Hemmie H.G. Berendsen

The role of serotonin in hot flushes.

Hot flushes are experienced in those periods of the female life when estrogen levels are low. Hormone replacement therapy is thus the first choice for treatment of hot flushes. However this treatment is not always accepted or contraindicated for a variety of reasons. Estrogen (and progestogen) strongly interact with a number of neurotransmitters and this has led to a range of non-hormonal treatments including compounds that act via the noradrenergic or dopaminergic systems as well as herbal remedies. These treatments (which are shortly reviewed) are not always successful. Surprisingly, apart from treatment with some selective serotonin (5-HT) reuptake inhibitors (SSRIs), up till now, little attention is given to the strong interaction of estrogens with the serotonergic system. These interactions are shortly reviewed. Based on these interactions, a hypothesis on the genesis of hot flushes is postulated. Especially the 5-HT(2A) receptor subtype may play a key role in the occurrence of hot flushes. A number of arguments that support this hypothesis are discussed.

The yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity

The efficacy of several drugs to elicit yawning and penile erections were determined in rats. The dopamine agonists, N-propylnorapomorphine, apomorphine, pergolide, (+/-)-3-PPP, TL-99 and N,N-dipropylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (N,N-dipropyl A-5,6-DTN) all elicited yawning accompanied by an increase in spontaneous penile erections. The potencies of these drugs in causing yawning closely resemble published data concerning their actions in biochemical tests reputedly indicative of autoreceptor activity. In contrast, SK&F 38393, A-5,6-DTN and clonidine produced no yawning and few or no penile erections. Although physostigmine also caused yawning, the effect was not accompanied by penile erections. Studies with the optical isomers of 3-PPP showed that (+)-3-PPP was considerably more potent than (-)-3-PPP. Haloperidol antagonised dopamine agonist-induced yawning and penile erections. Apomorphine-induced yawning and penile erections were also antagonised by sulpiride and atropine but not by domperidone. The suitability of elicitation of the combined syndrome of yawning plus penile erections as useful behavioural model for dopamine autoreceptor agonists is discussed.

Involvement of 5-HT1C-receptors in drug-induced penile erections in rats

Drug-induced penile erections (PE) were initially suggested to be 5-HT1B receptor mediated. However, since the discovery of the 5-HT1C receptor a number of compounds, considered to be 5-HT1B selective, appear to bind more strongly to the 5-HT1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22–2.2 mg/kg), TFMPP (0.46–1.0 mg/kg) and MK 212 (0.1–1.0 mg/kg). The 5-HT agonist DOI (0.022–0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT2 antagonists it did. These compounds have in common a strong affinity for the 5-HT1C receptor. mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED50s were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT1C receptor versus the 5-HT2 receptor. Spiperone (0.1–1.0 mg/kg) and GR 38032F (1–10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED50s were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0–10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT1C receptor and are functionally inhibited by activation of 5-HT1A or 5-HT2 receptors.

Behavioural evidence for functional interactions between 5‐HT‐receptor subtypes in rats and mice

1 Different 5‐hydroxytryptamine (5‐HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5‐HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5‐HT receptor subtypes was studied. 2 Hypothermia and hypoactivity in mice induced by the 5‐HT1A‐agonist 8‐hydroxy‐dipropylaminotetralin (8‐OH‐DPAT) could be attenuated by the preferential 5‐HT1C‐agonists MK 212, 1‐(meta‐chlorophenyl)‐piperazine (mCPP) and m‐trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5‐HT2/1C‐agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI). The mixed 5‐HT1A/1B‐agonist CGS 12066B at 10 mg kg−1 potentiated hypothermia and had no effect on hypoactivity. 3 Forepaw treading in rats induced by the 5‐HT1A‐agonist 8‐OH‐DPAT was attenuated by the 5‐HT1C‐agonists MK 212 and mCPP. The 5‐HT1C‐agonist TFMPP had a bimodal effect: at low doses (> 1 mg kg−1) it potentiated, and at higher doses (> 2.2 mg kg−1) it attenuated forepaw treading. the mixed 5‐HT2/1C‐agonist DOI produced 5‐HT2‐related behaviours and potentiated 8‐OH‐DPAT‐induced forepaw treading. This indicates an attenuating effect of 5‐HT1C‐receptor activation and a potentiating effect of 5‐HT2‐receptor activation. CGS 12066B had no effect in this respect. 4 Head shakes in rats induced by DOI could be attenuated by 8‐OH‐DPAT, TFMPP, mCPP and MK 212. The ID50s were 0.03, 0.7, 0.1 and 2 mg kg−1, respectively. This suggests that a 5‐HT2‐receptor‐mediated effect may be attenuated by activation of 5‐HT1A‐ or 5‐HT1C‐receptors. CGS 12066B attenuated the head shake response but only at 10 mg kg−1. 5 The results suggest that interactions exist between the different 5‐HT receptor subtype‐mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5‐HT‐receptor subtype.

ANTIAVERSIVE EFFECTS OF 5HT2C RECEPTOR AGONISTS AND FLUOXETINE IN A MODEL OF PANIC-LIKE ANXIETY IN RATS

Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of 5HT2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activation by fluoxetine. Potency and efficacy of 5HT2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these 5HT2C receptor agonists. In addition, these data suggest that the 5HT2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the 5HT2C receptor subtypes and that the anxiogenic action reported under certain circumstances for 5HT mimetics are not mediated by 5HT2C receptor subtypes.

Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats

5-hydroxytryptamine (5HT)-depleted rats were subjected to behavioral experiments in which the response to activation of 5HT1A, 5HT1c, and 5HT2 receptor subtypes was measured. Depletion of 5HT was produced by unilateral intracerebroventricular injection of 5,7-dihydroxytryptamine (100 micrograms/rat) or by systemic injection of p-chlorophenylalanine (150 mg/kg injected intraperitoneally 72, 48, and 24 h before the test). The dose-response curve of the 5HT1A-mediated, 8-hydroxy-2-(di-n-propylamino)tetralin (0.022-0.46 mg/kg)-induced lower lip retraction was not changed after depletion, nor was the dose-response curve of the 5HT2 receptor-mediated (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.046-1.0 mg/kg)-induced head shake response. The dose-response curve for penile erections, a 5HT1c receptor-mediated response after mCPP (0.1-1.0 mg/kg), a direct 5HT1c agonist, is shifted to the left after 5HT depletion, whereas the response to indirect activation of the 5HT1c receptor with the 5HT reuptake inhibitors citalopram (2.2-4.6 mg/kg) and paroxetine (0.22-2.2 mg/kg) was inhibited after 5HT depletion. These results suggest that 5HT1c receptors are more subject to denervation supersensitivity than 5HT1A and 5HT2 receptors. This lesion model may be useful to discriminate behaviorally between direct and indirect activation of the 5HT1c receptor.

Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine

SummaryThe influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s. c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.

Treatment of hot flushes with mirtazapine: four case reports

OBJECTIVE To evaluate the effect of mirtazapine on the severity of hot flushes and bouts of perspiration in women. METHOD In two women with depression a reduction in hot flushes was noticed by serendipity during treatment with mirtazapine 15-30 mg/daily. On the basis of this observation clinical studies were extended with two non-depressed and non-anxious women with hot flushes. Both subjects were prescribed mirtazapine daily. RESULTS Four cases are described as case reports. All subjects reported a practically complete disappearance of hot flushes and associated perspiration, within the first week of treatment. CONCLUSION Mirtazapine appears to have a substantial ameliorating effect on hot flushes and perspiration bouts. It is postulated that the 5-HT(2A) blocking properties of mirtazapine is accounted in the symptomatic relief of hot flushes. In addition it is hypothesized that the serotonergic system is crucially involved in the pathogenesis of hot flushes and perspiration bouts. Further evaluation in double-blind placebo-controlled studies is encouraged.

Opiate-androgen interactions in drug-induced yawning and penile erections in the rat

The effects of pretreatment with drugs on drug-induced yawning and penile erection in intact and chronically castrated rats were investigated. Naloxone partially blocked yawning in intact rats and in castrated rats pretreated with dihydro-testosterone propionate (DHTP) but not in control castrates. In contrast, naloxone potentiated apomorphine-induced penile erections in intact rats. Morphine, haloperidol and atropine blocked yawning and penile erections. Methyl naloxone, methyl atropine and domperidone at doses which are selectively peripheral-acting had no effect on drug-induced yawning or penile erection indicating that both effects are mediated centrally. Pretreatment with morphine did not change the naloxone effects in intact rats. The results indicate a naloxone-androgen interaction in drug-induced yawning but the results with morphine are not consistent with a role of opiates in this interaction. The penile erection data support a direct opiate-dopamine receptor interaction in this response. The haloperidol and atropine effects support a cholinergic-dopaminergic interaction in both yawning and penile erections.

Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure

Pre-exposure to 5-hydroxytryptamine (5-HT) receptor agonists in conditioned taste aversion experiments was used to characterize the stimulus properties of fluoxetine. The taste aversion induced by fluoxetine (10 mg/kg) was completely prevented when mice were pre-exposed to fluoxetine or when they were pre-exposed to the preferential 5-HT1C receptor agonist MK 212. Pre-exposure to MK 212 also prevented the conditioned taste aversion induced by another serotonin uptake inhibitor, paroxetine. A partial attenuation of fluoxetine-induced conditioned taste aversion was seen after pre-exposure to a high dose of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1 mg/kg), but not to lower doses. No familiarization for the fluoxetine stimulus was obtained by pre-exposure to treatments with the mixed 5-HT1C/2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). With the reversed sequence, pre-exposure to fluoxetine prevented the conditioned taste aversion induced by MK 212 or 8-OH-DPAT and reduced that induced by DOI. It is concluded that the acute stimulus properties of fluoxetine mostly resemble those of a 5-HT1C receptor agonist. This supports the suggestion that the 5-HT1C receptor can play an important role in the therapeutic effect of 5-HT reuptake inhibitors.