Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms

 A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (>80% correct, <20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (–)-sulpiride, a D₂ receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D₁ receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission. Received: 12 September 1996 / Final version: 3 April 1997     

Measuring impulsivity in mice using a novel operant delayed reinforcement task: effects of behavioural manipulations and<Emphasis Type="Italic"> d-</Emphasis>amphetamine

Rationale The increasing use of genetically modified mice to probe genetic contributions to normal and abnormal behaviours requires the development of sensitive and selective behavioural tasks.Objectives To develop a discrete trial assay of impulsivity (delayed reinforcement) that is tractable in mice utilising a mouse operant nine-hole box apparatus and to specify the task with respect to behavioural and pharmacological manipulations.Methods Mice were trained to respond with a nose-poke to one of two visual stimuli; one response resulted in a small quantity of reinforcer, the other in a larger quantity of reinforcer. As the session proceeded increasing delay was introduced onto the response leading to the large reward. Hence, the nature of the choice was a small quantity of reinforcer immediately versus a larger but progressively delayed amount of reinforcer. At stable baseline performance the mice were challenged with a variety of task manipulations and systemic d-amphetamine in order to discern aspects of the underlying psychological and neurochemical substrates of the choice behaviour.Results The mice showed a systematic shift in responding away from the large reinforcer with increasing delay (0, 2, 4, 8, 12 s), such that at the longest delay >80% of nose-pokes were for the smaller, immediate reinforcer. Task manipulations indicated that behaviour was controlled in a trial discrete manner by the contingency between delay and reward and was not due to non-specific factors such as satiation. d-Amphetamine had complex, dose dependent effects on choice behaviour which revealed dissociations between impulsive choice and hyperactivity. Conclusions We have successfully developed an assay of impulsivity in mice that will be of utility to examine impulsive behaviours and their genetic substrates. In addition, our data provided evidence of distinct dopaminergic mechanisms mediating aspects of impulsivity and hyperactivity.     

Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.     

Potentiation of d-amphetamine and l-dopa-induced acoustic startle activity after long-term exposure to amphetamine

The startle response to an auditory atimulus was potentiated by treatment with d-amphetamine sulfate. Administration of l-dopa after pretreatment with the extracerebral decarboxylase inhibitor MK-486 also increased startle activity. After long-term exposure to amphetamine the startle response to l-dopa and d-amphetamine was enhanced. These findings are consistent with the consequences of longterm amphetamine administration on other amphetamine-induced behaviors (e.g. stereotypy), and are discussed in terms of the effects of long-term amphetamine treatment on pre-and postsynaptic dopamine receptors and serotonin.     

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-HT₂ 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 – a selective marker of dopaminergic or serotonergic neurons?

The aim of the present study was to investigate whether 5,7-dihydroxytryptamine (5,7-DHT), an autofluorescent serotonin derivative, can be used as a specific marker for serotonergic or dopaminergic neurons in rat mesencephalic cultures. To this end, primary cultures were prepared from the ventral brain stem of 14-day-old Wistar rat foetuses and kept in culture for 10 days (DIV10). At DIV10, the cultures were characterized immunocytochemically with antibodies raised against tyrosine hydroxylase (TH; a marker for catecholaminergic/ dopaminergic neurons) and serotonin (5-HT). 5,7-DHT labelling of the neurons was investigated after incubation with 25 microM of the serotonin derivative (plus 0.005% ascorbic acid) for 60 min at 37 degrees C, followed by incubation with primary antibodies against TH or serotonin and a fluorescence (Cy3)-labelled secondary antibody. Using confocal laser scanning microscopy, this double immunofluorescence approach demonstrated that all cells which had accumulated 5,7-DHT additionally displayed anti-5-HT immunoreactivity, whereas no evidence was found for 5,7-DHT labelling of TH immunoreactive cells. Preincubation with the selective serotonin reuptake inhibitor fluvoxamine maleate (10 microM) prevented the loading of the 5-HT-positive cells with 5,7-DHT. In conclusion, the present data indicate that 5,7-DHT specifically labels serotonergic cells in rat midbrain cultures. Thus, 5,7-DHT can be used for the identification of living serotonergic neurons even in the presence of dopaminergic neurons.     

A comparative study of different amphetamines on copulatory behavior and stereotype activity in the female rat

The influence of d- and l-amphetamine, fenfluramine, and p-chloroamphetamine on female copulatory behavior (lordosis response) and the induction of stereotype activity was compared. Lordosis response in the female rat has been shown to be inhibited by increased central nervous serotonergic (5-HT) as well as dopaminergic (DA) activity. A dosedependent inhibitory effect on the estroge- + progesterone-induced lordosis response in ovariectomized rats was demonstrated after treatment with the four amphetamines. In contrast, only d- and l-amphetamine induced a stereotype activity, which is considered to be mediated by DA mechanisms. A decrease in DA receptor activity, achieved by pimozide pretreatment, abolished the effect of d-amphetamine on lordosis behavior, but the effect of l-amphetamine was only slightly diminished and the action of fenfluramine and p-chloroamphetamine was unaffected. On the other hand, both l- and d-amphetamine-induced stereotype activity was prevented by pimozide treatment.The data suggest that the d-amphetamine effect on lordosis behavior is mediated by increased DA receptor activity. Although it induces stereotype activity by increased DA activity, l-amphetamine, like fenflueramine and p-chloroamphetamine, inhibits the lordosis response by some other action presumably related to serotonergic mechanisms.     

The 5-HT1A receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors

Rationale: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. Objective: The present study investigated the role of pre- and postsynaptic 5-HT_1A receptors on rats’ attentional performance in the five-choice serial reaction time task (5-CSRT). Methods: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT_1A receptor agonist, at various subcutaneous (SC) doses (10–100 μg/kg) on measures of rats’ discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT_1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. Results: A dose of 100 μg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10–100 μg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the other effects on rats’ performance. An ICV injection of 150 μg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 μg/0.5 μl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. Conclusions: The results suggest that stimulation of presynaptic 5-HT_1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of postsynaptic 5-HT_1A receptors. Received: 7 August 1999 / Final version: 14 December 1999     

Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior.

Reducing levels of 5-HT in the central nervous system has been associated with increases in impulsive behavior. However, the impulsivity construct describes a wide range of behaviors, including the inability to withhold a response, intolerance to delay of reward and perseveration of a nonrewarded response. Although these behaviors are generally studied using instrumental paradigms, impulsivity may also be reflected in simple Pavlovian tasks such as autoshaping and conditioned activity. This experiment aimed to characterize further the effects of central 5-HT depletion and to investigate whether different behavioral measures of impulsivity are inter-related, thus validating the construct. Rats received intracerebroventricular (ICV) infusions of vehicle (n=10) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (n=12) which depleted forebrain 5-HT levels by about 90%. Lesioned animals showed significant increases in the speed and number of responses made in autoshaping, increased premature responding on a simple visual attentional task, enhanced expression of locomotor activity conditioned to food presentation, yet no change in impulsive choice was observed, as measured by a delay-discounting paradigm. Significant positive correlations were found between responses made in autoshaping and the level of conditioned activity, indicating a possible common basis for these behaviors, yet no correlations were found between other behavioral measures. These data strengthen and extend the hypothesis that 5-HT depletion increases certain types of impulsive responding. However, not all measures of impulsivity appear to be uniformly affected by 5-HT depletion, or correlate with each other, supporting the suggestion that impulsivity is not a unitary construct.     

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. Received: 31 August 1998 / Final version: 16 August 1999     

Serotonin Depletion Induces ‘Waiting Impulsivity' on the Human Four-Choice Serial Reaction Time Task: Cross-Species Translational Significance

Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behavior. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analog of a rodent 5-choice serial reaction time task (5-CSRTT)— the human 4-CSRTT—and a reward delay-discounting questionnaire to measure effects on these different forms of ‘waiting impulsivity''. There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire. However, TD significantly increased 4-CSRTT premature responses (or impulsive action), which is remarkably similar to the previous findings of effect of serotonin depletion on rodent 5-CSRTT performance. Moreover, the increased premature responding in TD correlated significantly with individual differences on the motor impulsivity subscale of the Barratt Impulsivity Scale. TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing. The results suggest: (i) the 4-CSRTT will be a valuable addition to the tests already available to measure impulsivity in humans in a direct translational analog of a test extensively used in rodents; (ii) TD in humans produces a qualitatively similar profile of effects to those in rodents (ie, enhancing premature responding), hence supporting the conclusion that TD in humans exerts at least some of its effects on central serotonin; and (iii) this manipulation of serotonin produces dissociable effects on different measures of impulsivity, suggesting considerable specificity in its modulatory role.     

Serotonergic lesions of the dorsal hippocampus differentially modulate locomotor hyperactivity induced by drugs of abuse in rats: implications for schizophrenia

Rationale

Psychotomimetic drug-induced locomotor hyperactivity is a widely used animal model of psychotic states, such as in schizophrenia. We previously found that serotonergic lesions of the dorsal, but not ventral, hippocampus in rats result in enhanced phencyclidine-induced locomotor hyperactivity.

Objectives

The objective of this study was to investigate the effect of serotonin depletion in the dorsal and ventral hippocampus on hyperlocomotion induced by ketamine, cocaine, 3,4-methylenedioxymethampethamine (MDMA), methamphetamine, and d-amphetamine.

Materials and methods

Male Sprague–Dawley rats were bilaterally microinjected with vehicle or the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the dorsal or ventral hippocampus using a stereotaxic approach. Separate cohorts of rats were used for each drug of abuse; each rat received saline and a low, medium, and high dose of the drug in a random-sequence, repeated-measures protocol. Locomotor hyperactivity following treatment was measured using automated photocell cages.

Results

Similar to phencyclidine, 5,7-DHT-induced lesions of the dorsal hippocampus enhanced ketamine-induced hyperlocomotion at all doses. They also reduced methamphetamine-induced hyperlocomotion at the high dose only and caused a minor, biphasic modulation of responses to cocaine. Locomotor responses to d-amphetamine and MDMA were unchanged by lesions of the dorsal hippocampus. Serotonergic lesions of the ventral hippocampus did not significantly alter locomotor hyperactivity induced by any of the drugs investigated.

Conclusions

These findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.     

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     

The effects of lesions produced by 5,7-dihydroxytryptamine on 5-hydroxytryptamine-mediated behaviour induced by amphetamine in large doses in the rat

The role of 5-hydroxytryptamine (5-HT)-containing terminals in the spinal cord and basal ganglia in behavioural responses induced by amphetamine in large doses have been investigated using the neurotoxin for 5-HT, 5,7-dihydroxytryptamine (5,7-DHT). The effects of pretreatment with 5,7-DHT were also examined using the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). d-Amphetamine (25 mg/kg) induced several classical 5-HT-dependent behavioural responses (head weaving, forepaw treading, hind limb abduction, “wet dog” shakes, Straub tail), together with some classical dopamine (DA)-dependent behaviour and backward locomotion which requires both transmitters. Pretreatment with 5,7-DHT, given into the striatum significantly decreased “wet dog” shakes and virtually abolished backward walking. Pretreatment with 5,7-DHT in the nucleus accumbens or substantia nigra did not significantly alter behaviour. Pretreatment with 5,7-DHT intraspinally did not significantly alter behaviour induced by amphetamine, although a decrease of Straub tail just failed to reach significance (P = 0.056). Similar pretreatment in rats given 5-MeODMT (8 mg/kg) significantly enhanced both Straub tail and tremor but did not alter the other behavioural responses induced by this drug (limb abduction, forepaw treading, head weaving). The results in general suggest that behavioural responses induced by 5-HT can be classified into 3 groups (a) those requiring striatal 5-HT (“wet dog” shakes and backward locomotion), (b) those requiring spinal 5-HT (Straub tail, tremor) and (c) those requiring neither spinal nor striatal 5-HT (hind limb abduction, head weaving and forepaw treading).     

Serotonin depletion in the dorsal and ventral hippocampus: effects on locomotor hyperactivity, prepulse inhibition and learning and memory

We present an overview of our studies on the differential role of serotonergic projections from the median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) in behavioural animal models with relevance to schizophrenia. Stereotaxic microinjection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the MRN or one of its main projections regions, the dorsal hippocampus, induced a marked enhancement of phencyclidine-induced locomotor hyperactivity and a disruption of prepulse inhibition (PPI) in rats. There was no enhancement of locomotor hyperactivity induced by amphetamine or MK-801 or after 5,7-DHT lesions of the DRN or ventral hippocampus. Rats with dorsal hippocampus lesions did not show significant changes in the Y-maze test for short-term spatial memory, the Morris water maze for long-term spatial memory, or in the T-maze delayed alternation test for working memory. These chronic lesion studies suggest a modulatory influence of serotonergic projections from the MRN to the dorsal hippocampus on phencyclidine effects and prepulse inhibition, but not on different forms of learning and memory. The results provide new insight into the role of serotonin in the dorsal hippocampus in aspects of schizophrenia.     

Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor,citalopram

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mol/kg for 13 days and after oral bolus injection (49 mol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.     

Amphetamine and LSD as discriminative stimuli: Alterations following neonatal monoamine reductions

Male adult Sprague-Dawley rats (70 days of age), neonatally depleted of either 5-hydroxytryptamine (5HT) via 5,7-dihydroxytryptamine (5,7-DHT; ICS) + desmethylimipramine (DMI; IP) at 3 days of age or dopamine (DA) via 6-hydroxydopamine (6-OHDA; ICS) + DMI at 14 days of age, were trained to discriminate either d-LSD-tartrate (80 μg/kg; IP) or d-amphetamine (d-AMPH sulfate (0.90 mg/kg; IP) from saline utilizing a two lever drug discrimination paradigm. A neurochemical analysis at the termination of these studies revealed the following in terms of %DA or %5HT (presented in that order) depleted with respect to the appropriate vehicle control group; telencephalon; 96 and 96%, diencephalon; 51 and 31%, and brain stem; 76 and 80%. Rats learned to discriminate either d-AMPH or LSD regardless of amine depleted. In addition, the depletion of 5HT had little effects on dose or drug generalizations, or the ability of known antagonists to antagonize the discrimination stimulus (DS) effects of either LSD or d-AMPH. The effect of DA depletion, on the other hand, was to increase the sensitivity of the LSD DS at low doses, while decreasing the sensitivity of the d-amphetamine DS. DA depletion alsp had the effect of reducing the effectiveness of the LSD-antagonists, pizotifen maleate (BC 105), while the opposite was observed for the d-AMPH antagonist, trifluoperazine HCl. These data suggest that: (1) LSD and d-amphetamine discrimination stimuli are not mediated and/or influenced via the compromised aspects of the 5HT systems (other central mechanisms may have compromised for these 5HT deficits); (2) the LSD DS is mediated or influenced both by serotonergic and dopaminergic mechanisms; and (3) the d-amphetamine DS is mediated by certain aspects of the dopaminergic system with little evidence for the involvement of 5HT systems.     

Drug-induced activation of the inferior olivary nucleus in young rabbits. Differential effects of harmaline and quipazine

Ontogenic evolution of behavioural and electrophysiological responses to the serotonergic agents, quipazine and harmaline, was studied in the maturing rabbit in normal and pretreated conditions. As regards behavioural effects, tremor induced by quipazine was present from the first postnatal day and was antagonized by methysergide, but not by p-chlorophenylalanine (PCPA) or pretreatment with 5,7-dihydroxytryptamine (5,7-DHT). In contrast, tremor induced by harmaline could not be elicited before the second postnatal week and was partially antagonized by methysergide and 5,7-DHT, but not by PCPA. Electrophysiological studies of cell activity in the inferior olivary nucleus revealed a similar dependency on age since rhythmic activation of the inferior olivary nucleus could be registered from the first postnatal day with quipazine and only from the 8th postnatal day with harmaline; drug interactions with methysergide, PCPA and 5,7-DHT were the same as for the behavioural observations. It is suggested that quipazine directly activates serotonin receptors which are already present at birth, whereas harmaline requires the presence of serotonergic fibres for such activation.     

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core

Rationale Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (d-amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% l-amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for d-amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between d-amphetamine and l-amphetamine have not been well characterized.Objectives To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes.Results The presence of l-amphetamine in the d,l-amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The d,l-amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When l-amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of d,l-amphetamine.Conclusions These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that l-amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.     

Impact of strain and d-amphetamine on impulsivity (delay discounting) in inbred mice

Rationale Many studies have shown that human drug abusers are more impulsive than nonusers, but the mechanisms underlying this difference are unknown. C57BL/6J (B6) and DBA/2J (D2) mouse strains differ in sensitivity to the associative effects and in self-administration of several drugs of abuse.Objective To determine whether these strains exhibit differences in impulsivity that might correspond to the differences in phenotypes related to drug seeking.Methods We examined impulsive choice in drug-naive B6 and D2 mice using a delay discounting protocol (adjusting amount procedure, J Exp Anal Behav 67:353–366, 1997).Results Contrary to our initial expectations, we observed greater delay discounting (higher impulsivity) in D2 rather than in B6 mice. For both strains, discounting was enhanced by 0.80 and 1.20 mg/kg (i.p.) d-amphetamine relative to saline.Conclusions Data demonstrate the sensitivity of the procedure to strain differences and pharmacological manipulations. However, additional data are required to clarify the factors underlying this difference and how the delay discounting measure of impulsivity relates to phenotypic models of drug reinforcement and drug seeking.