像仪探测器发展

小动物正电子发射断层成像仪（PET）探测器的性能直接决定系统的性能,设计高分辨率、高灵敏度的探测器单元是小动物PET研究的热点。综述几款经典的环形探测器、平板型探测器以及商业化小动物PET的特点和性能,主要从组成探测器单元的晶体、光电倍增管层面分析总结小动物PET探测器技术的发展状况,并且展望小动物PET在新的深度效应 (DOI)方法、半导体探测器以及通用电子学设计方面的发展前景。