Effects Of 5-HT1A Receptor Ligands Research Articles

Effects of 5-HT1A, 5-HT2A and 5-HT2C receptor agonists and antagonists on responding for a conditioned reinforcer and its enhancement by methylphenidate.

These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate. Water-restricted rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were made available; responding on one lever delivered the CS (now a CRf), while responding on the second lever had no consequences. The effects of agonist and antagonists of 5-HT1A (8-hydroxy-2(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635)), 5-HT2A (DOI and M100907) and 5-HT2C (Ro60-0175 and SB242084) receptors on responding were examined alone, as well as in the presence of methylphenidate. Responding for a CRf was reduced by the agonists 8-OH-DPAT, DOI and Ro60-0175. 8-OH-DPAT also reduced responding for water and seemed to impair responding in a non-specific fashion. None of the receptor antagonists affected responding. Methylphenidate dose-dependently enhanced responding for a CRf, and this was attenuated by DOI and Ro60-0175. Conversely, the 5-HT2C receptor antagonist SB242084 potentiated the effect of methylphenidate. No evidence was found for a behaviourally selective effect of 5-HT1A receptor ligands on responding for a CRf. Activation of 5-HT2A receptors selectively inhibits responding for a CRf. 5-HT2C receptor ligands exerted bidirectional modulation of responding for a CRf, especially when DA activity was increased. This indicates that 5-HT2C receptor activity is an important modulator of DA-dependent reward-related behaviours.

P.1.c.036 Lipopolysaccharide -induced oxidative stress in rat striatum

Studies have shown that 5-HT1A receptor ligands modulate antipsychotic-induced catalepsy. Here, we further examined the role of intrinsic activity at 5-HT1A receptors in these effects. The anti-cataleptic effects of 5-HT1A receptor ligands with positive intrinsic activity [from high to low: 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone fumaric acid salt (F 13714), eptapirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 2-[4-[4-(7-methoxy-1-naphtyl) piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione maleic acid salt (F 11461), buspirone, 2-[4-[4-(7-benzofuranyl)piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione (F 12826), ipsapirone, and (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride (WAY 100135)] and negative intrinsic activity [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide dihydrochloride (WAY 100635)] were examined. Catalepsy was induced by the classical antipsychotic haloperidol (0.63 mg/kg) and measured in the cross-legged position test and in the bar test. All 5-HT1A receptor agonists, except WAY 100135, significantly attenuated the effects of haloperidol in the cross-legged position test. All agonists had similar effects in the bar test, except ipsapirone, which failed to attenuate haloperidol-induced catalepsy. In contrast to the effects observed with the agonists, the inverse agonist WAY 100635 appeared to enhance haloperidol-induced catalepsy in both tests, in agreement with earlier findings. The maximal effects of the 5-HT1A receptor ligands to attenuate catalepsy correlated positively with the rank order of their intrinsic activity at 5-HT1A receptors (either catalepsy test: rS=0.92, P<0.001). F 13714, which had the highest intrinsic activity, maximally inhibited haloperidol-induced catalepsy in the cross-legged position and bar tests (100% and 99% inhibition, respectively). Because the magnitude of the anti-cataleptic effects of 5-HT1A receptor ligands correlates positively with their intrinsic activity, it is likely that F 13714 has marked anti-cataleptic effects because of its high intrinsic activity at 5-HT1A receptors.

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats

While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT-/-) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study. The SERT-/- rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration. In addition, the function and expression of 5-HT1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT1A receptor ligands on cocaine's psychomotor effects were studied. Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced in SERT-/- rats. Furthermore, SERT-/- rats displayed a reduced hypothermic response to the 5-HT1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT+/+), while it increased SIH in SERT-/- rats. As 5-HT1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity in SERT-/- rats, but not SERT+/+ rats. At a high cocaine dose, only SERT+/+ animals responded to 8-OHDPAT and S-15535. These data indicate that SERT-/- -associated 5-HT1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive animals. The role of postsynaptic and somatodendritic 5-HT1A receptors is discussed.

5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy

Studies have shown that 5-HT1A receptor ligands modulate antipsychotic-induced catalepsy. Here, we further examined the role of intrinsic activity at 5-HT1A receptors in these effects. The anti-cataleptic effects of 5-HT1A receptor ligands with positive intrinsic activity [from high to low: 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone fumaric acid salt (F 13714), eptapirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 2-[4-[4-(7-methoxy-1-naphtyl) piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione maleic acid salt (F 11461), buspirone, 2-[4-[4-(7-benzofuranyl)piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione (F 12826), ipsapirone, and (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride (WAY 100135)] and negative intrinsic activity [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide dihydrochloride (WAY 100635)] were examined. Catalepsy was induced by the classical antipsychotic haloperidol (0.63 mg/kg) and measured in the cross-legged position test and in the bar test. All 5-HT1A receptor agonists, except WAY 100135, significantly attenuated the effects of haloperidol in the cross-legged position test. All agonists had similar effects in the bar test, except ipsapirone, which failed to attenuate haloperidol-induced catalepsy. In contrast to the effects observed with the agonists, the inverse agonist WAY 100635 appeared to enhance haloperidol-induced catalepsy in both tests, in agreement with earlier findings. The maximal effects of the 5-HT1A receptor ligands to attenuate catalepsy correlated positively with the rank order of their intrinsic activity at 5-HT1A receptors (either catalepsy test: rS=0.92, P<0.001). F 13714, which had the highest intrinsic activity, maximally inhibited haloperidol-induced catalepsy in the cross-legged position and bar tests (100% and 99% inhibition, respectively). Because the magnitude of the anti-cataleptic effects of 5-HT1A receptor ligands correlates positively with their intrinsic activity, it is likely that F 13714 has marked anti-cataleptic effects because of its high intrinsic activity at 5-HT1A receptors.

Effect of 5-HT(1A) receptor ligands on Fos-like immunoreactivity in rat brain: evidence for activation of noradrenergic transmission.

This study investigated the effects of 8-OH-DPAT and various other 5-HT(1A) receptor agonists on brain noradrenergic transmission using Fos-like immunoreactivity (Fos-LI) as a marker of neural activation. Administration of 8-OH-DPAT (0.1 and 1 mg/kg) induced a marked and dose-related increase in the number of cells positive for Fos-LI in the locus coeruleus (LC), the main source of noradrenergic projections to the forebrain. This effect was also induced by the non-selective, partial 5-HT(1A) receptor agonist buspirone (10 mg/kg). The effect of both 8-OH-DPAT (0.1 mg/kg) and buspirone (10 mg/kg) on Fos-LI in the LC was blocked by pretreatment with the selective 5-HT(1A) receptor antagonist WAY 100635 (1 mg/kg). The active S(-)-enantiomer of the partial 5-HT(1A) receptor agonist (+/-)-MDL 75005EF (1 mg/kg) also induced the expression of Fos-LI in the LC, whereas the inactive R(+)-enantiomer of (+/-)-MDL 73005EF at the same dose did not. In addition to the LC, 8-OH-DPAT (0.1 mg/kg) also induced a marked increase in Fos-LI in various forebrain areas including the medial prefrontal cortex (infralimbic and cingulate cortical areas). More detailed analysis of the Fos response to 8-OH-DPAT in the medial prefrontal cortex revealed that the effect was attenuated by pretreatment with a combination of the beta(1)- and beta(2)-adrenoceptor antagonists ICI 118551 (4 mg/kg) and metoprolol (4 mg/kg), but not the alpha(1)-adrenoceptor antagonist prazosin (5 mg/kg). Taken together, the present findings provide immunocytochemical evidence that 5-HT(1A) receptor agonists activate noradrenergic neurones in the LC and that this leads to increased noradrenergic transmission at postsynaptic sites in the forebrain (specifically medial prefrontal cortex).

Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat.

In the present study, the effects of 5-HT1A receptor ligands with varying degrees of intrinsic activity at the 5-HT1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever pressing. The 5-HT1A receptor partial agonist, buspirone (0.1-1.0 mg/kg), the 5-HT1A receptor agonist, 8-OH-DPAT (0.01-0.10 mg/kg), and the 5-HT1A receptor antagonist, WAY-100635 (0.03-3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats.

Anxiolytic and sedative effects of 5-HT1A ligands, 8-OH-DPAT and MDL 73005EF, in mice

The actions of the 5-HT1A receptor ligands, MDL 73005EF and 8-OH-DPAT, were assessed in mice. They were confronted with a free exploratory test especially adapted to reveal sedation, and with a two-box light/dark choice situation validated for the detection of anti-anxiety agents. Both drugs were found to have sedative properties at high doses and anxiolytic-like effects at lower doses. The results show that both drugs have a comparable profile of action to that of benzodiazepines in the two-box light/dark procedure. These findings are in line with earlier reports describing anxiolytic effects of 5-HT1A receptor ligands in different animal models of anxiety.