Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

The 5-HT_2B receptor agonist, BW 723C86 (10, 30 mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5–10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2–5 mg/kg p.o. 1 h pre-test), but not the 5-HT_2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3–3 mg/kg i.p) or the 5-HT_1A receptor agonist, buspirone (5–20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT_2C/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT_2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT_2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT_1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT_2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.     

Involvement of 5-hydroxytryptamine1A receptors in Delta9-tetrahydrocannabinol-induced catalepsy-like immobilization in mice

The present study investigated the involvement of 5-hydroxytryptamine_1A (5-HT_1A) receptors in Δ⁹-tetrahydrocannabinol (THC)-induced catalepsy-like immobilization in mice. THC (10 mg/kg, i.p.) induced catalepsy-like immobilization but had no effect on motor coordination in the rota-rod test. The selective cannabinoid CB₁ receptor antagonist rimonabant (3 mg/kg, i.p.) completely antagonized THC-induced catalepsy-like immobilization. The 5-HT_1A/5-HT₇ receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.3 and 1 mg/kg, i.p.) and 5-HT_1A receptor partial agonist buspirone (0.06 and 0.1 mg/kg, i.p.) inhibited this THC-induced catalepsy-like immobilization. Moreover, the selective 5-HT_1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohezane carboxamide dihydrochloride (WAY100635; 0.3 or 1 mg/kg, i.p.) reversed the inhibition of THC-induced catalepsy-like immobilization by 8-OH-DPAT (1 mg/kg) or buspirone (0.06 mg/kg). In contrast, the selective 5-HT₇ receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this inhibitory effect of 8-OH-DPAT. On the other hand, WAY100635 (0.3 and 1 mg/kg, i.p.) enhanced the catalepsy-like immobilization induced by THC (6 mg/kg, i.p.). These findings suggest that the 5-HT_1A receptors are involved in THC-induced catalepsy-like immobilization.     

5-HT receptor ligands differentially affect operant oral self-administration of ethanol in the rat

The present study evaluated the effects of the selective serotonin (5-hydroxyhyptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT_1B receptor agonist, tetrahydro-4-pyridyl[3,2-b]pyridine, CP-94,253 the preferential 5-HT_2A receptor agonist, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane, DOI and the mixed 5-HT_2C/1B receptor agonist, 1-(3-chlorophenyl)piperazine, mCPP, on oral ethanol (10% v/v) self-administration in a two-lever, fixed-ratio:1, water vs. ethanol choice procedure in the rat. All compounds affected operant behavior, with varying degrees of specificity, that is, the extent to which a reduction of ethanol-reinforced lever pressing coincided with a reduction of ethanol preference, and selectivity, that is, the extent to which a reduction of ethanol-reinforced lever pressing could be dissociated from an effect on total responding on both levers. Fluoxetine (5–20 mg/kg, i.p.) and CP-94,253 (1–10 mg/kg, i.p.) induced a nonselective disruption of operant behavior; the profile being weakly specific for CP-94,253. DOI (0.1–0.3 mg/kg, i.p.) and mCPP (0.3–1 mg/kg, i.p.) induced a specific effect; the profile being more selective for DOI. These findings suggest that operant ethanol self-administration can be suppressed in a specific manner by activation of 5-HT_2A and, possibly, 5-HT_2C receptors, and in a nonselective manner by activation of 5-HT_1B receptors. As fluoxetine indirectly stimulates these receptors and its behavioral profile resembles more that of a 5-HT_1B receptor agonist, activation of 5-HT_1B receptors may underlie its effects on operant ethanol self-administration.     

Characterization of a novel effect of serotonin 5-HT1A and 5-HT2A receptors: increasing cGMP levels in rat frontal cortex

Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years. Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens, the signaling pathways activated by these agents are unclear. Here it is shown that administration of serotonin (5-hydroxytryptamine, 5-HT) increased cyclic guanosine monophosphate (cGMP) production in frontal cortical slices of rat brain. The effect of 5-HT was greater than that of N-methyl-D-aspartate (NMDA), a stimulant of cGMP formation in the central nervous system. The 5-HT_2A/2C receptor phenethylamine agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), increased cGMP content in the slices. Additionally 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5-_HT1A/7 receptor agonist also increased cGMP production. Stimulation of cGMP formation by DOM was prevented by a 5-HT_2A/2C receptor antagonist, pirenperone, as well as by a 5-HT_2A receptor selective antagonist, MDL100907. A 5-HT_2C receptor antagonist, SB242084, did not block the effect of DOM. Stimulation of cGMP production by DPAT was blocked by the 5-HT_1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be prevented by pirenperone orWAY100635. In summary, activation of serotonin 5-HT_1A and 5-HT_2A receptors increase brain cGMP levels.     

Evidence that the hyperphagic response to 8-OH-DPAT is mediated by 5-HT1A receptors

The 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) at dose of 1 mg/kg s.c. increased food intake in free feeding rats. 8-OH-DPAT-induced feeding was blocked by metergoline which has comparable affinity for 5-HT_1A, 5-HT_1B, 5-HT_1C and 5-HT₂ receptors. This is consistent with the hyperphagia being mediated by an action at 5-HT receptors. Evidence against the involvement of 5-HT₂ or 5-HT₃ receptors was provided by the lack of effect of methysergide, ketanserin, MDL 72222 and ICS 205930 on the feeding response. Blockade of the hyperphagia by (−)- but not (+)pendolol which stereoselectively interacts with 5-HT₁ receptors indicated an involvement of this receptor type. The lack of effect of ketanserin suggest that the 5-HT_1C site is not involved as it has high affinity for both 5-HT₂ and 5-HT_1C receptors. Blockade of the hyperphagia by spiperone suggest mediation by 5-HT_1A rather than 5-HT_1B receptors. Although spiperone also blocks dopamine and ₂-adrenoreceptors, involvement of these sites is unlikely as neither the DA antagonist haloperidol nor the ₂-adrenoceptor antagonist idazoxan blocked 8-OH-DPAT-included feeding. These results indicate that 8-OH-DPAT-induced feeding is mediated by 5-HT_1A receptors.     

Pharmacological characterization of serotonin receptor subtypes involved in vasopressin and plasma renin activity responses to serotonin agonists

Serotonergic drugs with 5-HT₂ receptor agonist properties have been suggested to increase plasma vasopressin concentration, blood pressure (BP) and plasma renin activity (PRA). To study whether these actions are mediated by the same or different receptors, we used three potent 5-HT agonists with different structures and receptor binding profiles. All drugs were administered i.v. to conscious, unrestrained rats. The selective agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has high affinity for 5-HT₂ receptors, caused marked increases in BP and PRA but no change in plasma vasopressin concentrations. The 5-HT_1C agonist, m-chlorophenylpiperazine (m-CPP), which also binds to other 5-HT receptors, caused moderate increases in BP and PRA and significantly elevated plasma vasopressin concentrations. The 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), did not increase any of these parameters. BP and PRA elevations paralleled each other after all drugs, while vasopressin responses were clearly different. Vasopressin responses to m-CPP were entirely antagonised by the 5-HT₁/5-HT₂ antagonist metergoline, partially by the 5-HT₂/5-HT_1C antagonists ritanserin and LY 53857, but not by the 5-HT₂ antagonist ketanserin. Ritanserin, LY53857 and ketanserin all very effectively blocked BP responses to m-CPP. These findings suggest that BP and PRA but not vasopressin responses are mediated by 5-HT₂ receptors. Vasopressin secretion is mediated by 5-HT₁ receptors, most likely by 5-HT_1C receptors.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: Role of serotonin 5-HT1A receptors

Accumulating evidence suggests that the serotonin 5-HT_1A receptor may play a role in the pathophysiology of schizophrenia. The present study was undertaken to examine the effects of perospirone, an atypical antipsychotic drug with 5-HT_1A receptor agonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of perospirone (1.0, 3.0, or 10 mg/kg) significantly attenuated PCP (10 mg/kg)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of perospirone (10 mg/kg) were significantly antagonized by co-administration of the selective 5-HT_1A receptor antagonist WAY100635 (1.0 mg/kg). Furthermore, hypothermia by the 5-HT_1A receptor agonist 8-OH DPAT (0.25 mg/kg) was significantly attenuated in mice treated with PCP. Moreover, a receptor binding assay using [³H]WAY100635 revealed that levels of 5-HT_1A receptors in the hippocampus, but not in the frontal cortex, of PCP-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration alters 5-HT_1A receptor function in the mouse brain, and that subsequent subchronic administration of perospirone ameliorates PCP-induced cognitive deficits via 5-HT_1A receptors. Therefore, perospirone could be a potential therapy for the cognitive deficits observed in schizophrenic patients.     

5-HT2/5-HT1C receptor-mediated facilitatory action on unit activity of ventral horn cells in rat spinal cord slices.

5-Methoxy-N,N-dimethyltryptamine (5-McODMT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) facilitate motoneuron excitability through 5-HT_1C/5-HT₂ receptors in rats. Using spinal cord slices prepared from adult rals, we recorded unitary cell discharges, evoked by local stimulation of the adjacent site, extracellularly in the motor nuclei of the ventral horn. 5-MeODMT, DOI, 5-hydroxytryptamme (5-HT), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and tandospirone facilitated the probability of firing in the motor nuclei, with 5-MeODMT and DOI being the most potent. The effect of 5-MeODMT was significantly suppressed by ketanserin (a 5-HT₂ receptor-selective antagonist), spinerone (a 5-HT_1A/5-HT₂ receptor antagonist) and cyproheptadine (a 5-HT_1A/5-HT₂ receptor antagonist), but not by 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, a 5-HT₃ receptor-selective antagonist) or pindolol (a 5-HT_1A/5-HT_1B receptor antagonist). This suggests that 5-HT₂ and/or 5-HT_1C receptors are involved in the facilitatory effects of 5-HT receptor agonists on the synaptic activity of ventral horn cells.     

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT_2C/5-HT_2B receptors was assessed using a putative in vivo model of 5-HT_2C/5-HT_2B receptor function, mCPP-induced hypolocomotion. mCPP (2,4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily × 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily × 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o.daily × 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT_2C/5-HT/_2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.     

The quipazine- and YFMPP-increased conditioned avoidance response in rats: Role of 5-HT1C/5-HT2 receptors

The role of serotonin (5-HT) in the acquisition of the conditioned avoidance response was investigated. The effects of different serotonin agonists and antagonists, administered prior to learning sessions, were studied in groups of naive rats using the two-way shuttle box. Quipazine, an agonist at 5-HT_1B/1C/2 receptors, significantly increased avoidance responding in a dose-dependent manner (1.25–10 mg/kg, s.c.). The putative 5-HT_1B/1C receptor agonist TFMPP (1-[m-trifluoromethylphenyl] piperazine) at doses of 1.25 and 2.5 mg/kg (s.c.), increased acquisition of conditioned avoidance but showed no significant difference from control at doses of 5 and 10 mg/kg. The 5-HT_1A agonist, buspirone, significantly decreased acquisition of conditioned avoidance. Increased acquisition of conditioned avoidance induced by either quipazine or TFMPP was effectively antagonized by the mixed 5-HT_1C/2 receptor antagonists, ketanserin (0.2 and 2 mg/kg, s.c.) and mianserin (1 mg/kg, s.c.). In contrast, spiperone (5-HT_1A/2 receptors antagonist: 0.2 mg/kg, s.c.) only inhibited the increased acquisition induced by TFMPP. On the other hand, the 5-HT_1A/1B receptors antagonist, pindolol, failed to antagonize the increase in acquisition of conditioned avoidance caused by quipazine or TFMPP. These results suggest that quipazine increases the conditioned avoidance behaviour by an action that might be mediated through stimulation of 5-HT_1C receptors. The acquisition of conditioned avoidance induced by TFMPP, which was blocked by ketanserin, mianserin and spiperone but not by pindolol, suggests the involvement of 5-HT_1C/2 receptors in the action of TFMPP.     

5-HT1A receptor-mediated inhibition in the hippocampus of the alert rat — effects of repeated gepirone treatment

The effects of acute and repeated treatment with the 5-HT_1A receptor ligand gepirone on hippocampal excitatory synaptic transmission were investigated. Recordings of the electrically evoked field population excitatory postsynaptic potentials (e.p.s.p.s.) were made in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert male Wistar rats. Acute injection of gepirone reduced the e.p.s.p. amplitude in a transient dose-dependent (0.5 – 10 mg/kg, i.p.) manner. This effect was blocked by the 5-HT_1A receptor antagonist MDL 73005EF (8-[2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethys]-8-azaspirol[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg, i.p.). Gepirone (1 mg/kg per day, i.p.) administered for 7 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a concomitant reduction of the acute response to the drug. The chronic baseline reduction was transiently reversed by the 5-HT_1A receptor antagonist spiroxatrine and complete recovery to pretreatment levels was observed 48 h after the last gepirone dose. The data indicate that with repeated administration, a prolongation and enhancement of the 5-HT_1A receptor-mediated reduction in the e.p.s.p. by gepirone occurs. This delayed effect may contribute to the slow onset of therapeutic action of gepirone.     

SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats

Social behaviour is frequently impaired in schizophrenic patients, and current antipsychotics appear poorly effective in alleviating this deficit. SSR181507 is a selective dopamine D₂ receptor antagonist and 5-HT_1A receptor agonist [Neuropsychopharmacology 28 (2003) 2064] with an atypical antipsychotic profile and additional antidepressant/anxiolytic activities [Neuropsycho pharmacology 28 (2003) 1889]. Here, we sought to assess the efficacy of SSR181507, and of reference antipsychotics and antidepressant/anxiolytics, to counteract phencyclidine (PCP)-induced social interaction deficit in rats. Pairs of unfamiliar rats were placed for 10 min each day into a dimly lit arena, during four consecutive days. On the test day (5th day), each pair was placed into the arena 30 min after i.p. treatment with PCP (or vehicle) and a challenge compound or vehicle (same for both rats, i.p. or s.c.). The time spent in social interaction was scored during 10 min. PCP (1 mg/kg) decreased social interaction time by about 35%. This effect was fully antagonized by pre-treatment with SSR181507 (1 mg/kg). In contrast, neither haloperidol (0.05 and 0.1 mg/kg) nor clozapine (0.3 and 1 mg/kg) antagonized this PCP-induced deficit. The selective 5-HT_1A receptor agonist 8-OH-DPAT (0.025 and 0.05 mg/kg s.c.), but not the anxiolytic diazepam (0.75 and 1.5 mg/kg), also improved social interaction impairment in PCP-treated rats: this would indicate that the 5-HT_1A receptor agonist properties of SSR181507 are responsible for the reversal of PCP-induced social deficit. These data suggest that, in addition to its atypical antipsychotic profile and antidepressant/anxiolytic activities, SSR181507 has a potential therapeutic activity in another key feature of schizophrenia poorly controlled by current antipsychotics, namely deterioration in social functioning.     

The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats

In this study, we assessed the effects of the acute administration of various 5-HT receptor antagonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges, respectively, and the latency of secondary discharge was also determined. The administration of either the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-c yclohe xanecarboximimde 3 HCl (WAY 100635, 0.1-1 mg/kg i.p.), the selective 5-HT(3) receptor antagonist granisetron (0.3-3 mg/kg i.p.), the selective 5-HT(2A) receptor antagonist R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidine-methanol (MDL 100907, 0.3-3 mg/kg i.p.) or the 5-HT(2B,C) receptor antagonist antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea HCl (SKB 200646A, 5-50 mg/kg i.p.) did not alter the pulse number threshold compared to vehicle-treated animals. However, the acute administration of WAY 100635 (0.3 mg/kg) and M100907 (1 mg/kg) significantly increased, whereas granisetron (1 mg/kg) decreased, the primary afterdischarge duration compared to vehicle-treated animals. The latency of secondary after discharge was significantly decreased by WAY 100635 (1 mg/kg) and granisetron (3 mg/kg) compared to vehicle-treated animals. These results suggest that in this model, the antagonism of 5-HT(1A), 5-HT(2A), 5-HT(3) or 5-HT(2B,C) receptors do not lower or raise seizure threshold. However, the antagonism of 5-HT(1A) receptors may increase or augment seizure severity.     

Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera

The mouse 5-HT_2C receptor and its third and fourth (C-terminal) cytoplasmic domain have been expressed as fusion proteins in bacteria. After purification antisera were generated against the fusion proteins. Characterization by immunoblotting using eukaryotic cells expressing the 5-HT_2C and 5-HT_2A receptors showed that high titer antibodies could be obtained only against the third and fourth cytoplasmic domain but not the entire receptor. Affinity purified antibodies were used to study the location of 5-HT_2C receptors in rat and human brain sections. This distribution was compared with the location of 5-HT_2C receptor binding sites as determined by [³H]mesulergine, a 5-HT_2C receptor radioligand. The antibodies recognized sites in the rat choroid plexus, hippocampus, cerebral cortex, striatum and substantia nigra with a similar distribution as the 5-HT_2C binding sites. One antiserum directed against the 5-HT_2C receptor C-terminus crossreacted with the human receptor protein in immunoblots. In human brain sections it labelled sites including cerebral cortex, substantia nigra and cerebellum. Our results demonstrate that the antibodies are suitable to identify 5-HT_2C receptors in rat and human brain. They visualize a protein distribution which correlates well with the location of the 5-HT_2C receptor binding sites as would be expected if affinity states do not influence the binding pattern.     

Is the potent 5-HT1A receptor agonist, alnespirone (S-20499), affecting dopaminergic systems in the rat brain?

The effects of the new methoxy-chroman 5-HT_1A receptor agonist, alnespirone (S-20499), on the dopamine systems in the rat brain were assessed in vivo by means of electrophysiological and neurochemical techniques. Cumulative doses of alnespirone (0.032–4.1 mg kg⁻¹, i.v.) did not modify the spontaneous firing rate of dopamine neurons in the substantia nigra as well as in the ventral tegmental area. The local application of alnespirone (0.1–10 μM) by reverse microdialysis into the dorsal striatum did not affect the dopamine output but induced a moderate, although dose-independent, increase of 5-HT (5-hydroxytryptamine, serotonin) concentrations in the dialysate. As expected of a 5-HT_1A receptor agonist, intraperitoneal (i.p.) administration of alnespirone at 2–32 mg kg⁻¹ markedly decreased 5-HT turnover in the striatum. Parallel measurements of dopamine turnover showed that alnespirone exerted no effect except at the highest dose (32 mg kg⁻¹, i.p.) for which a significant increase was observed. Interestingly, both alnespirone-induced reduction in 5-HT turnover and increase in dopamine turnover could be prevented by pretreatment with the selective 5-HT_1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]–N-(2-pyridinyl)cyclohexane carboxamide). Altogether, these data indicate that alnespirone does not exert any direct influence on central dopamine systems. The enhanced dopamine turnover due to alnespirone at high dose appeared to result from 5-HT_1A receptor stimulation, further supporting the idea that this receptor type may play a key role in 5-HT-dopamine interactions in brain.     

Chronic fluoxetine upregulates arachidonic acid incorporation into the brain of unanesthetized rats

Serotonergic 5-HT_2A / 2C receptors can be coupled to phospholipase A₂ (PLA₂) activation to release the second messenger, arachidonic acid (AA), from membrane phospholipids. We wished to see if this signaling process in rat brain would be altered by chronic administration followed by 3 days of washout of the selective serotonin reuptake inhibitor, fluoxetine. We injected [³H]AA intravenously in unanesthetized rats and used quantitative autoradiography to determine the incorporation coefficient k for AA (regional brain radioactivity/integrated plasma radioactivity), a marker of PLA₂ activation, in each of 86 brain regions. k was measured following acute i.p. saline or (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI, 1.0 mg/kg i.p.), a 5-HT_2A / 2C receptor agonist, in rats injected for 21 days with 10 mg/kg i.p. fluoxetine or saline daily, followed by 3 days without injection. Acute DOI produced statistically significant increments in k in brain regions with high densities of 5-HT_2A / 2C receptors, but the increments did not differ significantly between the chronic fluoxetine- and saline-treated rats. Additionally, chronic fluoxetine compared with saline widely and significantly increased baseline values of k. These results suggest that 5-HT_2A / 2C receptor-initiated AA signaling is unaffected by chronic fluoxetine plus 3 days of washout in the rat, but that baseline AA signaling is nevertheless upregulated. This upregulation likely occurs independently of significant active drug in brain, considering the short brain half-lives of it and its norfluoxetine metabolite. Such upregulation may contribute to fluoxetine's efficacy against human depression.     

Local modulation of the 5-HT release in the dorsal striatum of the rat: an in vivo microdialysis study

Using in vivo microdialysis in freely moving rats, we examined the involvement of major striatal transmitters on the local modulation of the 5-HT release. Tetrodotoxin reduced the striatal 5-HT output to 15–20% of baseline. The selective 5-HT_1B receptor agonist CP 93129 (50 μM) reduced (50%) and the 5-HT_2A/2C receptor agonist DOI (1–100 μM) increased (220%) the 5-HT output. Neither GABA nor baclofen (100 nM–100 μM) altered the 5-HT output. The glutamate reuptake inhibitor -trans-PDC (1–4 mM) raised 5-HT to 280% of baseline. This effect was not antagonized by the NMDA receptor antagonist MK-801 (0.5 mg/kg i.p.). Local MK-801 (10–100 μM) did not significantly alter the 5-HT output. Finally, neither carbachol (10–100 μM) nor quipirole (10 μM–1 mM) affected 5-HT. These data suggest that the striatal 5-HT release is influenced by local serotonergic and glutamatergic (but not GABAergic) inputs.     

Contribution of the serotonin 5-HT1A receptor agonism of 8-OH-DPAT and EMD 128130 to the regulation of haloperidol-induced muscle rigidity in rats

The aim of the present study was to find out whether (±)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT_1A agonist, and (R)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT_1A-agonist and dopamine D₂-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat’s hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125–0.5 mg/kg i.p.) and EMD 128130 (1–10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities.

Provided these results can be extrapolated to humans, the efficacy of EMD 128130 in relieving the haloperidol-induced muscle rigidity supports the concept that novel antipsychotics with 5-HT_1A agonist and dopamine D₂ antagonist activities should have a favourable extrapyramidal side-effect profile.     

5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential.

To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT_1A receptors determines the magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various 5-HT_1A receptor ligands and their antidepressant-like effects (i.e., decreased immobility in the forced swimming test in rats). Using three different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT_1A receptor agonists, ligands were identified with intrinsic activities ranging from low-negative (i.e., the inverse agonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane-carboxamide (WAY 100635)) to high-positive (i.e., 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F 13714)). In addition, novel compounds with intermediate intrinsic activity, like buspirone, but with high selectivity for 5-HT_1A receptors, unlike buspirone, were identified. The maximal effects of the 5-HT_1A receptor ligands in the forced swimming test correlated positively (r_S=0.91, P<0.005) with the rank order of their intrinsic activity at 5-HT_1A receptors. This relationship constitutes evidence that the magnitude of the psychotropic activity of 5-HT_1A receptor ligands is a positive function of their intrinsic activity at the receptor, and suggests that F 13714, which had maximal effects in the forced swimming test significantly larger than any of the other compounds examined here, did so because of its higher intrinsic activity at 5-HT_1A receptors.     

The effects of acute and repeated administration of T3 to mice on 5-HT1 and 5-HT2 function in the brain and its influence on the actions of repeated electroconvulsive shock

The effects of the administration of L-triiodothyronine (T₃) On the function of 5-HT in the CNS and its influence on the actions of electroconvulsive shock have been examined in mice. A single injection of T₃ (100 μg/kg) had no effect 24 hr later on either 5-HT_1A-mediated hypothermia, induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5 mg/kg) or the 5-HT_1B-mediated locomotor response to 5-methoxy-3-(l,2,3,6-tetrahydropyridin-4-yl) 1-H-indole (RU 24969; 50 ng i.c.v.). This treatment increased 5-HT₂-induced head-twitches, produced by 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT; 2 mg/kg), but did not alter 5-HT₂ receptors in the frontal cortex, suggesting that this potentiation was mediated indirectly through a modulatory neurotransmitter. One injection of T₃ had no effect on the concentrations of 5-HT in the forebrain or mid/hindbrain, but increased 5-HIAA in the latter region. Daily injections of T₃ for 10 days attenuated the responses to both 8-OH-DPAT and RU 24969. Furthermore, 5-MeODMT-induced head-twitches returned to control values and this was accompanied by a 10% decrease in 5-HT₂ receptors in the cortex. Repeated administration of T₃ increased levels of 5-HT in mid/hindbrain and concentrations of 5-HIAA both here and in forebrain. Hence, treatment with T₃ attenuated the function of 5-HT_1A and 5-HT_1B receptors, but increased 5-HT₂-mediated responses, although the time-courses for these effects were different. Triiodothyronine also enhanced the synthesis and turnover of 5-HT in the brain of the mouse. Repeated electroconvulsive shock (90 V, 1 sec) decreased the hypothermia induced by 8-OH-DPAT. However, 5-MeODMT-induced head-twitches were enhanced by acute and repeated electroconvulsive shock. Administration of T₃ together with electroconvulsive shock did not alter the effects of electroconvulsive shock on 5-HT_1A-mediated hypothermia, but markedly potentiated its actions on 5-HT₂-mediated responses. These findings provide possible pharmacological evidence for the suggested antidepressant effects of T₃ and the potentiation of antidepressant therapy by this thyroid hormone.