Central Serotonergic Neurotransmission Research Articles

Auditory Evoked Potentials Reflect Serotonergic Neuronal Activity—A Study in Behaving Cats Administered Drugs Acting on 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus

A valid indicator of central serotonergic neurotransmission would be useful for various diagnostic and psychopharmacological purposes in psychiatry. However, known peripheral serotonergic measures only partially reflect serotonergic function in the brain. Previous findings suggest that the intensity dependence of auditory evoked potentials (AEPs) is closely related to central serotonergic activity. The present study examines the effects of microinjection of a 5-HT1A agonist (8-OH-DPAT) and a 5-HT1A antagonist (spiperone) into the dorsal raphe nucleus (DRN) on AEP recorded epidurally from the primary and secondary auditory cortex in behaving cats. We found a stronger intensity dependence only of AEP from the primary auditory cortex after 8-OH-DPAT, which inhibits the firing rate of serotonergic DRN neurons, and a weaker intensity dependence after spiperone, which increases serotonergic cell firing, as compared to baseline measurements. These results demonstrate that the intensity dependence of AEP is inversely related to serotonergic neuronal activity and that it may be a promising tool for assessing central serotonergic function in humans (e.g., identifying patients with low serotonergic neurotransmission).

Drug-induced headache--pathomechanisms of addiction

The pathogenesis of drug abuse in patients suffering from drug-induced headache is not known in detail. It is unclear whether drug abuse in chronic daily headache should be classified as a form of drug dependence. Current findings concerning the neurobiological correlates of addictive behavior and affective disorders point to the importance of monoaminergic dysregulation, especially a dysfunction of central serotonergic neurotransmission. We reviewed the literature on drug-induced headache and examined hypothetical pathomechanisms of addiction. Drugs causing drug-induced headache such as paracetamol, coffein and ergotamine interfere with behavior patterns or neurotransmitter systems that are also affected by drugs of abuse. Several drugs that ameliorate acute headache interact with central serotonergic neurotransmission and may affect anxiety and depression in patients with chronic daily headache. Non human primate and human studies revealed mechanisms of serotonergic dysfunction in drug dependence, which may also be relevant for drug-abuse in medication-induced headache. Medication-induced dysfunction of monoaminergic, especially serotonergic neurotransmission, may affect drug dependence by exacerbating mood disorders. Further studies are necessary to assess serotonergic neurotransmission in patients with drug-induced headache and abuse of medication.

455 Auditory evoked dipole source activity and low central serotonergic neurotransmission in patients with borderline personality disorder

455 Auditory evoked dipole source activity and low central serotonergic neurotransmission in patients with borderline personality disorder

213 Attentional modulation of auditory event-related potentials — study of intracortical mechanisms in cat

Due to the increasing importance of the central serotonergic neurotransmission for pathogenetic concepts and as a target of pharmacotherapeutic interventions in psychiatry, reliable indicators of this system are needed Several findings from basic and clinical research suggest that the stimulus intensity dependence of auditory evoked potentials (AEP) may be such an indicator of behaviorally relevant aspects of serotonergic activity (Hegerl and Juckel 1993, Biol Psychiatry 33:173–187.). In order to study this relationship more directly, epidural recordings over the primary and secondary auditory cortex were conducted in chronically implanted cats under intravenous (i.v.) administration of drugs influencing the serotonergic and other modulatory systems (8-OH-DPAT, m-CPP, ketanserin, DOI, apomorphine, atropine, clonidine). The intensity dependence of the cat AEP component with the highest functional similarity to this of the N1/P2-component in humans was significantly changed by influencing 5-HT1a and 5-HT2 receptors, but not 5-HT1c receptors. This serotonergic modulation of the intensity dependence was only found for the primary auditory cortex which corresponds to the known different innervation of the primary and secondary auditory cortex by serotonergic fibers. Our study supports the idea that the intensity dependence of AEP could be a valuable indicator of brain serotonergic activity; however, this indicator seems to be of relative specificity because at least cholinergic effects on the intensity dependence were also observed.

Modulation of central serotonergic neurotransmission by risperidone: Underlying mechanism(s) and significance of action

1. 1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. 4. Systemic administration of risperidone (200 μg/kg i.v.) or the selective α 1 adrenoceptor antagonist prazosin (400 μg/kg i.v.) decreased, whereas selective α 2 adrenoceptor antagonist idazoxan (20 μg/kg i.v.) increased the 5-HT cell firing in the DRN. 5. 5. Pretreatment with the selective 5-HT 1A receptor antagonist WAY 100,635 (5.0 μg/kg i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA ( p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its α 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT 1A autoreceptor activation and, in turn, to inhibition of cell firing.

High ethanol tolerance in young adults is associated with the low-activity variant of the promoter of the human serotonin transporter gene

Central serotonergic neurotransmission has been implicated in the aetiology of ethanol tolerance and dependence. Cellular expression of the serotonin transporter and serotonin reuptake is modulated via a polymorphic, repetitive element in the 5′-flanking regulatory region of the serotonin transporter gene (5-HTTLPR). We report the association of the low-activity, short variant of the 5-HTTLPR with high ethanol tolerance among young adults in a case-control association study ( n=713). The low-activity 5-HTTLPR showed a significantly increased allele frequency ( χ 2=7.30; df=2; P=0.007) and genotype frequency among young adults (≤26 years) with high ethanol tolerance homozygous for the short allele ( χ 2=7.58; df=1; P=0.02). The estimated odds ratio for the homozygous short variant compared to the homozygous long variant was 2.82 (95% CI 1.30–6.11). This indicates that the low-activity 5-HTTLPR may be involved in the neuronal mechanisms responsible for ethanol tolerance and dependence.

The serotonin syndrome scale: first results on validity

As a modification of the diagnostic criteria of the serotonin syndrome proposed by Sternbach, we developed the Serotonin syndrome scale for the operationalized assessment of both the presence and the severity of the core symptoms of the serotonin syndrome. In a first study on the validity of this scale, the relationships between the serotonin syndrome score (SSS) and both the paroxetine plasma levels (n = 42) and the loudness dependence of the auditory evoked potentials (LDAEP; n = 24) were investigated in depressed patients treated with paroxetine. A strong LDAEP is supposed to indicate low central serotonergic neurotransmission, and vice versa. The SSS was positively related to paroxetine plasma levels and negatively to the LDAEP. Both results support the validity of the serotonin syndrome scale. Using a SSS > 6 as diagnostic criterion, mild serotonin syndromes were diagnosed in 5 of our 42 patients. The Serotonin syndrome scale may become a useful tool for clinicians and scientists dealing with the serotonin syndrome.

Regional brain serotonin receptor changes in portacaval shunted rats.

The pathogenesis of hepatic encephalopathy is unknown, but metabolic perturbations, including hyperammonaemia and increased brain turnover of serotonin (5-HT), have been identified. Possible alterations of 5-HT receptors in the brain have been rudimentarily studied. We therefore investigated the 5-HT1A, 5-HT1B and 5-HT2A receptor density in 18-22 different regions in the brain of portacaval shunted rats by means of radioligand binding with autoradiographical evaluation. The results revealed a decreased 5-HT1A receptor binding in seven serotonergic projection areas of the brain, and an increase in the nucleus accumbens, hypothalamus and subiculum. No changes in the raphe nuclei were observed. An increased 5-HT1B receptor binding was seen in five brain regions: basal ganglia, olfactorial regions, hippocampus, mid brain and thalamus. However, decreased binding was seen in three regions of cortical areas and hippocampus. The 5-HT2A receptor binding site density was essentially unaltered. These findings suggest that perturbations in the central serotonergic neurotransmission may play a functional role in chronic hepatic encephalopathy.

Effects of subchronic treatment with valproate on l-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission

The mechanisms underlying the acute and prophylactic antimanic properties of valproate have remained elusive. There are some reports that treatment with valproic acid may increase brain serotonergic neurotransmission in the rodent. This study was carried out in order to investigate the effects of subchronic therapy with valproate on central serotonin metabolism in manic patients. Toward this end, the authors examined plasma cortisol responses to 200 mg (orally) l-5-hydroxy- tryptophan ( l-5-HTP) in 10 manic patients both before and after subchronic treatment with valproate. Administration of l-5-HTP resulted in significantly increased cortisol responses both before and after treatment with valproate. The l-5-HTP-induced cortisol responses were significantly higher after treatment with valproate than before treatment. It is suggested that valproate may increase central serotonergic neurotransmission and that this stimulation may play a role in the antimanic effects of valproate. © 1997 Elsevier Science Ireland Ltd.

99-2 - The serotonin syndrome scale: First results on validity

As a modification of the diagnostic criteria of the serotonin syndrome proposed by Sternbach, we developed the Serotonin syndrome scale for the operationalized assessment of both the presence and the severity of the core symptoms of the serotonin syndrome. In a first study on the validity of this scale, the relationships between the serotonin syndrome score (SSS) and both the paroxetine plasma levels (n = 42) and the loudness dependence of the auditory evoked potentials (LDAEP; n = 24) were investigated in depressed patients treated with paroxetine. A strong LDAEP is supposed to indicate low central serotonergic neurotransmission, and vice versa. The SSS was positively related to paroxetine plasma levels and negatively to the LDAEP. Both results support the validity of the serotonin syndrome scale. Using a SSS > 6 as diagnostic criterion, mild serotonin syndromes were diagnosed in 5 of our 42 patients. The Serotonin syndrome scale may become a useful tool for clinicians and scientists dealing with the serotonin syndrome.

Auditory-evoked potentials as indicator of brain serotonergic activity first evidence in behaving cats

Due to the increasing importance of the central serotonergic neurotransmission for pathogenetic concepts and as a target of pharmacotherapeutic interventions in psychiatry, reliable indicators of this system are needed. Several findings from basic and clinical research suggest that the stimulus intensity dependence of auditory evoked potentials (AEP) may be such an indicator of behaviorally relevant aspects of serotonergic activity (Hegerl and Juckel 1993, Biol Psychiatry 33:173-187). In order to study this relationship more directly, epidural recordings over the primary and secondary auditory cortex were conducted in chronically implanted cats under intravenous (i.v.) administration of drugs influencing the serotonergic and other modulatory systems (8-OH-DPAT, m-CPP, ketanserin, DOI, apomorphine, atropine, clonidine). The intensity dependence of the cat AEP component with the highest functional similarity to this of the N1/P2-component in humans was significantly changed by influencing 5-HT1a and 5-HT2 receptors, but not 5-HT1c receptors. This serotonergic modulation of the intensity dependence was only found for the primary auditory cortex which corresponds to the known different innervation of the primary and secondary auditory cortex by serotonergic fibers. Our study supports the idea that the intensity dependence of AEP could be a valuable indicator of brain serotonergic activity; however, this indicator seems to be of relative specificity because at least cholinergic effects on the intensity dependence were also observed.

Biphasic effects of 8-OH-DPAT on endurance of treadmill performance in the male rat

Administration of the 5-HT 1A receptor agonist 8-OH-DPAT produced a biphasic pattern of effects on endurance performance of rats walking on top of a treadmill drum (Ø=166 mm, 16 rpm; ≈8 m min −1), with enhanced performance at a low dose (0.1 mg kg −1 s.c.) followed by impairment (0.2–0.8 mg kg −1). The partial 5-HT 1A receptor agonist (−)-pindolol improved the performance in the low dose range (0.5–2.0 mg kg −1 s.c.), whereas a higher dose (8 mg kg −1) was ineffective. The 5-HT 1A receptor antagonist WAY-100,635 produced an impaired performance at a low dose (12.5 μg kg −1 s.c.), with a recovery of performance at higher doses (50–200 μg kg −1). It is suggested that the inhibition of central serotonergic neurotransmission produced by stimulation or blockade of 5-HT 1A auto- and post-synaptic receptors, respectively, results in an improved endurance performance on the treadmill, whereas stimulation of postsynaptic 5-HT 1A receptors has the opposite action. In support of this contention, the impaired performance produced by a high dose of 8-OH-DPAT (0.8 mg kg −1) was antagonized by pretreatment with (−)-pindolol (2 mg kg −1 s.c.).

ERP and neurotransmitters

The increasing knowledge concerning anatomical structures and cellular processes underlying event‐related potentials (ERP) and methodological advances in ERP data analysis (e.g. dipole source analysis) begins to bridge the gap between ERP and neurochemical aspects. Several recent reports are summarized suggesting that quite specific relationships may exist between certain ERP‐parameters and central cholinergic, noradrenergic and especially serotonergic function. Reliable indicators of the serotonin system are urgently needed because of its role in pathogenetic concepts and as target of pharmacotherapeutic interventions in psychiatric and neurologic disorders. Converging arguments from preclinical and clinical studies are presented supporting the hypothesis that the dependence of the auditory evoked N1/P2‐response on stimulus intensity (loudness) is regulated by the level of central serotonergic neurotransmission. Dipole source analysis represents an important methodological advance in this context, because N1/P2‐subcomponents, generated by different cortical structures with different serotonergic innervations, can be separated. A pronounced intensity dependence of the evoked activity of primary auditory cortices is supposed to indicate a low central serotonergic neurotransmission and vice versa. This intensity dependence is shown to be a parameter with clinical value because subgroups of patients with a serotonergic dysfunction can be identified and can be treated more specifically.

Are impulse-control disorders related to bipolar disorder?

We reviewed available evidence regarding a possible relationship between impulse-control disorders (ICDs) and bipolar disorder. Studies examining the phenomenology, course, comorbidity, family history, biology, and treatment response of ICDs were compared with similar studies of bipolar disorder. Although no studies directly compare a cohort of ICD patients with a cohort of mood disorder patients, available data suggest that ICDs and bipolar disorder share a number of features: (1) phenomenologic similarities, including harmful, dangerous, or pleasurable behaviors, impulsivity, and similar affective symptoms and dysregulation; (2) onset in adolescence or early adulthood and episodic and/or chronic course; (3) high comorbidity with one another and similar comorbidity with other psychiatric disorders; (4) elevated familial rates of mood disorder; (5) possible abnormalities in central serotonergic and noradrenergic neurotransmission; and (6) response to mood stabilizers and antidepressants. However, ICDs and bipolar disorder differ in important respects. In particular, some ICDs may be more closely related to obsessive-compulsive disorder (OCD) than is bipolar disorder. Although the similarities between ICDs and bipolar disorder may be coincidental, they suggest that the two conditions may be related and thus may share at least one common pathophysiologic abnormality. To explain this possible relationship, we hypothesize that impulsivity and bipolarity (or mania) are related, that compulsivity and unipolarity (or depression) are similarly related, and that each state may represent opposing poles of related, or even a single, psychological dimension.

Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine.

Mirtazapine (Org 3770, Remeron) is a new alpha2-adrenoceptor antagonist which is an effective antidepressant drug. An in vivo electrophysiological paradigm in the rat was used to assess the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha2-adrenoceptors and to determine whether this drug can modulate serotonin (5-HT) neurotransmission. The acute administration of mirtazapine produced a rapid increase in both noradrenaline and 5-HT neurotransmission by blocking both alpha2-adrenergic auto- and heteroreceptors, resulting in an enhanced tonic activation of postsynaptic 5-HT receptors. Long-term administration showed that this tonic activation of postsynaptic 5-HT receptors was most likely enhanced after such a treatment, as a result of a sustained increase in 5-HT neuronal activity in the presence of and due to inactivated alpha2-adrenergic heteroreceptors.

Neuroendocrine responses to serotonergic agonists as indices of the functional status of central serotonin neurotransmission in humans: A preliminary comparative analysis of neuroendocrine endpoints versus other endpoint measures

The status of central serotonergic neurotransmission and of specific serotonin (5-HT) receptor subtype sensitivity has been inferred from neuroendocrine and other endpoint responses to serotonergic agents given to humans. The question of whether changes in neuroendocrine responsivity to the 5-HT 2 C partial agonist, meta-chlorophenylpiperazine (m-CPP), are accompanied by similar changes in other endpoints (temperature, behavior) is addressed in this brief review of published studies. These studies were selected based on the following criteria: (1) neuroendocrine (cortisol, prolactin increases) and at least one other endpoint (behavior and/or temperature increases) were measured in the same populations, and (2) statistically significant changes were observed after m-CPP in the healthy volunteer control or pre-long-term-treatment subjects. Parenthetically, in the 13 of 14 studies that reported both prolactin and cortisol responses, the results were congruent for the two neuroendocrine measures in 12 of the 13 (92%). However, neuroendocrine versus behavioral results were in agreement in fewer (7 of the 13) studies (54%). Neuroendocrine vs. temperature results were non-concordant in all 4 of the studies which included temperature measurements. These generally disparate findings suggest that these different endpoints may reflect brain serotonin neuroanatomic and receptor subsystem complexity and/or m-CPP's complex pharmacological properties. Thus, these neuroendocrine response measures cannot at this time be considered a general index of the other response measures, nor necessarily an index of the functional status of central serotonergic neurotransmission until this is established by more direct experimental investigations.

The neuroendocrine challenge paradigm in headache research.

The neuroendocrine challenge paradigm provides a "window" on central neurotransmitter function in vivo. This strategy is based on the premise that the sensitivity of certain central receptors can be inferred from the magnitude of the hormonal response to specific pharmacologic probes. For example, the serotonin (5HT) receptor agonist m-chlorophenylpiperazine (m-CPP) stimulates the release of cortisol and prolactin and induces migraine-like headaches. We have previously reported that the headache and cortisol responses to m-CPP are highly correlated, which may implicate a disturbance in central serotonergic neurotransmission in the pathogenesis of migraine. As pharmacologic probes with greater specificity for 5HT receptor subtypes become available, we may be able to elucidate these mechanisms with greater precision. The neuroendocrine challenge methodology is also applicable to the study of other neurotransmitter systems and other headache disorders.

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT1A receptor antagonists, [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl-propionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)-WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.). We have also studied the effects of (S)-UH-301 (0.03-0.50 mg/kg i.v.) on the firing rate of single DRN-5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. x 14 days). Administration of (S)-UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 ml/kg/day i.p. x 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

The tridimensional personality questionnaire and the intensity dependence of auditory evoked dipole source activity

The relationship between the tridimensional personality questionnaire's (TPQ) dimensions "novelty seeking," "harm avoidance," and "reward dependence" and the intensity dependence of the auditory evoked N1/P2-component was investigated in healthy subjects. Using dipole source analysis, evoked activity of the primary auditory cortex (tangential dipole) could be analyzed at least in part separately from that of secondary auditory areas (radial dipole). It was found that the intensity dependence of the tangential dipole was positively correlated to the TPQ dimension "novelty seeking," but not to "harm avoidance" and "reward dependence." This is in line with findings concerning similar personality traits like "sensation seeking," "impulsivity," or "extraversion." It is therefore concluded that a strong intensity dependence may characterize subjects with an action-oriented and extroverted personality style. The results are discussed within the concept that a low central serotonergic neurotransmission is underlying both an impulsive personality type and a strong intensity dependence of the tangential dipole.

Antisocial Tendencies and Cortical Sensory‐Evoked Responses in Alcoholism

Alcohol-dependent patients with antisocial, aggressive, and impulsive behaviors form a subgroup, in which a dysfunction of the brain serotonin system is discussed as a pathogenetic factor. Early onset and a transmission from fathers to sons (type II alcoholism; Cloninger, 1987) are supposedly further characteristics of this subgroup. The response pattern of primary auditory cortices to auditory stimuli with different intensities is discussed as a noninvasive indicator of the level of central serotonergic neurotransmission. A strong intensity dependence of these responses is supposed to indicate low serotonergic neurotransmission and vice versa. A strong intensity dependence is therefore expected to characterize patients with antisocial tendencies. Auditory-evoked potentials (N1/P2 component) to stimuli in five different intensities were recorded in 53 hospitalized patients after 1 week of withdrawal. Dipole source analysis was performed to separate responses of primary and secondary auditory cortices. Patients with antisocial tendencies showed a significantly stronger intensity dependence of their evoked responses of primary auditory cortices (tangential dipoles). Age at onset and family history were not related to the intensity dependence of the evoked responses. The results support the notion that alcohol-dependent patients with strong intensity dependence and antisocial tendencies form a subgroup with a serotonergic hypofunction. These patients may respond favorably to a relapse prevention with serotonergic drugs.