The effects of monoamine oxidase inhibitors on the ejaculatory response induced by 5-methoxy-N,N-dimethyltryptamine in the rat.

The ejaculatory response and other components of the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1, i.p.) were studied following single and repeated treatment of rats with eight different monoamine oxidase (MAO) inhibitors. Single and repeated treatment with the 5-HT agonist 5-MeODMT, and with low doses of the potent releaser of 5-HT, p-chloroamphetamine (PCA) were also included in the study. Repeated but not single treatment with 5-MeODMT reduced strongly but reversibly the ejaculatory response and the behavioural responses. Repeated but not single treatment with the nonselective and irreversible MAO inhibitors nialamide and pargyline reduced markedly the ejaculatory response but only slightly the 5-HT behavioural responses. Repeated treatment with the irreversible MAO-B inhibitor (-)-deprenyl, with the irreversible MAO-A inhibitor, clorgyline, with the reversible MAO-A inhibitor moclobemide, and with low doses of PCA did not affect either of the responses. Repeated but not single combined treatment with clorgyline plus PCA caused an almost complete blockade of all the four responses. The selective and reversible MAO-A inhibitors (as well as 5-HT releasers) amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced markedly the ejaculatory response after both single and repeated treatments. The behavioural responses were blocked only after repeated treatment. It is concluded that single and repeated treatments of rats with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions. Repeated treatment with 5-MeODMT caused a blockade of 75-95% of the ejaculatory response and 5-HT behavioural responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: Comparison with other antidepressant agents,test of selectivity and sub-chronic studies

The dose-dependent effect of acute zimeldine and alaproclate treatment upon the acquisition of two-way and one-way active avoidance in the rat was studied in a single-session and in a repeated-sessions design. Zimeldine (5–20 mg/kg, IP), but not alaproclate, caused disruptions of two-way avoidance acquisition. Acquisition deficits were also caused by citalopram and fluoxetine but not the other antidepressant drugs tested. Zimeldine, but not alaproclate or desipramine, caused a slight but non-significant impairment of one-way active avoidance; neither zimeldine nor alaproclate produced any effects upon fear conditioning and retention testing. The long-term action of p-chloroamphetamine (2×10 mg/kg) antagonised the acute zimeldine effect totally, and chronic treatment with zimeldine (15 days, 1×50 mol/kg) and chlorimipramine (15 days, 2×10 mol/kg) also caused some partial blockade of the two-way avoidance deficit. These data seem to suggest some involvement of serotonin (5-HT) in the observed disruptions of two-way active avoidance caused by acute zimeldine treatment.     

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.     

Attenuation of the post-decapitation convulsions after repeated treatment of rats with desipramine, imipramine and maprotiline

The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post-decapitation convulsions (PDC's) after repeated administration of 10 mumol/kg orally twice daily, or 66 mumol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.     

Ejaculations induced by p-chloroamphetamine in the rat

The ejaculatory response following acute injections of p-chloroamphetamine (PCA) and several other drugs was measured by weighing the compact seminal material accumulated over 2 hr. p-Chloroamphetamine caused a dose-dependent ejaculatory response that was inhibited by the inhibitor of the synthesis of 5-hydroxytryptamine (5-HT), p-chlorophenylalanine (PCPA), neurotoxic doses of PCA, reserpine, DSP 4 a selective noradrenergic neurotoxin given 48 hr before PCA, the inhibitor of synthesis of noradrenaline (NA) FLA 63, the specific inhibitors of uptake of 5-HT, alaproclate, fluoxetine and norzimeldine and the selective inhibitor of the uptake of NA, CPP 199, the E form of norzimeldine. The doses of several receptor antagonists producing a 50% decrease in the weight of seminal material were determined. The non-selective 5-HT receptor antagonists, metitepine and methergoline, the selective alpha 1-adrenoreceptor antagonists, prazosin and phenoxybenzamine and the non-selective alpha-adrenoreceptor antagonist, phentolamine, had strong effects, followed by the selective 5-HT2 antagonists, ketanserin and pirenperone. Yohimbine, an alpha 2-adrenoreceptor antagonist and atropine, a muscarinic receptor antagonist, only produced a partial blockade. The rank order of potency for some dopamine (DA) receptor antagonists was chlorpromazine, domperidone, haloperidol, pimozide. Remoxipride, a selective DA2 receptor antagonist and the selective DA1 antagonist, Sch 23390, had no effect. The following drugs had no effect: propranolol, naloxone, picrotoxin, cimetidine and mepyramine. The 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT 3 mg/kg, i.p.) produced a small effect on the weight of seminal material, although 72% of the rats ejaculated. d-Amphetamine did not induce ejaculation at 5 mg/kg but had a marked effect at 15 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antagonism of 5-methoxy-N,N-dimethyltryptamine-induced changes in postdecapitation convulsions in rats by repeated treatment with drugs enhancing 5-hydroxytryptamine neurotransmission

Repeated administration of drugs that increase tryptaminergic neurotransmission antagonized the increase in latency to onset and the duration of postdecapitation convulsions (PDCs) induced by an acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) injection; Zimelidine (2 X 5 mg kg-1), fluoxetine (2 X 5 mg kg-1), amiflamine (2 X 2.5 mg kg-1) and alpha-ethyltryptamine (2 X 2.5 mg kg-1) administered orally over 10 days caused a substantial blockade of the increase in latency to onset and duration of PDCs following 5-MeODMT, whereas alaproclate (2 X 5 mg kg-1), clorgyline (1 X 1 mg kg-1) and pargyline (2 X 2.5 mg kg-1) caused a lesser blockade. Repeated 5-MeODMT (3 X 2 mg kg-1) administration blocked the acute effects of 5-MeODMT (2 and 4 mg kg-1) upon PDCs completely. These findings indicate down-regulation of the 5-hydroxytryptamine receptors which mediate the action of 5-MeODMT on the PDCs and offer a simple model system for studying 5-HT receptor sensitivity changes at the spinal level.     

Serotonin 5-HT2C receptor-mediated phosphoinositide hydrolysis in rat choroid plexus after fluoxetine and citalopram treatments.

Selective serotonin reuptake inhibitors (SSRIs) bind directly to various neurotransmitter receptors. The clinical effects of SSRIs appear gradually during weeks of treatment, suggesting a role for adaptive changes in neurotransmitter receptors. Most clinically used antidepressants, e.g. fluoxetine, bind to 5-HT2C receptors. When administered chronically, many antidepressants elicit adaptive regulation of 5-HT2C receptors. The present study was conducted in order to determine the effects of acute and chronic fluoxetine and citalopram treatments on the density and function of 5-HT2C receptors in the rat choroid plexus. Acute and chronic treatments followed by phosphoinositide (PI) hydrolysis assays and quantitative receptor autoradiography were performed. Acute (single-dose) treatment with neither drug significantly affected basal or 5-HT-stimulated PI hydrolysis, but acute citalopram (20 mg/kg) treatment increased both agonist and antagonist binding to 5-HT(2C) receptors. Chronic (14 days) citalopram treatment (20 mg/kg) increased the maximal PI hydrolysis response by 40%, but fluoxetine lacked this effect. The present data suggest that sensitisation of 5-HT2C receptor-mediated intracellular signal transduction may play a role in the effects of citalopram. In contrast, fluoxetine treatment does not functionally sensitise 5-HT2C receptors. Thus, functional 5-HT2C receptor sensitisation is not a common effect of antidepressants, but the differential effects may explain some of the pharmacodynamic differences seen with these drugs, especially upon repeated administration.     

Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine

The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function.     

5-Hydroxytryptamine-mediated behaviour in male and female rats

The responses of male and female rats to drugs causing the behavioural syndrome induced by 5-hydroxytryptamine (5-HT) were compared. Preliminary experiments showed that females had largely similar responses to the releaser of 5-HT, p-chloroamphetamine (PCA) and the 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) at different stages of the oestrus cycle. The behavioural responses to 5-MeODMT (with and without the monoamine oxidase inhibitor pargyline) or to p-chloroamphetamine were not significantly different to those of males except for tremor after p-chloroamphetamine which was more marked in the females. However, concentrations of p-chloroamphetamine in brain in these animals, when killed immediately after behavioural recording were greater in the females. When rats, pretreated with the monoamine oxidase inhibitor, pargyline, were given the precursor of 5-HT, tryptophan, the females showed substantially greater hypothermia and larger scores for components of the 5-HT syndrome than the males. This sex difference may have been due to the moderately but significantly higher levels of 5-HT (and possibly tryptamine) in brain attained by the female rats, than by similarly-treated males. The results as a whole therefore suggest that the greater behavioural response of female rats to pargyline and tryptophan reflects a greater effect of this treatment on the synthesis of indoleamines than that occurring in males.     

Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: effect on dopaminergic and serotonergic functions

The effect of prolonged administration of the clinically effective and specific serotonin (5-HT)-uptake-inhibitor, citalopram, has been studied in rats on behavioural measures of dopaminergic (DA) and serotonergic activity and on DA D-2, 5-HT2, alpha 1- and beta-adrenergic receptor number and affinity in vitro. Thirteen days treatment with citalopram in the diet (40 mg/kg/day) did not change receptor binding for either of the ligands studied, although citalopram was detected in high concentrations in brain and plasma and induced a 75% depletion of 5-HT in whole blood. This citalopram dose-regimen was followed by a potentiated hypermotility response to d-amphetamine. Also DA-dependent hypermotility induced by methylphenidate and (+)-3-PPP was increased. In contrast, the 5-HT2-receptor mediated head shake syndrome induced by 1-5-HTP or quipazine was decreased after prolonged citalopram treatment. Two weeks oral bolus treatment (10 mg/kg once or twice daily) with the 5-HT-uptake-inhibitors citalopram, fluoxetine, zimelidine, cyanimipramine or paroxetine induced d-amphetamine potentiation, whereas amitriptyline, nortriptyline, imipramine, iprindole, and mianserin treatment showed no effect. It is suggested that d-amphetamine potentiation induced by citalopram is mainly dependent on DA mechanisms, and that this profile is characteristic for preferential 5-HT-uptake-inhibitors. The lack of correlation between behavioural effect and receptor changes was important. Since citalopram has been shown to have clinical antidepressant activity, it is concluded that down-regulation of beta-adrenoceptors is not a prerequisite for antidepressant action.     

Serotonergic potentiation of muscarinic agonist evoked tremor and salivation in rat and mouse

The dose-effect of oxotremorine upon the onset, duration and magnitude of tremor and salivation was studied in both mice and rats. The threshold doses of oxotremorine (SC) for eliciting tremor were above 50 g/kg in mice and above 150 g/kg in rats and the threshold doses for eliciting salivation were above 75 g/kg in mice and above 200 g/kg in rats. Alaproclate, a nontricyclic 5-HT uptake inhibitor, when injected 30 min prior to the administration of the cholinergic agonist, produced a dose-dependent enhancement of tremor and salivation in both rats and mice. Alaproclate itself did not produce these effects in the absence of a muscarinic cholinergic stimulant such as oxotremorine, arecoline or the acetylcholine esterase inhibitor physostigmine. Both salivation and tremor could be fully blocked by atropine at any dose of the cholinergic stimulant and of alaproclate used. The potentiating effects of alaproclate on salivation and tremor could also be blocked by two serotonin receptor antagonists, metitepine and danitracen, but not by metergoline or cinanserin. Other compounds which inhibit the uptake of 5-HT such as fluoxetine, citalopram, norzimeldine, zimeldine and the non-tricyclic antidepressant, iprindol, did not enhance the cholinergic agonist induced tremor or salivation under the same conditions as did alaproclate. It is suggested that alaproclate exerts the potentiating effect at a hitherto undefined serotonergic receptor site.     

The behavioural response to intrathecal serotonin is changed by acute but not by repeated treatment with zimelidine or metergoline.

The behavioural response to intrathecal serotonin (5-HT) was examined in mice after acute and after withdrawal of repeated treatment with the 5-HT uptake inhibitor zimelidine or the 5-HT receptor antagonist metergoline. Intrathecal 5-HT elicits a response consisting of biting or licking of the lower part of abdomen and reciprocal hindlimb scratching, indicative of nociceptive stimulation. Acute injection of zimelidine (20 mg/kg) significantly increased the response to intrathecal 5-HT (0.25-1 micrograms) whereas a single dose of metergoline (5 mg/kg) completely blocked the response to intrathecal 5-HT (2 micrograms). The behavioural response to intrathecal 5-HT (0.25-2 micrograms) was not significantly changed 48 hr after withdrawal of repeated treatment with zimelidine (2 x 10 mg/kg/day for 14 days) or metergoline (2 x 2.5 mg/kg/day for 14 days). In the present experiments acute zimelidine appeared to increase nociceptive responsiveness, whereas metergoline had the opposite effect. This study does not provide evidence that long-term treatment with zimelidine or metergoline leads to adaptive changes in the response to spinal cord 5-HT receptor stimulation.     

The Behavioural Response to Intrathecal Serotonin is Changed by Acute but not by Repeated Treatment with Zimelidine or Metergoline

Abstract: The behavioural response to intrathecal serotonin (5-HT) was examined in mice after acute and after withdrawal of repeated treatment with the 5-HT uptake inhibitor zimelidine or the 5-HT receptor antagonist metergoline. Intrathecal 5-HT elicits a response consisting of biting or licking of the lower part of abdomen and reciprocal hindlimb scratching, indicative of nociceptive stimulation. Acute injection of zimelidine (20 mg/kg) significantly increased the response to intrathecal 5-HT (0.25-1 μg) whereas a single dose of metergoline (5 mg/kg) completely blocked the response to intrathecal 5-HT (2 μg). The behavioural response to intrathecal 5-HT (0.25-2 μg) was not significantly changed 48 hr after withdrawal of repeated treatment with zimelidine (2 × 10 mg/kg/day for 14 days) or metergoline (2 × 2.5 mg/kg/day for 14 days). In the present experiments acute zimelidine appeared to increase nociceptive responsiveness, whereas metergoline had the opposite effect. This study does not provide evidence that long-term treatment with zimelidine or metergoline leads to adaptive changes in the response to spinal cord 5-HT receptor stimulation.     

5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour following antidepressant treatment to mice.

The effects of repeated administration of antidepressant drugs or electroconvulsive shock on the binding of [3H]-spiperone to the 5-hydroxytryptamine 2 (5-HT2) receptor in mouse frontal cortex and the 5-HT-mediated head-twitch response have been examined. Repeated electroconvulsive shock increased both the head-twitch response and the number of 5-HT2 binding sites (Bmax). After 35 d but not 24 h or 14 d oral tranylcypromine (5.6 mg kg-1 per day) there was a marked decrease in both the behavioural response and the number of 5-HT2 receptors. Repeated oral doses of zimeldine (20 mg kg-1 per day, 14 days) also decreased the head-twitch response and the number of 5-HT2 binding sites and these effects persisted after 48 h withdrawal. Oral mianserin (2.1 mg kg-1 per day, 14 days) decreased both the behaviour and the number of 5-HT2 binding sites, but this change was also seen after acute (1 day) administration. After 48 h withdrawal from chronic treatment the head-twitch response was still decreased but the Bmax had returned to control values. Desipramine given orally (27 mg kg-1 per day, 14 days) decreased both the behaviour and number of 5-HT2 binding sites. After 48 h withdrawal, binding was still decreased but the head-twitch response was enhanced above control values. In contrast to repeated electroconvulsive shock (ECS), all drugs decreased both 5-HT2 binding and the head-twitch response, while the mice were still on treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.

1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

5-Hydroxytryptamine release in vivo from a cytoplasmic pool: studies on the 5-HT behavioural syndrome in reserpinized rats.

Treatment of rats with reserpine in order to disrupt vesicular amine storage reduces 5-hydroxytryptamine (5-HT) levels throughout brain by 90-95%. Despite the drastic reduction in brain 5-HT content by reserpine, the 5-HT releasing drug p-chloramphetamine (PCA) produces a behavioural syndrome in reserpine-treated rats which is not different from that observed in normal animals given PCA. Prior treatment of reserpinized rats with p-chlorophenylalanine (PCPA), the irreversible tryptophan hydroxylase inhibitor which inhibits the synthesis of new 5-HT, prevents the PCA-induced behavioural syndrome. The 5-HT receptor antagonist methergoline, blocks the PCA effect in reserpine-treated rats. Treatment of reserpinized rats with pargyline, a non-selective inhibitor of monoamine oxidase, in order to increase cerebral 5-HT levels, shifts the PCA dose-response curve for inducing the 5-HT behavioural syndrome to the left. The specific 5-HT uptake blocker, fluoxetine, protects normal and reserpine-treated rats from the 5-HT depleting effects of PCA but does not always prevent the PCA-induced 5-HT behavioural syndrome. These results indicate that PCA releases 5-HT into the synapse from a small cytoplasmic pool which is resistant to reserpine and suggest that this newly synthesized compartment of 5-HT represents the 'functional' transmitter pool.     

Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.     

Antidepressant treatment in helpless rats: effect on the electrophysiological activity of raphe dorsalis serotonergic neurons

Chronic treatment with antidepressants renders serotonergic neuronal firing less sensitive to the inhibitory effect of serotonin (5-HT) reuptake blockers in the rat, and this has been considered as a major correlate of the therapeutic action of these drugs. We investigated whether the same mechanisms could be evidenced in an experimental model of depression, the learned helplessness paradigm. Rats rendered helpless by a single session of inescapable electrical footshocks exhibit, for several days, depression-like behavioural deficits which can be reversed by sub-chronic, but not acute, treatment with antidepressants. Recording of serotonergic neurons in the dorsal raphe nucleus revealed that, under baseline conditions, the spontaneous firing was similar in helpless rats and in non-helpless controls. However, neurons in the former group exhibited an enhanced sensitivity to the inhibitory action of the 5-HT reuptake blocker, citalopram (ED₅₀ = 0.18 ± 0.02 mg/kg IV in helpless rats versus 0.27 ± 0.03 mg/kg IV in controls, P < 0.05). Treatment with zimeldine during 3 consecutive days induced in both helpless and control rats, a decrease in the inhibitory response of serotonergic neurons to the citalopram challenge, which resulted in a normalization of the neuronal reactivity in the helpless group (ED₅₀ = 0.31 ± 0.03 mg/kg IV). Since this adaptive phenomenon parallels the behavioural improvement induced by the repeated administration of zimeldine and other antidepressants in helpless rats, it might be considered as a crucial event in the mechanism of therapeutic action of these drugs. Received: 14 August 1996 / Final version: 4 November 1996     

Selective cross-tolerance to 5-HT1A and 5-HT2 receptor-mediated temperature and corticosterone responses

The repeated administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 3 mg/kg, twice daily for 14 days) significantly diminished hypothermia and corticosterone secretion induced by an acute challenge with the 5-HT1A agonist 8-OH-DPAT (0.1 mg/kg) when compared to the responses in animals treated chronically with the solvent vehicle. In contrast, the chronic administration of 5-MeODMT did not alter the magnitude of hyperthermia or corticosterone secretion induced by the acute administration of MK-212 (1.0 mg/kg). The repeated administration of the 5-HT2 agonist DOI (1.0 mg/kg, daily for 7 days) significantly reduced the increase in corticosterone, but not body temperature, produced by MK-212. Chronic treatment with DOI did not alter the hypothermia or increase in corticosterone secretion elicited by 8-OH-DPAT. These data are consistent with other evidence that these physiological effects of 8-OH-DPAT and MK-212 are mediated by 5-HT1A and 5-HT2 receptors, respectively. Thus, data presented in these studies are suggestive that the chronic administration of 5-MeODMT diminishes the responsiveness of 5-HT1A receptor-mediated changes in body temperature and corticosterone secretion without altering the responses mediated by 5-HT2 receptors. In contrast, the chronic administration of DOI selectively diminishes the magnitude of 5-HT2 receptor-mediated changes in corticosterone secretion without affecting the responsiveness of those receptors involved in thermoregulatory responses. These selective changes in receptor responsiveness following the chronic administration of these 5-HT agonists further establishes the independence of 5-HT1A and 5-HT2 receptor-mediated pharmacological effects.     

The effects of tianeptine on wet-dog shakes, fore-paw treading and a flexor reflex in rats are consistent with enhancement of 5-hydroxytryptamine uptake

Tianeptine is a novel antidepressant which uniquely facilitates 5-hydroxytryptamine (5-HT) uptake. When given in a dose of 10 mg/kg to rats pretreated with either carbidopa or phenelzine, it markedly reduced the frequency of wet-dog shakes, fore-paw treading, tremor and hind-limb abduction evoked by L-5-hydroxytryptophan (L-5-HTP) given 30 or 60 min later. This effect of tianeptine was opposite to that of paroxetine, a selective 5-HT uptake inhibitor, which greatly increased the 5-HTP-induced behavioural syndrome. In contrast, tianeptine did not affect behaviours elicited by the 5-HT receptor agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), which are not substrates for the 5-HT uptake process. In spinal animals, tianeptine attenuated an ipsilateral flexor reflex, an effect opposite to that of citalopram, a selective 5-HT uptake inhibitor. These effects of tianeptine are consistent with its ability to increase 5-HT reuptake.