Prepulse inhibition in fawn-hooded rats: increased sensitivity to 5-HT1A receptor stimulation.

Prepulse inhibition of startle is a model of sensorimotor gating, which is disrupted in alcoholism, as well as mental illnesses such as schizophrenia. The fawn-hooded (FH) rat strain has been used as an animal model of alcoholism. FH rats showed significantly lower startle amplitude than Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Increasing doses of the 5-HT(1A) receptor agonist 8-OH-DPAT caused disruption of PPI, with the effect being significantly greater in FH rats compared to WKY rats. In all strains, treatment with 0.5 mg/kg of 8-OH-DPAT significantly reduced PPI. In contrast, 0.1 mg/kg of 8-OH-DPAT caused disruption only in the FH strain. Treatment with amphetamine, apomorphine and MK-801 also significantly reduced PPI, however, there was no difference between the strains. This study shows increased sensitivity of FH rats to the disruption of PPI caused by 5-HT(1A) receptor stimulation, suggesting a link between 5-HT(1A) receptors, sensorimotor gating and aspects of the FH rat phenotype.     

Effects of OPC-14523, a combined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors

OPC-14523 (OPC) is a novel compound with high affinity for sigma and 5-HT1A receptors that shows 'antidepressant-like' effects in animal models of depression. We have previously demonstrated that OPC produces an increase in 5-HT neurotransmission and a decreased response of 5-HT neurons to the acute administration of paroxetine in the DRN, an effect that appears to be mediated by OPC's 5-HT1A receptor affinity. The current study sets out to investigate more specifically the effects of OPC on 5-HT1A pre- and post-synaptic receptors, to assess whether it acts as an agonist or antagonist. Using an electrophysiological model of in vivo extracellular recordings in anaesthetized rats, the effects of OPC was assessed on pre-synaptic DRN 5-HT1A autoreceptors and post-synaptically on hippocampal 5-HT1A receptors of CA3 pyramidal neurons. OPC applied by microiontophoresis, produced a significant decrease in the firing activity of 5-HT neurons of the DRN and of quisqualate-activated CA3 pyramidal neurons of the dorsal hippocampus. The effects of OPC on 5-HT1A receptors were significantly reduced by the co-application of the 5-HT1A antagonist WAY-100635. In addition, the effects of OPC were not blocked by the injection of the sigma antagonists NE-100 or haloperidol. Therefore, OPC is acting as an agonist on both pre- and post-synaptic 5-HT1A receptors. The current findings combined with previous data on OPC suggest a pharmacological profile that warrants further investigation.     

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.     

8-OH-DPAT disruption of prepulse inhibition in rats: reversal with (+)WAY 100,135 and localization of site of action

Recent studies have implicated central serotonergic systems in the modulation of prepulse inhibition (PPI), an operational measure of sensorimotor gating, which has been used to identify gating deficits in psychiatric disorders, such as schizophrenia, Huntington's disease, and obsessive compulsive disorder. Both serotonin (5-HT) releasers and agonists at 5-HT_1A, 5-HT_1B, and 5-HT₂ receptors reduce PPI in the rat. The present experiments demonstrate that the disruption of PPI in rats induced by the systemic administration of the 5-HT_1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin; 0.2 mg/kg), can be attenuated by the novel, selective 5-HT_1A antagonist (+)WAY 100,135, (20.0 mg/kg),N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenyl-propanamide. Further experiments addressing the central site of action of 8-OH-DPAT revealed that the microinjection of 8-OH-DPAT (5.0 µg/0.5 l) into either the median raphe nucleus (MR) or dorsal raphe nucleus (DR) disrupts PPI. The reduction in PPI produced by intra-raphe microinjections of 8-OH-DPAT was prevented by a systemic injection of (+)WAY 100,135. These results support the hypothesis that somatodendritic 5-HT_1A autoreceptors within the midbrain raphe subserve the PPI-disruptive effects of systemically administered 8-OH-DPAT. The decrement in PPI after intra-raphe infusions of a high dose of 8-OH-DPAT, however, was substantially less than the decrement in PPI after systemic administration of the drug. Hence, sites in addition to the somatodendritic autoreceptors may also play an important role in 8-OH-DPAT-induced disruption of PPI. Together with previous reports that 5-HT releasers and other 5-HT agonists also disrupt PPI, the results support the hypothesis that the serotonergic system modulates PPI through multiple receptor and anatomical systems.     

Neuroanatomical basis for the antidepressant-like effects of the 5-HT(1A) receptor agonists 8-OH-DPAT and ipsapirone in the rat forced swimming test

In the rat forced swimming test, systemic application of the serotonin 1A (5-HT(1A)) receptor agonist 8-OH-DPAT reduced immobility (ID(50) 0.17-1.37mg/kg, depending on route of application and application schedule). Intracerebroventricular (i.c.v.) or local application into the dorsal raphe nucleus (DRN), a brain area rich in presynaptic 5-HT(1A) receptors, resulted in a parallel shift of the dose-response curve to the left (ID(50) 5.1 and 3.9μg/rat, respectively). Systemic application of the 5-HT(1A) receptor partial agonist ipsapirone resulted in a U-shaped dose-response curve (maximal effect about 30% immobility reduction at 3-10mg/kg). Local application of ipsapirone in the DRN reduced immobility (maximal effect 40% at 60μg/rat). However, 8-OH-DPAT and ipsapirone were still effective after depletion of brain 5-HT by means of 5,7-DHT (150μg, i.c.v.) or pCPA (either 2 x 150mg/kg or 2 x 350mg/kg, i.p.) Additionally, in non-lesioned rats: (1) the putative (postsynaptic) 5-HT(1A) antagonist NAN-190, but not spiperone, haloperidol, prazosin or 1-PP, was able to block the anti-immobility effects of 8-OH-DPAT in a behaviorally specific manner; (2) local application of 8-OH-DPAT and ipsapirone in the lateral septum (a brain area rich in postsynaptic 5-HT(1A) receptors) reduced immobility (8-OH-DPAT: ID(50) 11.4μg/rat; ipsapirone; maximal effect at 30μg/rat 38%); and (3) pretreatment with ipsapirone resulted in an attenuation of the effect of 8-OH-DPAT when both compounds were administered either systemically or in the lateral septum but not when both compounds were microinjected into the DRN. It is hypothesized that the anti-immobility effects of 5-HT(1A) receptor agonists are mediated by pre- and postsynaptic 5-HT(1A) receptors and that they closely reflect the intrinsic activity of these compounds at these receptors.     

Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.     

Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission.

Neurochemical, molecular, immunohistochemical and behavioral methods were used to examine the in vivo effects of the neuropeptide galanin on central 5-HT neurotransmission and on 5-HT(1A) receptor-mediated responses. Intraventricularly infused galanin caused a long-lasting and dose-dependent reduction of basal extracellular 5-HT levels in the ventral hippocampus of awake rats as measured by microdialysis. Infusion of galanin into the dorsal raphe nucleus (DRN), but not intra-hippocampally, reduced 5-HT release. The effect of i.c.v. galanin on 5-HT release was blocked by the galanin receptor antagonist M35, acting most likely via galanin receptors at the level of the DRN. Galanin also reduced the levels of tryptophanhydroxylase mRNA in the DRN. Therefore, the effects of galanin on 5-HT(1A) receptor-mediated responses were further investigated. Surprisingly, galanin significantly attenuated the reduction of hippocampal 5-HT release induced by systemic injection of the 5-HT(1A) receptor agonist 8-OH-DPAT. Galanin also attenuated 8-OH-DPAT-induced hypothermia and locomotor activity in rats. These results indicate that galanin has important inhibitory actions on central 5-HT neurotransmission and on 5-HT(1A) receptor-mediated events.     

The importance of baseline in identifying 8-OH-DPAT-induced effects on prepulse inhibition in rats

BACKGROUND AND PURPOSE: Prepulse inhibition (PPI) of the acoustic startle response is a model of sensorimotor gating which is disrupted in schizophrenia and other mental illnesses. We and others have shown that treatment with the 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist, 8-OH-DPAT, disrupts PPI in rats. In the present study, we highlight the importance of baseline levels on the effect of 8-OH-DPAT on PPI. EXPERIMENTAL APPROACH: Adult male and female Sprague-Dawley rats were gonadectomised. These rats were treated with saline, 0.02 and 0.5 mg kg(-1) of 8-OH-DPAT using a random-sequence, repeated-measures protocol. The rats were allocated into high and low baseline groups depending on their baseline PPI observed after saline treatment. KEY RESULTS: Treatment with 0.5 mg kg(-1) of 8-OH-DPAT significantly disrupted PPI in both male and female rats. In male rats only, 0.02 mg kg(-1) 8-OH-DPAT caused a small, but significant, increase in PPI. When these male rats were allocated to either a high or low baseline PPI group, 0.5 mg kg(-1) 8-OH-DPAT disrupted PPI in the high baseline group only. In contrast, treatment with 0.02 mg kg(-1) 8-OH-DPAT increased PPI only in the low baseline PPI group. There were no changes in the effect of 8-OH-DPAT administration in female rats when they were divided into high and low baseline PPI groups. CONCLUSIONS AND IMPLICATIONS: The level of baseline PPI is an important variable that can influence the direction of drug effects induced by 8-OH-DPAT. The explanation for this phenomenon could be differential activation of pre- and postsynaptic 5-HT(1A) receptors.     

Activation of 5-HT(1A) autoreceptors enhances the inhibitory effect of galanin on hippocampal 5-HT release in vivo

The microdialysis technique was used to examine interactions between 5-HT(1A) and galanin receptors in the dorsal raphe nucleus (DRN), by measuring the extracellular levels of 5-HT in the ventral hippocampus of awake rats. The rats were pretreated with the 5-HT(1A) receptor agonist (R,S)-8-OH-DPAT (0.3 mg/kg, s.c.) or saline. 8-OH-DPAT caused a time-dependent reduction of basal 5-HT levels down to 43-48% at 40 min while at 140 min, the hippocampal 5-HT had returned to control values. At that time point, the rats received a second injection of 8-OH-DPAT or galanin (0.15, 0.5 and 1.5 nmol/0.5 microl) infused into the lateral ventricle. The second injection of 8-OH-DPAT caused a significantly smaller reduction of hippocampal 5-HT levels. In contrast, galanin at all three doses in the 8-OH-DPAT-pretreated groups, was significantly more potent in reducing 5-HT levels (maximal reduction to 74%, 52% and 49%, respectively) than it was in saline-pretreated rats (maximal reduction to 96%, 85% and 69%, respectively). The inhibitory effect of galanin (1.5 nmol) on extracellular 5-HT levels in the rat hippocampus was significantly attenuated by co-administration of the 5-HT(1A) receptor antagonists WAY-100635 (0.3 and 0.6 mg/kg s.c.) and, to a lesser extent, with pindolol (20 mg/kg s.c.). These data provide direct in vivo evidence of agonistic 5-HT(1A)-galanin receptor interaction at the presynaptic level. Furthermore, the findings indicate that a down-regulation of the somato-dendritic 5-HT(1A) autoreceptors, following their stimulation with 8-OH-DPAT and possibly also indirectly with 5-HT reuptake inhibitors, may be compensated by a subsequent 'sensitization' of the inhibitory galanin receptors in the DRN. Thus, the enhanced galanin receptor-mediated inhibition of 5-HT neurotransmission may contribute to the pathophysiology of depression or to the reduced and delayed efficacy of antidepressant therapies.     

Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat

1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2. Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) significantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.5-16 microg kg(-1), i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory effect of 8-OH-DPAT was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.) in all neurones tested. 3. In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1-0.8 mg kg(-1) , i.v.). 4. 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5-32 microg kg(-1), i.v.) in the range of those which inhibited 5-HT cell firing. At higher doses (32-512 microg kg(-1), i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg(-1), s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5. These data add further support to the view that the inhibitory effect of 5-HT1A receptor agonists on the firing activity of DRN 5-HT neurones involves, in part, activation of a 5-HT1A receptor-mediated postsynaptic feedback loop centred on the mPFC.     

Role of serotonin-1A receptors in the action of antipsychotic drugs: comparison of prepulse inhibition studies in mice and rats and relevance for human pharmacology

This study aimed to explore strain and species differences in the involvement of 5-HT1A receptors in the action of antipsychotic drugs, using prepulse inhibition (PPI), a model of sensory processing which is deficient in schizophrenia patients. We used automated startle boxes to compare the effect of the 5-HT1A receptor agonist, (+/-)-8-hydroxy-dipropyl-amino-tetralin (8-OH-DPAT), on PPI in three mouse strains. Balb/c mice were then pretreated with antipsychotics, treated with 8-OH-DPAT or saline, and tested for PPI. 8-OH-DPAT treatment dose dependently increased PPI in Balb/c mice, but had less effect in 129Sv and C57Bl/6 mice. In Balb/c mice, the effect of 8-OH-DPAT was blocked by the typical antipsychotic and dopamine D2 receptor antagonist, haloperidol and the third generation antipsychotic, aripiprazole, which has activity at both 5-HT1A and dopamine D2 receptors. The atypical antipsychotics, clozapine, olanzapine and risperidone, had lesser effects. Similar to our earlier studies in rats, the present PPI results suggest that 5-HT1A receptors are involved in the action of some antipsychotic drugs in mice. Despite strain and species differences in the magnitude and direction of the effect of 8-OH-DPAT, downstream dopamine D2 receptor activation seems to be an important mediator. These comparative results allow a theoretical framework of receptor interactions, which may guide further studies on the involvement of 5-HT1A receptors in schizophrenia.     

Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenylalanine.

These experiments examined the impact of extensive depletions of forebrain 5-hydroxytryptamine (5-HT; serotonin) levels on prepulse inhibition (PPI) of the acoustic startle reflex in rats. In Experiment 1, injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei disrupted PPI. This deficit was observed beginning 2 days after lesioning and was still apparent 8 weeks later. Basal startle reactivity was not altered. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg) and the dopamine receptor agonist apomorphine (1mg/kg) also disrupted PPI; the effect of 8-OH-DPAT, but not apomorphine, was potentiated in 5-HT-depleted rats. Basal startle reactivity was enhanced by 8-OH-DPAT in sham-lesioned rats but not in 5,7-DHT-lesioned rats. In Experiment 2, a second method for depleting 5-HT was used. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) also disrupted PPI without altering basal startle reactivity. Again, 8-OH-DPAT disrupted PPI in control animals; this effect was not altered in PCPA-treated rats but the increase in basal startle reactivity induced by 8-OH-DPAT was not observed in PCPA-treated rats. Taken together with the results of previous experiments involving drugs that enhance 5-HT neurotransmission it appears that both increases and decreases in 5-HT activity disrupt PPI.     

Effect of a long-term low tryptophan diet on the prolactin responses to the 5-HT1A and 5-HT2C agonists, 8-OH-DPAT and mCPP in the male rat

The study was undertaken to assess the long term effects of tryptophan (TRP) depletion through diet on the prolactin (PRL) responses to the serotonin (5-hydroxytryptophan, 5-HT) agonists m-chlorophenyl-piperazine (mCPP) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the male rat. The low TRP diet caused significant reductions in both plasma total TRP and brain cortical 5-HT content together with a significant increase in the PRL responses to mCPP. In contrast the PRL responses to 8-OH-DPAT in animals on the low TRP diet for 1 week and 6 weeks were similar to control rats. However, a small but significant increase in PRL was observed at 2 min after dosing in the 1-week group. At the same time the 3H-8-OH-DPAT binding parameters, Kd and Bmax, were similar in both control and TRP depleted animals. The results confirm that long-term TRP depletion causes a deficiency of brain TRP and a subsequent reduction of brain 5-HT. This is associated with an enhanced PRL response to mCPP probably resulting from a functional up-regulation of post-synaptic 5-HT2C receptors. The small or transient changes brought about by long-term TRP depletion on post-synaptic 5-HT1A receptors, suggests that these receptors may be less susceptible to 5-HT depleting effects than the 5-HT2C subtype.     

A pharmacological analysis of the eating response induced by 8-OH-DPAT injected into the dorsal raphé nucleus reveals the involvement of a dopaminergic mechanism

Direct injection of the 5-hydroxytryptamine (5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the dorsal raphé nucleus (DRN) dose dependently increased food intake in free feeding rats. The hypothesis that this effect is mediated by 5-HT_1A receptors was tested by investigating the abilities of the putative 5-HT_1A antagonists metergoline, propanolol and spiperone to prevent 8-OH-DPAT-induced eating. Metergoline failed to affect 8-OH-DPAT-induced eating when injected either peripherally or into the DRN. Peripherally injected propranolol and spiperone prevented 8-OH-DPAT-induced eating, but these drugs were ineffective when injected into the DRN. These results indicate that 8-OH-DPAT-induced eating may not involve 5-HT_1A receptors within the DRN. The ability of peripherally injected spiperone to prevent the eating response to 8-OH-DPAT reflects its dopamine blocking activity since haloperidol was an effective antagonist of 8-OH-DPAT-eating. This result may indicate that 8-OH-DPAT produces a general behavioural activation by reducing the inhibitory influence which 5-HT normally exerts over the nigrostriatal dopamine pathway, and that this behavioural activation is expressed as eating when food is the most salient goal object present.     

The 5-HT1A receptor agonist, 8-OH-DPAT,preferentially activates cell body 5-HT autoreceptors in rat brain in vivo

Summary The present study was undertaken in an attempt to assess whether the effects of the potent and selective 5HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, on cerebral 5-hydroxytryptamine (5-HT) neurochemistry in vivo are mediated via 5-HT autoreceptors on the cell bodies or on the terminals, and/or via postsynaptic 5-HT receptors. To this end we determined in vivo indices of 5-HT synthesis and release/turnover rates in a number of prominent 5-HT neuronal projection areas in the CNS i) after systemic administration of 8-OH-DPAT to rats with an acute unilateral axotomy of the ascending mesencephalic monoamine neurones, or ii) after local infusion of the compound into the dorsal raphé (DRN) 5-HT cell body region of intact rats. Transection did not alter 5-HT synthesis per se, but prevented the synthesis-inhibitory effect of 8-OH-DPAT. Thus, the 5-HT synthesis-inhibiting action of 8-OH-DPAT is highly dependent upon intact impulse flow in the central 5-HT neurones. On the other hand, local DRN application of the compound (1 g) resulted in a clearcut reduction of the 5-HT synthesis and release indices measured in 5-HT terminals in, e. g., the striatum. These findings provide direct neurochemical evidence that by preferentially stimulating somatodendritic 5-HT_1A receptors, 8-OH-DPAT inhibits the 5-HT neuronal impulse flow, thereby effectuating decreased terminal 5-HT synthesis and release. Taken together, the data are consistent with the suggestion that 8-OH-DPAT acts as an agonist preferentially at cell body vs. terminal 5-HT autoreceptors, therefore also emphasizing the distinction between terminal and cell body 5-HT autoreceptors. The results obtained may have important implications for the understanding of mechanisms involved in regulating the activity of central serotoninergic neurones.Part of these data were presented at the 6th European Winter Conference on Brain Research, Avoriaz, France, March 9–15, 1985, and at the 18th Annual Meeting, Society for Neuroscience, Washington (DC), USA, Nov. 9–15, 1986 (Hjorth et al. 1986, 1987). Send offprint requests to S. Hjorth at the above address     

Role of 5-HT(1A) and 5-HT(2) receptors of dorsal and median raphe nucleus in tolerance to morphine analgesia in rats

Several studies indicate that central serotonergic neurons have important role in morphine analgesia and tolerance. The aim of this study was to investigate possible role of 5-HT(1A) and 5-HT(2) receptors in dorsal and median raphe nucleus on development of tolerance to analgesic effect of morphine using hot plate test. Chronic injection of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) (2, 4 and 8 mug/rat/day) to dorsal raphe nucleus (DRN) delayed tolerance to morphine analgesia, whereas injection of the same doses of 8-OH-DPAT to the median raphe nucleus (MRN) did not alter tolerance to morphine. In addition, chronic administration of ketanserin (1.5, 3 and 6 mug/rat/day), as a 5-HT(2) receptors antagonist, in DRN and MRN did not produce any significant effect. We conclude that 5-HT(1A) receptors of DRN are involved in tolerance to antinociceptive effect of morphine. However, the exact mechanism of interaction between serotonergic and opioidergic systems is not clear and remains to be elucidated.     

Effects of repeated treatment with 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on the autoregulatory control of dorsal raphe 5-HT neuronal firing and cortical 5-HT release.

These experiments were designed to examine the effects of repeated 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) treatment on the autoregulatory control of cortical 5-HT release and dorsal raphe nucleus (DRN) 5-HT neuronal cell firing. Repeated DOI treatment decreased the behavioural responsiveness (wet-dog shakes) of 5-HT2 receptors and attenuated the inhibitory effects of the 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), on both cortical 5-HT release and DRN 5-HT neuronal firing. In contrast, the inhibitory effect of acute DOI on cortical 5-HT release and DRN 5-HT neuronal firing was unaffected by repeated DOI treatment. The results demonstrate that changes in the responsiveness of 5-HT2 receptor function may influence the responsiveness of presynaptic 5-HT1A receptors regulating 5-HT neuronal function. The results also provide further evidence that the inhibition of cortical 5-HT release and DRN 5-HT neuronal firing produced by DOI is not mediated by 5-HT2 receptor activation.     

Chronic rTMS induces subsensitivity of post-synaptic 5-HT1A receptors in rat hypothalamus

Chronic administration of several antidepressants, notably the selective serotonin re-uptake inhibitors (SSRIs) induces sub-sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus. Chronic repetitive transcranial magnetic stimulation (rTMS) is a form of treatment for depression which is often compared to electroconvulsive shock therapy (ECT). rTMS was applied to rats either on a single occasion (acute) or daily for 8 d (chronic). Twenty-four hours after the last treatment, the rats were injected with saline or 8-OH-DPAT (50 microg/kg). The rats were killed 20 min later and trunk blood taken for measurement of corticosterone and ACTH levels. Chronic rTMS did not affect basal corticosterone or ACTH levels but significantly blunted the responses to 8-OH-DPAT, while acute rTMS had no effect on either basal or 8-OH-DPAT-stimulated responses. In common with several other antidepressant treatments, chronic rTMS reduces the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus. This effect may be significant in relation to the therapeutic mechanism of rTMS.     

Stimulation of corticosterone secretion by the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat

The selective 5-HT1A receptor agonist 8-OH-DPAT increased serum corticosterone concentration in rats in a dose-dependent manner. The synthetic corticoid dexamethasone lowered the serum corticosterone level and abolished its rise induced by 8-OH-DPAT. The corticosterone response to 8-OH-DPAT was also antagonized by spiperone, (+/-)- and (-)-pindolol and (+/-)-propranolol, all of which have been shown to have a high affinity for 5-HT1A receptors, though in most cases no complete blockade was found. A partial antagonism of the response was also observed after flumazenil, a benzodiazepine antagonist. On the other hand, the 5-HT1B receptor antagonist 21009, the 5-HT2 receptor antagonists ketanserin and pirenperone, the 5-HT3 receptor antagonist ICS 205-930, the alpha 2-adrenoceptor antagonists yohimbine and idazoxan, the beta-adrenoceptor blocker with no affinity to 5-HT1 receptors, atenolol, the dopaminergic antagonist pimozide, the histamine receptor blocker chloropyramine and the opiate receptor antagonist naloxone did not affect the hormonal response to 8-OH-DPAT. The 8-OH-DPAT-induced corticosterone secretion was not affected either in rats pretreated with p-chlorophenylalanine (PCPA, an inhibitor of tryptophan hydroxylase) or p-chloroamphetamine (PCA, a drug-inducing lesion of serotonergic nerve terminals). It is concluded that 8-OH-DPAT-induced increase in serum corticosterone concentration results from its action at a site different than the adrenal cortex and is mediated by postsynaptic 5-HT1A receptors, whereas other subtypes (5-HT1B, 5-HT2, 5-HT3) of 5-HT receptors do not participate in this response.(ABSTRACT TRUNCATED AT 250 WORDS)     

The acute and chronic effects of MDMA ("ecstasy") on cortical 5-HT2A receptors in rat and human brain.

While the pre-synaptic effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT) neurons have been studied extensively, little is known about its effects on post-synaptic 5-HT(2) receptors. Therefore, cortical 5-HT(2A) receptor densities and 5-HT concentration were studied in MDMA treated rats (10 mg/kg s.c.). Furthermore, 5-HT(2A) post-synaptic receptor densities in the cerebral cortex of recent as well as ex-MDMA users were studied using [123I]R91150 SPECT. In rats we observed a decrease followed by a time-dependent recovery of cortical 5-HT(2A) receptor densities, which was strongly and positively associated with the degree of 5-HT depletion. In recent MDMA users, post-synaptic 5-HT(2A) receptor densities were significantly lower in all cortical areas studied, while 5-HT(2A) receptor densities were significantly higher in the occipital cortex of ex-MDMA users. The combined results of this study suggest a compensatory upregulation of post-synaptic 5-HT(2A) receptors in the occipital cortex of ex-MDMA users due to low synaptic 5-HT levels.