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PubMed1990

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

Changes in the function of presynaptic alpha 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 micrograms ICV) or administration of p-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 alpha 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 alpha 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.

5,7-Dihydroxytryptamine↗

PubMed1991

Evidence for an involvement of 5-hydroxytryptaminergic neurones in the maintenance of operant behaviour by positive reinforcement.

The possible involvement of the ascending 5-hydroxytryptaminergic (5HTergic) pathways in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Nine rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham injections. The rats were trained to steady-state in a series of variable-interval schedules of sucrose reinforcement affording a range of reinforcement frequencies. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value of KH (the parameter expressing the reinforcement frequency needed to obtain the half-maximum response rate) was significantly lower in the lesioned group than in the control group; the values of Rmax (the parameter expressing the maximum response rate) did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, nucleus accumbens and hypothalamus were markedly reduced in all four regions in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected. The results indicate that damage to the central 5HTergic pathways resulted in an increase in the "value" of the sucrose reinforcer, without affecting the animals' response capacity. The results are consistent with the suggestion that the 5HTergic pathways may exert some limiting control on the "values" of certain reinforcers.

5,7-Dihydroxytryptamine↗

PubMed1987

Microglia in the hypendyma of the rat subcommissural organ following brain lesion with serotonin neurotoxin.

The population of microglial cells in the subependymal layer of the subcommissural organ is sparse in normal adult rats. The number of microglial cells was substantially increased in this area following intraventricular injection of the serotonin neurotoxin 5,6-dihydroxytryptamine (5,6-DHT). In sections of plastic embedded material, 1 micron thick, the majority of phagocytic cells scattered in the subependymal layer had an appearance similar to that described in classical studies of microglial cells. At the electron microscopic level microglial cells exhibited the characteristic elongate nucleus with peripheral chromatin condensation. The perikaryon was scanty, containing strands of rough endoplasmic reticulum. The abundant organelles in the processes included Golgi complexes, mitochondria, rough and smooth endoplasmic reticulum as well as dense and multivesicular bodies. In addition, the processes contained phagocytosed axon terminals originating from the dense serotoninergic input to the subcommissural organ, which had degenerated on accumulating the serotonin neurotoxin. A fraction of the phagocytosed material was contained in subependymal subcommissural organ cells, astrocytes and oligodendrocytes. At the light microscopic level the phagocytosed terminals were visualized histochemically with Schmorl's reaction, which resulted in Prussian Blue precipitates. This allowed screening of microglial cells in complete series of sections through the well-defined subependymal layer of the subcommissural organ.

5,6-Dihydroxytryptamine↗

PubMedDate not supplied

Role of enkephalinergic brain structures in regulating motivated behavior in rats with lesioned serotoninergic neurons.

The behavioral effects of injections of enkephalin into the substantia nigra or dorsal raphe nucleus were studied in rats with lesioned serotoninergic structures. Lesions were produced by intracerebral administration of the neurotoxin 5,7-dihydroxytryptamine. Treated rats showed normalization of conditioned drinking reflex extinction. It is proposed that there is a tight connection between the normalizing effects of enkephalin on rat behavior in conditions of deficient brain serotoninergic system function and increases in the efficiency of presynaptic inhibition of dopaminergic neurons.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

The nature of d,l-fenfluramine-induced 5-HT reuptake transporter loss in rats.

The administration of the anorexigenic drug d,l-fenfluramine (Ponderax) to laboratory animals results in a dose-dependent reduction in presynaptically located serotonergic reuptake transporter protein. This long-term effect may represent an altered mechanism of synthesis of the transporter (downregulation). Alternatively, fenfluramine may destroy the serotonergic terminals on which 5-HT transporters are located. To distinguish between these two alternatives, we applied an assay of neurotransmitter-specific nerve endings (alpha) to brain tissue from two animal models of reduced 5-HT transporter density. In Model 1, serotonergic nerve terminals were destroyed (rats received 5,7-dihydroxytryptamine [5,7-DHT] intracisternally); in Model 2, there was a loss of 5-HT transporter per se on otherwise intact serotonergic nerve terminals. The manner in which alpha declined as transporter density was decreased (reducing Vmax values) in animal Models 1 and 2 was found to be significantly different. In rats treated with fenfluramine, the association between 5-HT transporter density and alpha was the same as in the neurotoxic model.

5,7-Dihydroxytryptamine↗

PubMed2004

Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity.

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMP releases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP (attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.

5,7-Dihydroxytryptamine↗

PubMed1999

Dependence of serotonin release in the locus coeruleus on dorsal raphe neuronal activity.

The serotonergic innervation of the locus coeruleus paetly derives from the dorsal raphe nucleus (DRN). Using the push-pull superfusion technique, we investigated whether and to what extent the release of serotonin and the extracellular concentration of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the locus coeruleus are influenced by the neuronal activity of the DRN. In anaesthetized rats, a push-pull cannula was inserted into the locus coeruleus, which was continuously superfused with artificial cerebrospinal fluid (aCSF). Serotonin and 5-HIAA levels in the superfusate were determined by HPLC combined with electrochemical detection. Electrical stimulation (5 Hz, 300 microA, 1 ms) of the DRN for 5 min, or its chemical stimulation by microinjection of glutamate (3.5 nmol, 50 nl), led to an increased release of serotonin in the locus coeruleus and to a slight (2 mmHg) decrease in blood pressure. Superfusion of the locus coeruleus with tetrodotoxin (1 microM) abolished the increase in the release rate of serotonin evoked by electrical stimulation of the DRN, while the slight fall in blood pressure was not influenced. Thermic lesion (75 degrees C, 1 min) of the DRN elicited a pronounced decline in serotonin release rate within the locus coeruleus, the maximum decrease being 52%. The decrease in the release of serotonin was associated with a long-lasting rise in blood pressure. Microinjection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5 microg, 250 nl) into the DRN led to an initial increase in the serotonin release rate that coincided with a short-lasting fall in blood pressure. Subsequently, the release of serotonin was permanently reduced and was associated with hypertension. Microinjection of the 5-HT1A receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT; 7.5 nmol, 50 nl) into the DRN led to a long-lasting reduction of the release rate of serotonin in the locus coeruleus. Microinjection of 8-OH-DPAT into the DRN also slightly lowered blood pressure (3 mmHg). Neither stimulations nor lesion of the DRN, nor microinjection of 8-OH-DPAT into this raphe nucleus, altered the extracellular concentration of 5-HIAA. Judging from the present biochemical results it appears that the serotonergic afferents to the locus coeruleus originate to more than 50% from cell bodies located in the DRN. The neuronal serotonin release in the locus coeruleus is modulated by 5-HT1A receptors lying within the DRN. Changes in blood pressure and release of serotonin elicited by stimulating or lesioning the DRN point to the importance of serotonergic neurons extending between this raphe nucleus and the locus coeruleus in central cardiovascular control.

5,6-Dihydroxytryptamine↗

PubMed1999

Serotonin and tolerance to delay of reward in rats.

RATIONALE: Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes. OBJECTIVE: The present study further examined the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer. METHODS: Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65-70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s. RESULTS: In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABA(A) receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1-2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4-8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT(1A) receptor agonist, 8-OH-DPAT (0.015-0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1-4 mg/kg IP), ipsapirone (0.5-1 mg/kg IP) and MDL 73005EF (1-2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg). CONCLUSIONS: These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT(1A) receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.

5,7-Dihydroxytryptamine↗

PubMed2002

Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors.

RATIONALE: Selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitors (SSRIs) such as fluoxetine produce a gradual desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems. It is assumed that the effects of SSRIs on post-synaptic 5-HT(1A) receptors are mediated by 5-HT reuptake inhibition, leading to an increase of 5-HT in the synapse. However, there is no direct evidence to support this hypothesis. OBJECTIVES: The present study determined whether 5-HT(1A) receptor desensitization was mediated by fluoxetine's effects on serotonergic nerve terminals. METHODS: Serotonergic nerve terminals were destroyed by intracerebroventricular (i.c.v.) injection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) combined with injection of the norepinephrine/dopamine reuptake inhibitor nomifensine. 5,7-DHT-induced loss of serotonergic terminals was confirmed by a 95% reduction in the density of [(3)H]paroxetine-labeled 5-HT transporters in the hypothalamus and a 97% reduction in the levels of 5-HT and 5-hydroxyindoleacetic acid in the cortex. Two weeks after the 5,7-DHT injections, rats were injected daily with fluoxetine (5 mg/kg or 10 mg/kg, i.p.) or saline for 14 days. RESULTS: Injections of 10 mg/kg fluoxetine produced a significant decrease in body weight gain. Destruction of serotonergic nerve terminals reduced body weight and potentiated the ability of fluoxetine to further inhibit body weight gain. Increases in plasma levels of adrenal corticotrophic hormone (ACTH, corticotropin), corticosterone, and oxytocin after injection of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin [(+/-)8-OH-DPAT] were used as peripheral markers of 5-HT(1A) receptor function in the hypothalamus. In vehicle-pretreated rats, fluoxetine produced a dose-dependent reduction in the (+/-)8-OH-DPAT-induced increase in plasma ACTH and oxytocin levels. Destruction of serotonergic nerve terminals blocked the ability of fluoxetine to produce a desensitization in the ACTH, corticosterone, and oxytocin responses to (+/-)8-OH-DPAT. CONCLUSIONS: The ability of fluoxetine to induce a desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems is dependent on the integrity of serotonergic nerve terminals in the hypothalamus, while its effect on body weight is not mediated by serotonergic nerve terminals in the hypothalamus.

5,7-Dihydroxytryptamine↗

PubMed2004

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-hydroxytryptamine; 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.

5,7-Dihydroxytryptamine↗

PubMed2004

5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion.

RATIONALE: Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT(2A) receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT(2A) and 5-HT(2C) receptors have opposing effects on behaviour, and that the 5-HT(2C) receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion. OBJECTIVES: To assess the effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents. METHODS: The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats. RESULTS. ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls. CONCLUSIONS: These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT(2) receptor family is functionally heterogeneous. Although both 5-HT(2A) and 5-HT(2C) receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

5,7-Dihydroxytryptamine↗

PubMed2005

Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A receptor in vivo.

RATIONALE: Associative learning during Pavlovian eyeblink conditioning has been shown to be regulated by 5-HT2A receptors. The existence of inverse agonists that retard learning through an action at the 5-HT2A receptor suggests the existence of constitutive activity at that receptor and that depletion of serotonin should have minimal effects on learning. OBJECTIVES: We examined whether depletion of serotonin would impair trace eyeblink conditioning or the enhancement of conditioning produced by the agonist lysergic acid diethylamide (LSD) and the retardation of conditioning produced by the inverse agonist MDL11,939. METHODS: Animals received bilateral intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) at doses of 760 or 1,140 microg/side (1.88 or 2.82 micromol/side) and were later exposed to eight daily conditioning sessions. RESULTS: Serotonin depletion produced by the lower dose of 5,7-DHT was 71 and 72% in cortex and hippocampus, respectively, with no change in 5-HT2A receptor density, no effect on learning, and no effect on the ability of LSD to enhance and MDL11,939 to retard learning. The higher dose of 5,7-DHT produced serotonin decreases of 85 and 90% in cortex and hippocampus, respectively, accompanied by a 96% decrease in the density of the serotonin transporter, but no significant effect on learning. CONCLUSIONS: Pavlovian trace eyeblink conditioning is regulated predominantly by the constitutive activity of the 5-HT2A receptor rather than by serotonin release onto the receptor during learning. It was suggested that the 5-HT2A receptor regulates learning by modulating the release of dopamine, acetylcholine, and glutamate, transmitters known to affect eyeblink conditioning.

5,7-Dihydroxytryptamine↗

PubMed2000

Effect of central 5-hydroxytryptamine depletion on inter-temporal choice: a quantitative analysis.

RATIONALE: It has been proposed that the ascending 5-hydroxytryptaminergic (5-HTergic) pathways are involved in "impulse control". Previous experiments have shown that rats whose 5-HTergic pathways have been destroyed are more liable than intact rats to select a smaller, immediate reinforcer rather than a larger, delayed reinforcer (impulsive choice). However, it remains unclear whether this effect of central 5-HT depletion reflects a change in the rate of time discounting (i.e. a change in the rate at which reinforcers become devalued as a function of delay) or a change in sensitivity to reinforcer size. OBJECTIVE: We examined the effect of central 5-HT depletion on time discounting using a quantitative model of inter-temporal choice (multiplicative hyperbolic model), which enables effects on time discounting to be differentiated from effects on sensitivity to reinforcer size. METHODS: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press two levers for food-pellet reinforcers in a discrete-trials adjusting-delay schedule. In free-choice trials, selection of lever A resulted in a brief fixed delay (dA) followed by delivery of one pellet; selection of lever B resulted in a longer variable delay (dB) followed by delivery of two pellets; dB was adjusted in accordance with the subject's choices. The value of dA was varied (0.5-8.0 s) in successive phases of the experiment, and the indifference value of dB was determined in each case. RESULTS: In both groups, the indifference value of dB was linearly related to the value of dA, in accordance with the multiplicative hyperbolic model. The lesioned group showed shorter indifference delays than the sham-lesioned group, this being reflected in a parallel displacement of the linear indifference function. In both experiments, the levels of 5-HT and 5-hydroxyindole-acetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. CONCLUSIONS: According to the multiplicative hyperbolic model, parallel displacement of the linear indifference function uniquely specifies a change in time discounting. Thus these results indicate that central 5-HT depletion results in an increase in the rate of time discounting for food reinforcers.

5,7-Dihydroxytryptamine↗

PubMed2000

Blockade of muscarinic, rather than nicotinic, receptors impairs attention, but does not interact with serotonin depletion.

RATIONALE: The cholinergic system is considered to be essential for attention and the degeneration of the cholinergic system in Alzheimer's disease (AD) correlates with the cognitive decline seen in AD patients. The serotonergic system also degenerates in AD, but its role in the modulation of cognitive functions, especially attention, is somewhat unclear. OBJECTIVES: The present study investigated possible differences between cholinergic muscarinic and nicotinic receptor mediated mechanisms, the role of serotonin (5-HT) and the interaction between the cholinergic and serotonergic systems in the modulation of attention and response control. METHODS: The influences of cholinergic receptor blockade and 5-HT lesions on the performance of rats in the five-choice serial reaction time task were assessed. The 5-HT lesions were neurochemically verified. RESULTS: The neurochemical analysis indicated that the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced quite specifically in the hippocampi, parieto-occipital and frontal cortices, and in the striatum of both p-chloroamphetamine (pCA) and 5, 7-dihydroxytryptamine (5,7-DHT) lesioned rats. The behavioural results showed that the pCA lesion caused a transient increase in impulsivity whereas the 5,7-DHT lesion temporarily reduced the motor activity and slightly impaired choice accuracy. Furthermore, the blockade of central muscarinic receptors by scopolamine (0.075 and 0. 150 mg/kg), but not nicotinic receptors by mecamylamine (1.0 or 3.0 mg/kg), impaired the choice accuracy, whereas the blockade of both muscarinic and nicotinic receptors interfered with motor activity, though possibly via peripheral mechanisms. Interestingly, mecamylamine (3.0 mg/kg) reduced impulsivity, whereas scopolamine slightly increased it. Serotonergic lesions did not make the rats more susceptible to the effects of cholinolytics on choice accuracy. CONCLUSIONS: 5-HT system is not essential for the modulation of attention, but it is important in the modulation of response control. Central muscarinic receptors are important in the modulation of attention, whereas central nicotinic receptors may be more essential in response control. The results do not support there being an interaction between the serotonergic and the cholinergic systems in the modulation of attention.

5,7-Dihydroxytryptamine↗

PubMed1996

Effect of destruction of the 5-hydroxytryptaminergic pathways on behavioural timing and "switching" in a free-operant psychophysical procedure.

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance in a free-operant timing schedule. Rats received either injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for a sucrose reinforcer. Training sessions consisted of 40, 50-s trials in which reinforcers were available on a variable-interval 25-s schedule; in the first 25 s of each trial, reinforcers were only available for responses on lever A, whereas in the last 25 s reinforcers were available only for responses on lever B. Data were collected from probe trials (four per session) in which no reinforcers were delivered, during the last ten of 50 training sessions. Both groups showed decreasing response rates on lever A and increasing response rates on lever B as a function of time from the onset of the trial. Response rate on lever B, expressed as a percentage of overall response rate, could be described by a two-parameter logistic function; neither the indifference point (i.e. the time corresponding to 50% responding on lever B) nor the slope of the function different between the two groups. However, the lesioned group showed a higher rate of switching between response alternatives than the sham-lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not significantly altered. The results confirm previous findings that behaviour in timing schedules is sensitive to destruction of the central 5HTergic pathways, and suggest that these pathways may contribute to the inhibitory regulation of switching between behavioural states.

5,7-Dihydroxytryptamine↗

PubMed1996

Possible mechanism of action for the attenuation of ethanol intake induced by ritanserin in rats.

The 5-HT2 receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT3 receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3 times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC.

5,7-Dihydroxytryptamine↗

PubMed1997

Effect of destruction of the 5-hydroxytryptaminergic pathways on temporal memory: quantitative analysis with a delayed interval bisection task.

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a "correct' response, reinforcer delivery. When > 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered.

5,7-Dihydroxytryptamine↗

PubMed1997

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 administration 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.

5,7-Dihydroxytryptamine↗