Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression

Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients'' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.     

Effects of Serotonin on the Induction of Long-term Depression in the Rat Visual Cortex

Long-term potentiation (LTP) and long-term depression (LTD) have both been studied as mechanisms of ocular dominance plasticity in the rat visual cortex. In a previous study, we suggested that a developmental increase in serotonin [5-hydroxytryptamine (5-HT)] might be involved in the decline of LTP, since 5-HT inhibited its induction. In the present study, to further understand the role of 5-HT in a developmental decrease in plasticity, we investigated the effect of 5-HT on the induction of LTD in the pathway from layer 4 to layer 2/3. LTD was inhibited by 5-HT (10 µM) in 5-week-old rats. The inhibitory effect was mediated by activation of 5-HT₂ receptors. Since 5-HT also regulates the development of visual cortical circuits, we also investigated the role of 5-HT on the development of inhibition. The development of inhibition was retarded by chronic (2 weeks) depletion of endogenous 5-HT in 5-week-old rats, in which LTD was reinstated. These results suggest that 5-HT regulates the induction of LTD directly via activation of 5-HT₂ receptors and indirectly by regulating cortical development. Thus, the present study provides significant insight into the roles of 5-HT on the development of visual cortical circuits and on the age-dependent decline of long-term synaptic plasticity.     

Serotonin and GI clinical disorders

Serotonin is widely distributed throughout the gut within both the enteric nerves and enterochromaffin (EC) cells. EC cells are located in the gut mucosa with maximal numbers in the duodenum and rectum where they act as signal transducers, responding to pressure and luminal substances both bacterial and dietary. Activation leads to serotonin release which acts on a range of receptors on mucosal afferent and myenteric interneurones to initiate secretomotor reflexes. These cause nausea and vomiting as well as intestinal secretion, propulsion and if pronounced, diarrhoea. Inflammation in animal models acts via T lymphocytes to increase EC cell numbers and mucosal serotonin (5-HT) content while inflammatory cytokines decrease serotonin transporter (SERT) function. Inflammation due to coeliac disease and following gastrointestinal infection increases mucosal 5-HT availability by a combination of increased EC cells and depressed SERT. Irritable bowel syndrome (IBS) developing after gastrointestinal infection and IBS with diarrhoea is associated with excess 5-HT. The associated diarrhoeal symptoms respond well to 5-HT₃ receptor antagonists. These drugs also inhibit the nausea and vomiting occurring in patients undergoing chemotherapy which cause a marked increase in release of 5-HT as well as other mediators. Other conditions including IBS-C and constipation may have inadequate 5-HT release and benefit from both 5-HT₃ and 5-HT₄ receptor agonists.     

Effects of carbamazepine on 5-hydroxytryptamine function in rodents

The effects of carbamazepine (CBZ) on brain 5-hydroxytryptamine (5-HT) function were investigated in rodents pretreated with CBZ acutely or for 14 days. In behavioural experiments, mice pretreated with 14 days CBZ showed increased 5-HT₂-mediated head twitch behaviour after injection of carbidopa (25 mg/kg) followed by 5-hydroxytryptophan (5-HTP, 100 mg/kg). However, no change in head twitches after 5-methoxy,N,N,-dimethyltryptamine (5MeODMT 5.0 mg/kg), a direct agonist, was observed. Chronic CBZ administration to rats did not alter either the behavioural syndrome induced by 8-hydroxy-2-dipropy-laminotetralin (8-OH-DPAT, 1.0 mg/kg), an index of post-synaptic 5-HT_1A responses, or hypothermia after 8-OH-DPAT (0.5 mg/kg) which is thought to reflect presynaptic 5-HT_1A activity. Both hyperactivity and the behavioural syndrome seen after tranylcypromine (20 mg/kg) followed byl-tryptophan (100 mg/kg) were decreased by prior treatment with CBZ (14 days). Accumulation of 5-HTP after administration of the amino acid decarboxylase inhibitor NSD1015 (100 mg/kg) was decreased after acute CBZ (50 mg/kg) in hippocampus. However, after 14 days oral treatment no change in this measure of 5-HT synthesis was seen, in either hippocampus or frontal cortex.CBZ (50 µM) added to superfused brain slices did not affect potassium-stimulated [³H]-5-HT release. However, hippocampal slices from rats pretreated with CBZ (14 days) showed increased potassium-stimulated [³H]-5-HT release. CBZ (14 days) did not alter 5-HT₂ binding in rat frontal cortex. These results indicate a depressant effect of acute CBZ upon presynaptic 5-HT activity and an increase in presynaptic 5-HT function when CBZ is given for 14 days. Post-synaptic 5-HT function was, however, not altered by CBZ.     

5-羟色胺综合征的临床特征、诊断及防治

5-羟色胺综合征是一种由治疗药物引起的可能危及生命的不良反应。发生机制为5-羟色胺(5-HT)在神经系统内积蓄,过度激活突触后5-HT受体,导致5-HT能神经系统活动增强,其临床特征为精神障碍、自主神经功能亢进及神经肌肉功能异常。本综合征常发生于抗抑郁药联用或与其他药物联用时,主要依据临床表现诊断。治疗包括停撤可疑药物、密切观察、控制激越行为、给予5-HT拮抗剂、对症治疗、并发症的处理等。本综合征重在预防。     

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT_2A receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT_2A receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT_2A receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT_2A receptor availability (binding potential, BP_ND) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP_ND and higher 5-HT_2A receptor BP_ND in cortical, but not subcortical regions. Decreased SERT BP_ND was regionally associated with upregulated 5-HT_2A receptor BP_ND. In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.     

Serotonin mechanisms in alcohol drinking behavior

Rat lines selectively bred for disparate alcohol-drinking behaviors exhibit innate differences in the contents of serotonin (5-HT) in several CNS limbic regions, e.g., nucleus accumbens (ACB), frontal cortex, hypothalamus, and olfactory tubercles. In these regions, the selectively bred alcohol-preferring (P) line has levels approximately 20% (P > 0.05) lower than values obtained for the alcohol-nonpreferring (NP) line. In addition, in some limbic regions, the densities of (1) 5-HT_1A receptors are higher by approximately 30% and (2) 5-HT_1B and 5-HT₂ receptors are lower (by 25-40%) in the P than in the NP line. systemic administration of agents that increase synaptic levels of 5-HT, such as fluoxetine (a 5-HT uptake inhibitor), d-fenfluramine (a 5-HT releaser) and D, L-5-hydroxytryptophan (an immediate precursor of 5-HT), significantly decreased alcohol consumption of the P line of rats. Systemic (1.0 and 2.0 g/kg ip) administration or local perfusion (100 mM) of ethanol significantly increased the extracellular levels of 5-HT in the ACB of unselected Wistar rats. An interaction of the dorsal raphe nucleus (DRN) 5-HT system with the ventral tegmental area (VTA) dopamine (DA) pathway projecting to the ACB was indicated by the findings that DA release in the ACB increased and decreased following stimulation and inhibition, respectively, of DRN 5-HT neurons. Moreover, an involvement of 5-HT in mediating alcohol-stimulated DA release in the ACB is indicated by the observation that local application of a 5-HT₃ antagonist can attenuate this stimulated release. Overall, the data suggest that an innate 5-HT deficiency in certain limbic structures of the P rat may be a major neurobiological factor underlying their high alcohol drinking characteristics. © 1993 wiley-Liss, Inc.     

N-Methyl-D-aspartate receptor antagonists counteract the long lasting 5-HT1A receptor-induced attenuation of postsynaptic responses in the rat in vivo

Summary The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine and phencyclidine, the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) and the antagonist at the glycine modulatory site of the NMDA receptor, 3-amino-l-hydroxy-2-pyrrolidone (HA-966) on the long lasting attenuation of some postsynaptic 5-HT_1A receptor-mediated responses in rats (increased corticosterone secretion and inhibition of the cage leaving response) produced by a single injection of the 5-hydroxytryptamine_1A 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied. It was found that these antagonists counter-acted the attenuation of these responses at dose levels known to block the NMDA receptor-ion channel complex in vivo. It is concluded that the long lasting attenuation of postsynaptic responses after a 5-HT_1A receptor agonist is initiated through stimulation of glutamate NMDA receptors indicating a functional interaction between the 5-HT and glutamate systems in at least two different models. Send offprint requests to S. B. Ross at the above address     

Effects of Sustained Administration of Quetiapine Alone and in Combination with a Serotonin Reuptake Inhibitor on Norepinephrine and Serotonin Transmission

Quetiapine is now used in the treatment of unipolar and bipolar disorders, both alone and in combination with other medications. In the current study, the sustained administration of quetiapine and N-Desalkyl quetiapine (NQuet) in rats in a 3 : 1 mixture (hQuetiapine (hQuet)) was used to mimic quetiapine exposure in patients because rats do not produce the latter important metabolite of quetiapine. Sustained administration of hQuet for 2 and 14 days, respectively, significantly enhanced the firing rate of norepinephrine (NE) neurons by blocking the cell body α₂-adrenergic autoreceptors on NE neurons, whether it was given alone or with a serotonin (5-HT) reuptake inhibitor. The 14-day regimen of hQuet enhanced the tonic activation of postsynaptic α₂- but not α₁-adrenergic receptors in the hippocampus. This increase in NE transmission was attributable to increased firing of NE neurons, the inhibition of NE reuptake by NQuet, and the attenuated function of terminal α₂-adrenergic receptors on NE terminals. Sustained administration of hQuet for 2 and 14 days, respectively, significantly inhibited the firing rate of 5-HT, whether it was given alone or with a 5-HT reuptake inhibitor, because of the blockade of excitatory α₁-adrenergic receptors on 5-HT neurons. Nevertheless, the 14-day regimen of hQuet enhanced the tonic activation of postsynaptic 5-HT_1A receptors in the hippocampus. This increase in 5-HT transmission was attributable to the attenuated inhibitory function of the α₂-adrenergic receptors on 5-HT terminals and possibly to direct 5-HT_1A receptor agonism by NQuet. The enhancement of NE and 5-HT transmission by hQuet may contribute to its antidepressant action in mood disorders.     

Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain

• 1.1. We studied the effects of tandospirone, a novel serotonin (5-HT)_1A receptor-related anxiolytic, on the intracellular second messenger systems and neurotransmitter release.
• 2.2. Tandospirone inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes by activation of 5-HT_1A receptors and had high efficacy comparable to 5-HT_1A receptor agonists such as 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
• 3.3. Tandospirone suppressed carbachol-stimulated phosphatidyl-inositol metabolism (PI response), which was shown to be a 5-HT_1A receptor-mediated event.
• 4.4. Tandospirone did not affect the release of 5-HT, norepinephrine (NE), dopamine (DA) and acetylcholine (ACh) from rat brain slice preparations.
• 5.5. These findings suggested that tandospirone shows high agonistic efficacy on the postsynaptic 5-HT_1A receptors but does not affect the presynaptic autoreceptors located on nerve endings. The modulation of the second messenger system via postsynaptic 5-HT_1A receptors might be involved in the anxiolytic efficacy of tandospirone.

     

Does brain 5-HIAA indicate serotonin release or monoamine oxidase activity?

The question of whether serotonin is deaminated by MAO before it can be released or after release has occurred was investigated by studying the 5-HT behavioral syndrome in acutely reserpinized rats. The release of serotonin from vesicles by reserpine does not produce the serotonin behavioral syndrome which is an in vivo index of serotonin release and receptor activation. However, if rats are first pretreated with a nonselective monoamine oxidase inhibitor (e.g., tranylcypromine), the injection of reserpine is followed by symptoms which are characteristic of the behavioral syndrome including forepaw treading, hindlimb abduction and head weaving. Neither selective MAO-A or -B inhibition with clorgyline or deprenyl, respectively, nor inhibition of serotonin reuptake with fluoxetine prior to reserpine produced the serotonin behavioral syndrome. However, the combination of clorgyline and deprenyl followed by reserpine does so. These behavioral data along with neurochemical analyses of serotonin and 5-hydroxyindoleacetic acid levels lead to the conclusion that serotonin does not have to be released before it is metabolized to 5-hydroxyindoleacetic acid. Consequently, the levels of 5-hydroxyindoleacetic acid in brain reflect MAO activity and not serotonin release or utilization.     

Effects of fenfluramine and para-chloroamphetamine on sexual behavior of male rats

The present studies have evaluated the effects of pharmacologically induced release serotonin on sexual responses of male rats during exposure to a sexually receptive female rat. Following acute administration of fenfluramine or para-chloroamphetamine (PCA), significant dose-related decreases in copulatory rate and copulatory efficiency, and increases in ejaculatory latency were observed. These effects were not observed when the animals were pretreated with LY53857, a 5-HT_1c/2 antagonist. These studies indicate that acute release of serotonin evoked by these releasing agents has inhibitory effects on sexual sexual drive, capacity to achieve erection and threshold for ejaculation, and these effects are mediated by either the 5-HT_1c or 5-HT₂ receptor.     

Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure

The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT₁ to 5-HT₇), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.     

Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.     

Potentiation of excitatory serotonergic responses by MK-801 in the medial prefrontal cortex

New atypical antipsychotics show a greater affinity to serotonergic rather than to dopamine receptors, suggesting that serotonin (5-HT) has a major role in the pathophysiology and treatment of schizophrenia. The goal of this study was to characterise the response of pyramidal neurons in the medial prefrontal cortex (mPFC) to 5-HT and NMDA before and after administration of the NMDA receptor antagonist, MK-801 (dizocilpine), a well-validated pharmacological model of psychosis. mPFC pyramidal (glutamatergic) neurons were recorded in urethane-anaesthetised rats. The responses to NMDA and 5-HT were assessed using in vivo electrophysiology and microiontophoresis. The 5-HT_2A/2C antagonist ritanserin and the 5-HT_1A antagonist WAY100635 were used to block 5-HT responses. MK-801 decreased the NMDA-induced excitatory responses and increased NMDA-evoked burst activity among mPFC pyramidal neurons. Three subpopulations of pyramidal cells were identified according to their responses to 5-HT: excitation (33%), inhibition (40%) and non-response (27%). The inhibitory responses were blocked by WAY100635 in 100% of cases, but not by ritanserin; the excitatory responses were blocked by ritanserin in 75% of cases, but not by WAY100635. The administration of MK-801 potentiated the firing rate of excitatory responses but did not modify the inhibitory responses induced by microiontophoretic application of 5-HT. These results suggest that MK-801 modifies 5-HT synapses in the mPFC by potentiating the excitatory 5-HT_2A/2C responses and attenuating NMDA excitations. These data indicate that 5-HT excitatory transmission is selectively impaired at the mPFC level in this pharmacological model of schizophrenia.     

Myo-inositol attenuates the enhancement of the serotonin syndrome by lithium

Lithium elicits opposite effects on two behavioural syndromes in rats: enhancement of the 5-HT_1A-linked serotonin syndrome and attenuation of the 5-HT₂-linked wet dog shakes. The ability of intracerebroventricular (ICV)myo-inositol or forskolin to reverse the enhancement of the serotonin syndrome by lithium was tested in rats that were fed chronic dietary lithium or control diet and injected with the serotonin agonist 5-MeODMT (5-methoxy-N, N-dimethyltryptamine). Lithium enhanced the total serotonin syndrome score and particularly flat posture and tremor. Inositol, but not forskolin, mitigated the effects of lithium. Inositol was also injected in the lateral ventricle of rats pretreated with chronic dietary lithium or regular rat chow for 3 weeks and injected with carbidopa andl-5-hydroxytryptophan (5-HTP). Lithium attenuated wet dog shakes, but inositol had no significant effect on lithium-treated or control rats. These findings suggest that the enhancement of the serotonin syndrome by lithium may be related to lithium-induced inositol depletion.     

Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT_1A, 5-HT_1B, α₂-adrenoceptors) and postsynaptic receptors (e.g., 5-HT₃). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT_1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT_1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT₃ receptors located in cortical and hippocampal GABA interneurons. 5-HT₃ receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.     

Serotonin and serotonin 1-A receptors in the failure of ethanol-treated rats to adapt to a repeated stress schedule

OBJECTIVE: The effects of repeated-restraint stress on brain 5-hydroxytryptamine; serotonin (5-HT) metabolism and functional responses to a selective 5-HT-1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), are compared in water- and ethanol-treated rats. METHOD: Locally bred male water- or ethanol-treated rats restrained 2 hours per day for 6 days were killed, and whole brains were collected for the neurochemical analysis by high performance liquid chromatography with electrochemical detection (HPLC-EC). In a separate experiment 8-OH-DPAT was injected in water- and ethanol-treated rats to compare elicited hyperactivity syndrome (a postsynaptic response) and effectiveness of the drug in reducing brain 5-HT synthesis (a presynaptic response). RESULTS: A single episode of 2-hour restraint stress decreased 24-hour cumulative food intake in both water- and ethanol-treated rats. Following repeated restraint stress of 2 hours per day for 5 days, the decreases were present in ethanol- but not water-treated rats. The sixth episode of 2-hour restraint stress did not alter brain tryptophan 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in water-treated repeatedly restrained rats but decreased tryptophan and increased 5-HT concentration in ethanol-treated rats. Ethanol-treated unrestrained and ethanol-treated repeatedly restrained rats exhibited higher levels of tryptophan 5-HT and 5-HIAA than their respective water-treated controls. Injecting 8-OH-DPAT at a dose of 0.25 mg/kg elicited comparable hyperactivity syndrome in water- and ethanol-treated rats but decreased 5-HT synthesis more in ethanol-treated than in water-treated rats. CONCLUSIONS: The present study shows that ethanol administration for 2 to 3 weeks, although it increases brain 5-HT metabolism, impairs adaptation by increasing the effectiveness of negative feedback control over 5-HT synthesis.     

Chronic treatment with meta-chlorophenylpiperazine (m-CPP) alters behavioral and cerebral metabolic responses to the serotonin agonists m-CPP and quipazine but not 8-hydroxy-2(di-N-propylamino)tetralin

The effects of the serotonin (5-HT) agonists meta-chlorophenylpiperazine (m-CPP), quipazine and 8-hydroxy-2(di-n-propylamino)tetralin (DPAT) on behavior and on regional cerebral metabolic rates for glucose (rCMRglc) were measured in control rats or in rats pretreated for 2 weeks with continuous infusion of saline or m-CPP (2.5 mg/kg/day, subcutaneously). rCMRglc was measured in 71 brain regions, using the quantitative autoradiographic [¹⁴C]2-deoxy-D-glucose technique, at 15 min after acute administration of m-CPP 2.5 mg/kg, 60 min after quipazine 20 mg/kg, or 10 min after DPAT 1 mg/kg. Behavioral effects were assessed for m-CPP with an activity monitor, for quipazine by counting head shakes and for DPAT by scoring the serotonin syndrome. Chronic m-CPP pretreatment produced tolerance to hypolocomotion induced by acute m-CPP and to head shakes caused by acute quipazine, but did not alter the serotonin syndrome produced by DPAT. m-CPP 2.5 mg/kg IP produced widespread rCMRglc reductions in control rats but failed to modify rCMRglc in any region after chronic m-CPP pretreatment. Quipazine increased rCMRglc in 4 regions in control rats, but reduced rCMRglc in 14 brain areas of chronically m-CPP-pretreated animals. DPAT altered rCMRglc to the same degree in control (25 regions affected) and in chronically m-CPP-pretreated rats (28 regions affected). Reduced behavioral and metabolic effects of acute m-CPP in chronically m-CPP-pretreated rats were not due to pharmacokinetic alterations. These results demonstrate that chronic administration of m-CPP produces behavioral and metabolic tolerance to acute administration of m-CPP, but not of DPAT. They suggest that hypolocomotion and the serotonin syndrome are mediated by different 5-HT receptor subtypes, and that chronic m-CPP administration produces functional down-regulation of 5-HT_1B/1C but not of 5-HT_1A-coupled mechanisms.     

5-HT1A receptor agonists: recent developments and controversial issues

During the last decade, serotonin (5-HT)_1A receptors have been a major target for neurobiological research and drug development. 5-HT_1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT_1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT_1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT_1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT_1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT_1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on theagonistic activity of these compounds, theoptimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre-and postsynaptic 5-HT_1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT_1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT_1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies. These studies have shown that a number of electrophysiological, biochemical, behavioral and endocrinological 5-HT_1A receptor-related events adapt differentially to repeated or sustained administration. Thus, several hypotheses accounting for the delayed onset of action have been advanced. Among these, time-dependent downregulation /desensitization of eitherpre- orpostsynaptic 5-HT_1A receptors, or cortical 5-HT₂ receptors have received much attention. However, these hypotheses have their weaknesses, and it is argued thatfunctional sensitization of particular postsynaptic 5-HT_1A receptor-mediated events remains a valuable alternate hypothesis. Basic research on the role of 5-HT_1A receptors in psychopathology and in the therapeutic effects of clinically effective therapeutics, as well as on the mechanism of action of 5-HT_1A receptor ligands, will enable rational design of ligands with particular profiles of intrinsic activity at different 5-HT_1A receptor populations, and may contribute to a more efficient treatment of a multiplicity of brain disorders.