Destruction of 5-hydroxytryptaminergic neurons and the dynamics of dopamine in nucleus accumbens septi and other forebrain regions of the rat

5,7-Dihydroxytryptamine (5,7-DHT) was injected into the lateral cerebral ventricle of rats which had been pretreated with desipramine; this treatment reduced the concentrations of 5-hydroxy-tryptamine (5-HT) but not of norepinephrine or dopamine (DA) in forebrain regions. When 5,7-DHT was injected bilaterally into the nucleus accumbens septi (NAS) of desipramine-pretreated rats, it selectively depleted 5-HT only from the NAS. Exploratory locomotor activity and the locomotor stimulation induced by f-amphetamine and apomorphine were enhanced in both NAS- and 5,7-DHT-injected rats. These locomotor effects in the 5-HT-depleted animals were not associated with changes in the activity of dopaminergic neurons, which were estimated biochemically from either the regional concentrations of dihydroxyphenylacetic acid (DOPAC) or the rate of accumulation of dihydroxyphenylalanine (DOPA) after the administration of a decarboxylase inhibitor. That is, the concentration of DOPAC and the accumulation of DOPA in the NAS, olfactory tubercle and striatum of NAS-5,7-DHT and 5,7-DHT-injected rats were the same as in controls. Furthermore, the ability of apomorphine to decrease, and of haloperidol to increase, DOPAC concentrations and DOPA accumulation were the same in control, NAS-5,7-DHT and 5,7-DHT-injected rats. These results indicate that the enhancement of spontaneous and drug-stimulated locomotor activity following destruction of 5-HT nerve terminals in the brain are not associated with changes in the activity of the major ascending DA-containing neuronal systems.     

Effects of neonatal treatment with 5,7-dihydroxytryptamine or 6-hydroxydopamine on the ontogenetic development of the audiogenic immobility reaction in the rat

The ontogenetic development of the audiogenic immobility reaction (freezing) was studied in rats given intracisternal injections of the neurotoxins 5,7-dihydroxytryptamine (5,7-DHT), 25 g, or 6-hydroxydopamine (6-OHDA), 100 g, neonatally (Day 1). The duration of the freezing response was strongly reduced in the 5,7-DHT-treated rats between 20–30 days of age, when normal animals show very prolonged responses. During the same period increased motor activity was observed in the 6-OHDA-treated rats while only a slight reduction of the freezing response was noted. Biochemical analyses performed on brains from animals 35 days of age showed a selective reduction (about 50%) of whole brain levels of serotonin in the 5,7-DHT-treated rats, while the noradrenaline levels were selectively reduced by about 60% in the 6-OHDA rats. A longitudinal investigation on the effects of neonatal treatment with 5,7-DHT showed a persistent selective reduction of the whole brain level of serotonin up to at least 90 days of age. Since 5,7-DHT mainly affects the serotonergic pathways, the results suggest that the disturbances noted in the ontogeny of the freezing response may be due to interference with the developing serotonergic system.     

Relation between yawning behavior and central serotonergic neuronal system in rats

Summary Subcutaneously (s.c.) administered apomorphine (0.0125–0.4 mg/kg) or physostigmine (0.025–0.4 mg/kg) to rats elicited yawning. The dose-response curves were bellshaped. The peak effects of apomorphine and physostigmine were observed with a dose of 0.1 mg/kg of each drug. Yawning elicited by apomorphine (0.1 mg/kg) or physostigmine (0.1 mg/kg) was reduced by intraperitoneally (i.p.) administered 5-hydroxytryptophan (5-HTP, 50–200 mg/kg, given 30 min before). Yawning elicited by apomorphine but not by physostigmine was enhanced by p-chlorophenylalanine (p-CPA, 25–400 mg/kg i.p., given 24 h before). Apomorphine elicited but not physostigmine-elicited yawning was enhanced by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 8 g/rat, given 14 days before into the dorsal raphe). This treatment led to a 35% depletion of serotonin (5-HT) in the striatum. 5-HTP, p-CPA or 5,7-DHT given alone did not elicit yawning. Bilateral, intrastriatal microinjection of apomorphine (1.5 –50 g/site) but not physostigmine (5–50 g/site) elicited yawning. The dose-response curve was also bell-shaped. These results indicate that central serotonergic pathways play an important role in modulating drug-elicited yawning in rats. Send offprint requests to S. Okuyama at the above address     

The role of the substantia nigra in the locomotor stimulant action of amphetamine

1. The electrolytic brain lesion technique was used to evaluate the role of the substantia nigra in the mediation of the locomotor stimulant effect of (+)-amphetamine in the rat. The effect upon the results of variations in strain and basal activity levels of the rats was assessed.2. In the immediate postoperative phase the lesioned animals developed spontaneous stereotyped behaviour patterns which were more intense in rats of initially high basal activity. Activity was depressed at this stage and only that of the low activity animals was stimulated by amphetamine.3. After the 2nd postoperative day rats with lesions of the substantia nigra developed hyperactivity, but this was only maintained in rats initially of low basal activity. During this stage the locomotor stimulant effect of amphetamine (1.0 mg/kg) was apparent and after the 9th postoperative day animals generally displayed an increased sensitivity to the drug effect.4. The involvement of the substantia nigra with the control of locomotor activity is indicated but its integrity would not appear essential for the mediation of the locomotor stimulant effects of amphetamine.     

The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour,and amphetamine-induced stereotypy

Summary 5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The stereotyped responses to all doses of amphetamine tested (2.5–10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.     

Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats

Rationale Psychomotor stimulant drugs such as methylphenidate and amphetamine decrease impulsive behaviour in attention deficit hyperactivity disorder patients by unknown mechanisms. Although most behavioural effects of amphetamine are attributed to the dopaminergic system, some recent evidence suggests a role for serotonin in this paradoxical "calming" effect.Objectives To investigate whether forebrain serotonin depletion affects the action of amphetamine in the rat on a delayed reward task where impulsive choice is measured as the selection of a smaller immediate over a larger delayed reward.Methods Following behavioural training, rats received i.c.v. infusions of either vehicle (n=10) or the serotonergic neurotoxin 5,7-DHT (n=10). Post-operatively, animals received i.p. d-amphetamine (0.3,1.0,1.5, and 2.3 mg/kg/ml), and d-amphetamine co-administered with the dopamine antagonist cis-z-flupenthixol.Results 5,7-DHT (i.c.v.) itself did not affect choice behaviour, despite depleting forebrain serotonin levels by over 85%. Amphetamine increased choice for the large reward, i.e. decreased impulsivity. This effect was attenuated by 5-HT depletion, particularly in animals showing a high level of impulsive choice. Co-administration of cis-z-flupenthixol (0.125 mg/kg) with d-amphetamine abolished the effect of amphetamine in the lesioned group, whereas this was only partially attenuated in the vehicle control group.Conclusions These data suggest that the ability of amphetamine to decrease impulsivity is not solely due to its effects on dopaminergic systems, but may also depend on serotonergic neurotransmission.     

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats. Received: 22 November 1995 / Final version: 25 November 1996     

Effects of amphetamine,methylphenidate, and apomorphine on regional brain serotonin and 5-hydroxyindole acetic acid

Electrophysiological and cytofluorometric data suggest that doses of amphetamine which enhance locomotor activity and promote focused stereotypies produce pronounced effects on serotonin pathways in the CNS. However, the biochemical evidence regarding changes in serotonergic function produced by moderate doses of this drug is inconsistent. Therefore, the present study was designed to further examine the effects of amphetamine (1–5 mg/kg) on regional brain serotonin and its metabolite and to compare these effects to behaviorally comparable doses of methylphenidate and apomorphine. At doses which produce a multiphasic behavioral response pattern, including a stereotypy phase consisting primarily of repetitive head movements and occasional oral stereotypies, amphetamine (3 mg/kg) and methylphenidate (30 mg/kg) increased levels of 5HIAA in striatum and frontal cortex, two brain regions which receive serotonergic projections from the dorsal raphe nucleus. In contrast, these drugs decreased or had no effect on 5HIAA levels in hippocampus, a brain region which receives its serotonergic innervation from the median raphe nucleus. A moderate dose of apomorphine (0.5 mg/kg) produced a comparable pattern of neurochemical effects. These data are consistent with electrophysiological and cytofluorometric data suggesting enhanced dorsal raphe serotonergic function following amphetamine-like stimulants. Pretreatment of animals with -methyltyrosine at a dose sufficient to prevent the locomotor stimulation and stereotypy promoted by amphetamine, or by haloperidol, failed to prevent the amphetamine-induced increase in 5HIAA, indicating that these serotonergic effects are not secondary to the amphetamine facilitation of dopaminergic transmission. The results of this study suggest that serotonin may play a modulatory role in the behavioral effects of amphetamine-like stimulants which is dependent for its expression on an intact dopamine system.Abbreviations DA dopamine - AMPH S(+)amphetamine - 5HT serotonin - MP methylphenidate - APO apomorphine - 5HIAA 5-hydroxyindoleacetic acid - MT -methyltyrosine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - HAL haloperidol     

Depletion of brain serotonin following intra-raphe injections

Objectives: These experiments investigated the effects of selective serotonin (5-HT) depletion on intravenous self-administration of d-amphetamine. Methods: Depletion of brain 5-HT levels was induced by injecting the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Rats were then trained to self-administer d-amphetamine according to various schedule and access conditions via chronically indwelling intravenous catheters. Results: Large reductions of brain 5-HT did not alter responding for a training dose of 120 μg/kg d-amphetamine delivered according to a fixed ratio 1 schedule during 3-h sessions. When the dose of d-amphetamine was altered (0, 3.75, 7.5, 15, 30, 60 μg/kg per infusion) a characteristic inverted U-shaped dose response function was obtained. The 5-HT depleted rats showed increased responding for the lower doses of d-amphetamine, with a large significant increase in responding for the 7.5 μg/kg dose. In these same rats, the suppressive effect of 10 mg/kg fluoxetine on d-amphetamine (60 μg/kg) self-administration was prevented. The 5,7-DHT lesion also did not alter responding for d-amphetamine (120 μg/kg) in longer (8 h) daily access sessions. Responding for d-amphetamine delivered on a progressive ratio schedule, in which response requirements increased for each successive infusion of d-amphetamine, was also determined in 5-HT depleted rats. The number of d-amphetamine infusions was not different from the number of infusions earned by sham-lesioned rats across a range of doses of d-amphetamine (7.5–60 μg/kg). In a final experiment, spontaneous acquisition of self-administration of low doses of d-amphetamine (10 and 30 μg/kg) was measured in 5-HT depleted and control rats. Again, self-administration behaviour in the 5-HT depleted rats did not differ from controls. Conclusions: These results provide no evidence that reducing 5-HT function alters the primary reinforcing effects of self-administered amphetamine. The increase in self-administration of a low dose of amphetamine observed in experiment 1 probably involves some other process such as increased resistance to extinction. Received: 28 December 1998 / Final version: 28 April 1999     

Evidence for involvement of 5-hydroxytryptamine in the actions of amphetamine

1 Pargyline treatment, 1 h before (+)-amphetamine (1 mg/kg), reduced amphetamine-stimulated motor activity. This inhibition was reversed in animals pretreated with p-chlorophenylalanine (PCPA).2 Following treatment with PCPA or 5,6-dihydroxytryptamine (5,6-DHT), amphetamine-induced locomotor activity was significantly potentiated. The increased response to amphetamine in PCPA-treated rats was reversed in animals pretreated with 5-hydroxytryptophan.3 The inhibition of amphetamine-stimulated locomotor activity by treatment with 6-hydroxydopamine was not reversed by PCPA treatment.4 Stereotypies produced by amphetamine were not found to be altered by depletion of 5-hydroxytryptamine.5 Induction of adrenal tyrosine hydroxylase activity produced by chronic amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5-hydroxytryptamine inhibitory system in more than one action of amphetamine.     

The effect of chronic administration and withdrawal of amphetamine on cerebral dopamine receptor sensitivity

Mice with a 6-hydroxydopamine induced unilateral nigro-striatal lesion received (+)-amphetamine sulphate (2.5–20 mg/kg) over a 3-month period by daily incorporation into the drinking water. During this period the circling response to apomorphine hydrochloride (0.01–0.5 mg/kg, s.c.) was increasingly suppressed in comparison to control animals, while spontaneous locomotor activity increased. Following drug withdrawal the circling response to apomorphine remained suppressed two months later. However, spontaneous locomotor activity was also reduced up to 1 month following drug removal.The dopamine content of the lesioned side of the forebrain was 25% of the intact side in control animals and was not further reduced by amphetamine administration. The dopamine content of the intact forebrain was reduced by 43% during amphetamine administration and remained 18% depressed 1 month following drug withdrawal. No changes in 5-hydroxytryptamine or noradrenaline concentrations were observed in either the intact or lesioned side.This data, while showing that chronic amphetamine treatment can induce persistent changes in dopamine receptor sensitivity, can be interpreted in terms of increased striatal receptor sensitivity or as a decreased response of dopamine receptors in the nucleus accumbens.     

Dietary tryptophan reversal of septal lesion and 5,7-DHT lesion elicited shock-induced fighting

Using two procedures known to enhance shock-induced defensive fighting (SIF) and mouse-killing--septal lesions and 5,7-DHT lesions--we determined if a 5% tryptophan-loaded diet could reverse the lesion effects. The results indicated that SIF, but not mouse-killing, could be maintained at normal levels following dietary tryptophan loading in both septally lesioned and 5,7-DHT lesioned rats. This behavioral reversal was independent of pain sensitivity, feeding, drinking and body weight levels. Regional brain analysis of monoamines and metabolites indicated that the lesions produced substantial depletions in 5-HT and 5-HIAA with minimal reduction or no change in catecholamines. Dietary tryptophan loading elevated 5-HT and 5-HIAA in unlesioned animals and partially restored 5-HT and 5-HIAA levels in lesioned animals. These patterns of depletion and repletion were confined to the hippocampus following septal lesions and distributed throughout the brain following 5,7-DHT lesions. The results are discussed in terms of a possible hippocampal mediation of the dietary tryptophan reversal in shock-induced defensive fighting following lesioning.     

Rotational behavior induced by 8-hydroxy-DPAT,a putative 5HT-1A agonist,in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3–3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems. Alternatively, it is proposed that rats with highly denervated striatal DA receptors show a loss of apparent molecular selectivity such that weak partial DA agonist properties of 8-OH-DPAT, although not demonstrable in normal rats, become manifested under these conditions. Offprint requests to: J.M. Liebman     

Fluoxetine,but not sertraline or citalopram,potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects

Rationale The selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances some of the behavioural effects of cocaine, including locomotor stimulation. While this effect has often been interpreted as evidence for a serotonergic component to the behavioural effects of cocaine, direct evidence for this hypothesis is lacking. One alternative explanation is that fluoxetine, by inhibiting cytochrome P450 (CYP) enzymes, interferes with the metabolism of cocaine.Objectives These experiments were undertaken to: 1) compare the effects of fluoxetine with those of two other SSRIs, sertraline and citalopram, on cocaine-induced locomotor activity, 2) examine the effects of fluoxetine on cocaine-stimulated locomotion in rats depleted of serotonin (5-hydroxytrptamine; 5-HT), and 3) determine the effect of fluoxetine on cocaine levels in the brain.Methods Locomotor activity was measured, using photocell based activity monitors, in rats habituated to those monitors. Depletion of 5-HT was achieved by injecting 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Cocaine levels in whole brain were measured using high-performance liquid chromatography with ultraviolet detection.Results In experiment 1, 5 mg/kg fluoxetine enhanced the ability of 10 and 15 mg/kg cocaine to increase locomotor activity. Neither citalopram nor sertraline (5 and 10 mg/kg) altered the stimulant effect of 10 mg/kg cocaine. Experiment 2 showed that this effect of fluoxetine was also apparent in rats with large and widespread depletion of brain 5-HT levels. The 5-HT depletion also failed to alter the response to cocaine itself. In experiment 3, brain levels of cocaine were elevated in rats pretreated with fluoxetine compared with rats that received cocaine alone.Conclusion Fluoxetine enhanced the ability of cocaine to increase locomotor activity. This effect appears not to depend upon increasing 5-HT function since fluoxetine was also effective in rats with substantial 5-HT depletions, and two other SSRIs did not alter the effects of cocaine. Fluoxetine-treated rats had higher brain levels of cocaine than rats treated with cocaine alone. This effect suggests that fluoxetine slows the metabolism of cocaine, perhaps by inhibition of CYP enzymes involved in metabolizing cocaine. The results also indicate that 5-HT reuptake inhibition may not play a prominent role in mediating the stimulant effects of cocaine.     

An investigation of the role of 5-hydroxytryptamine in the attenuation of presynapticα 2-adrenoceptor-mediated responses by antidepressant treatments

Changes in the function of presynaptic ₂-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 µg ICV) or administration ofp-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11–15 days produced 62–77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT₂ receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this ₂-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic ₂-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.     

The effects of kainic acid lesions on locomotor responses to haloperidol and clozapine

 Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg SC) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg SC) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine. Received: 1 April 1997/Final version: 6 August 1997     

Receptor mechanisms in increased sensitivity to serotonin agonists after dihydroxytryptamine shown by electronic monitoring of muscle twitches in the rat

Muscle twitches and autonomic changes were induced by systemic injections of L-5-hydroxytryptophan (5-HTP) or the serotonin agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats previously lesioned with intracranial 5,7-dihydroxytryptamine (5,7-DHT) after desmethylimipramine. Movements were recorded sensitively and continuously by an electronic activity monitor. Spontaneous locomotor activity was strongly reduced after 5-HTP in both intact and lesioned rats, so that electronically recorded activity correlated very closely with disordered jerking movements scored by a behavioral rating scale. This myoclonus was dependent on the doses of 5-HTP and of 5,7-DHT and was strongly inhibited by serotonin antagonists. In lesioned rats, myoclonus occurred with unaltered activity of monoamine oxidase (MAO) and after only small increases in serotonin levels after 5-HTP, but even large increases in availability of serotonin in intact rats, or strong inhibition of serotonin uptake failed to induce myoclonus unless MAO was first inhibited. The response to 5-HTP in lesioned rats was attenuated by repeated injections of 5-HTP or 5-MeO-DMT. This decreased response was in turn blocked by repeated doses of a serotonin antagonist, but appeared not to be due to altered metabolism of 5-HTP or of serotonin; repeated pretreatment with cyproheptadine potentiated the myoclonic response to 5-HTP after DHT. Changes in postsynaptic receptors may be important in the behavioral supersentivity following 5,7-DHT, and restitution of serotonin or stimulation of its receptors after presynaptic denervation may suppress an evolving supersensitivity at receptive postsynaptic membranes.     

Serotonin depletion by 5,7-dihydroxytryptamine or para-chloroamphetamine does not affect cancer anorexia

Anorectic tumor-bearing rats exhibited increased brain levels of the 5-HT precursor, tryptophan, and metabolite, 5-hydroxindoleactic acid (5-HIAA). In an effort to determine whether indoleamine systems had any role in the etiology of cancer anorexia the anorectic effects of cancer (Walker 256 carcinosarcoma) were investigated in immature female rats that had been depleted of brain serotonin (5-HT) by the intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT) or the systemic injection of para-chloroamphetamine (PCA). Although both 5,7-DHT and PCA significantly reduced brain concentrations of 5-HT and 5-HIAA by approximately 50%, no effects on the onset or severity of the anorectic response to cancer were observed. Similarly, neither drug affected eating in non-tumor-bearing control animals. Therefore, these data do not support increased brain 5-HT activity as a primary mediator of cancer anorexia.     

Intracerebroventricular administration of 5,7-dihydroxytryptamine to mice increases both head-twitch response and the number of cortical 5-HT2 receptors

5-Hydroxytryptamine-containing (5-HT) neurones in brain of the mouse were selectively destroyed by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 50 μg). Shamlesioned controls received vehicle (2 μl, i.c.v.). Two weeks later the head-twitch response induced by 5-methoxy-N,N-dimethyltryptamine (2.0mg/kg) and mediated by 5-HT₂ receptors was markedly enhanced in the lesioned mice. Furthermore, lesioning also increased 5-HT₂ binding sites in the cortex, assessed by the binding of [³H]ketanserin in these animals, and decreased levels of 5-HT in the cortex (70%) and mid/hindbrain (64%) regions. A second group of mice, lesioned with less 5,7-DHT (5–20 μg, i.c.v.) showed unaltered head-twitch responses to 5-methoxy-N,N-dimethyltryptamine (2.0 mg/kg) and did not have increased 5-HT₂ receptor binding in the cortex. Depletions of 5-HT were 32 and 40% in the cortex and mid/hindbrain, respectively.

Comparison of the extent of depletion of 5-HT in the mid/hindbrain after lesioning, with the increase in head-twitch response, suggested that depletions of < 40% did not affect this behaviour. However, depletions > 40% produced marked increases in this response and there was a good correlation between these two variables (r =0.701, P < 0.01).

In conclusion, these data suggest that enhanced head-twitch responses occurring after lesioning with 5,7-DHT may result from increased 5-HT₂ receptors in brain. Moreover, the magnitude of the observed behavioural enhancement was dependent upon the extent of depletion of 5-HT produced by the lesioning.     

Time course of amphetamine-induced locomotor stereotypy in an open field

Gamma ( ) is a recently proposed statistic that quantifies and describes the repetitive patterns of locomotion (locomotor stereotypy) exhibited by amphetamine-treated rats in an open field. The time-course of locomotor stereotypy after 1, 2, 3, and 4 mg/kg amphetamine was investigated in this research. Locomotor stereotypy was often evident during the first observation period after amphetamine. Lower doses of amphetamine produced qualitatively different locomotor stereotypy than higher doses. Rats given higher doses of amphetamine exhibited locomotor stereotypy during the hyperactivity phase of the three-phase response produced by higher doses of amphetamine (hyperactivity; absence of locomotions, increased sniffing, biting etc.; hyperactivity). Contrary to expections, rats injected with 2 mg/kg amphetamine exhibited the highest and most sustained increase in . We conclude that locomotor stereotypy is an important component of the behavioral effects of amphetamine in rats. Whether locomotor stereotypy and focused stereotypy are similar phenomena is still unclear.