Can auditory cues improve visuo-spatial neglect? Results of two pilot studies.

Although neglect is known to be a multimodal deficit, current interventions often address the visual modality only. Experimental studies, however, found that neglect patients can partially overcome their spatial inattention temporarily when being exposed to auditory cues that move towards the neglected side of space. Two pilot studies investigated the impact of dynamic auditory cueing on egocentric neglect severity in a clinical-therapeutic setting. In both studies, the patient groups received 15 sessions of intervention. Study 1, designed as double-blinded trial with a historical control group, targeted severely impaired early-acute patients who listened to music or audio books which were presented as moving dynamically from right to left. Results showed a reduction in egocentric neglect severity that persisted after therapy termination in the intervention but not in the historical control group. In study 2, based on the comparison with reported effect sizes of previous studies, dynamic meaningful auditory cues and optokinetic stimulation were combined in a computer-based training. Both studies found a significant reduction of neglect severity. Results provide evidence for the reduction of egocentric neglect severity after repetitive auditory cueing therapy in both severely and moderately impaired patients. Our promising findings should be verified thoroughly in randomized-controlled trials.

Effects of Acute Aerobic Exercise on Response Inhibition in Adult Patients with ADHD.

Previous studies suggest beneficial effects of aerobic exercise on executive functions, which are a core deficit in ADHD. The aim of the present fMRI study was to investigate acute effects of aerobic exercise on inhibitory control and related brain activation in adult patients with ADHD. 23 patients and 23 matched healthy controls performed on a Go/No-go task in an MRI scanner, following both, an exercise condition involving 30 min of cycling at moderate intensity, and a control condition. ADHD patients compared to healthy controls showed increased brain activation during successful inhibition in the exercise compared to the control condition in parietal, temporal, and occipital regions. Exercise did not improve behavioral performance in either group, but in ADHD patients, exercise-related increases in brain activation and behavioral task performance (i.e., correct inhibition rate) negatively correlated with correct inhibition rate in the control condition. Thus, patients with worse inhibition performance showed stronger exercise-related enhancements, indicating that the lack of improvements on the behavioral level for the whole patient group could be due to ceiling effects. Our findings might be an important step in understanding the neural basis of exercise effects and could, in the long term, help in developing alternative treatment approaches for ADHD.

Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE epsilon4 carriers.

Presence of the apolipoprotein E (APOE) epsilon4 allele is linked to an increased risk to develop Alzheimer's dementia (AD). However, there are controversial data concerning the impact of the APOE genotype on cognitive functioning and brain activity in healthy subjects. We used event-related functional magnetic resonance imaging (fMRI) to investigate the effects of APOE genotype on spatial contextual memory encoding and retrieval success in healthy older adults. Eighteen subjects (eight APOE4 heterozygotes (epsilon4+) and 10 non-carriers (epsilon4-), mean age 60.0+/-5.0 years) were included in the present analysis. Behaviorally, epsilon4+ subjects performed significantly worse than epsilon4- subjects in item memory and spatial context retrieval. fMRI data revealed that epsilon4+ subjects, compared to epsilon4-subjects, predominantly showed an increase of neural activity specific to encoding of items and their spatial context in prefrontal, temporal and parietal regions. In contrast, epsilon4+ subjects showed activity decreases in the right amygdala during successful item recognition and in the prefrontal cortex bilaterally during spatial context retrieval when compared to epsilon4- subjects. While the activity increases during encoding may reflect compensatory activity in the attempt to maintain normal performance, the decreases during retrieval indicate incipient neural decline in epsilon4+ subjects. These data highlight that preclinical ApoE-related changes in neural activity are not unidirectional but dissociate depending on the memory phase, i.e., encoding or retrieval.

Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT(2A) agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. Fourteen healthy volunteers participated in a randomized double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

The effect of nicotine on visuospatial attention in chronic spatial neglect depends upon lesion location.

The deficit to reorient attention from ipsilesional to contralesional space is one key feature of the spatial neglect syndrome. As previous studies suggest that reorienting of visuospatial attention is modulated by cholinergic neurotransmission, we investigated whether cholinergic stimulation with nicotine (Nicorette 2 mg, Pharmacia/Pfizer, Helsingborg, Sweden) facilitates attentional reorienting in spatial neglect patients. Nine nonsmoking patients with stable neglect symptoms were investigated in a within-subject cross-over design. We used a location-cueing paradigm and analysed reaction time (RT) differences between validly and invalidly cued, as well as between neutrally cued and uncued targets as a function of hemifield and drug. Moreover, since the nicotine effect is mediated by parietal brain areas in healthy subjects, we tested whether lesion location influences the pharmacological effect. Nicotine speeded RTs in valid and invalid trials nonspecifically, without modulating the validity effect in the location-cueing task in the whole group of patients. Lesion-symptom mapping revealed a relationship between lesion site and the pharmacological effect on reorienting to contralesional space in right parietal and temporal brain regions. We conclude that in patients with chronic spatial neglect the performance in the location-cueing paradigm can be modulated by a cholinergic stimulant provided that the lesion spares right parietal and temporal cortex.

Effects of the cholinergic agonist nicotine on reorienting of visual spatial attention and top-down attentional control.

The cholinergic agonist nicotine facilitates detection of invalidly cued trials in location-cueing paradigms and reduces the associated neural activity in human inferior parietal cortex. By using functional magnetic resonance imaging we test the hypothesis that the nicotinic modulation of attentional reorienting may result from reduced use of top-down information derived from prior cues. In a within subjects design non-smoking volunteers were given either placebo or nicotine (Nicorette 2 mg gum) prior to performing a cued target discrimination task. Attention was either validly (80%) or invalidly (20%) cued to the right or left visual hemifield. The difference in reaction times to invalidly and validly cued targets is termed the 'validity effect' and indicates the costs for attentional reorienting. Nicotine reduced the validity effect and reorienting-related neural activity in right inferior parietal cortex. Further regions consistently modulated in their activity by nicotine were the right middle temporal gyrus, left middle frontal gyrus, left parahippocampal gyrus and right cerebellum. The effects of nicotine upon top-down modulation were investigated by comparing occipital activity when attending to the right vs. left visual hemifield under placebo and nicotine. If nicotine reduced the use of top-down information attentional modulation in occipital cortex should be smaller under nicotine as compared with placebo. Even though an attention-related modulation of neural activity was observed in the fusiform and middle occipital gyrus we found no evidence for differences in attentional modulation under placebo and nicotine. Our data support a role of nicotinic cholinergic receptors in facilitating several subcomponents of attentional reorienting via modulation of right inferior parietal, temporal and frontal brain activity. In contrast, the findings in the occipital cortex do not support the hypothesis that the effects of nicotine on attentional reorienting are due to reduced reliance on top-down information derived from prior cues.

fMRI data predict individual differences of behavioral effects of nicotine: a partial least square analysis.

Reorienting of visuospatial attention can be investigated by comparing reaction times to validly and invalidly cued targets ("validity effect"). The cholinergic agonist nicotine reduces the validity effect and neural activity in the posterior parietal cortex. Behavioral effects of nicotine in nonsmokers are weak and it has been suggested that differences in baseline behavior before nicotine exposure may influence the effect of nicotine. This study investigates whether individual differences in reorienting-related neural activity under placebo may be used to predict individual nicotine effects. Individual nicotine effects are defined as the behavioral effects under nicotine that cannot be predicted by the behavioral data under placebo. Fifteen nonsmoking subjects were given either placebo or nicotine gum (2 mg) prior to performing a cued target detection task inside a magnetic resonance imaging scanner. The results of a partial least square analysis suggest that neural data under placebo can be used to predict individual behavioral effects of nicotine. Neural activity in the left posterior cingulate cortex, the right superior parietal cortex, the right dorsal medial prefrontal cortex, and the left ventral medial prefrontal cortex significantly contributes to that prediction. We conclude that nicotine effects on reorienting attention depend on individual differences in reorienting-related neural activity under placebo and suggest that functional magnetic resonance imaging data can contribute to the prediction of individual drug effects.

Effects of nicotine on visuo-spatial selective attention as indexed by event-related potentials.

Nicotine has been shown to specifically reduce reaction times to invalidly cued targets in spatial cueing paradigms. In two experiments, we used event-related potentials to test whether the facilitative effect of nicotine upon the detection of invalidly cued targets is due to a modulation of perceptual processing, as indexed by early attention-related event-related potential components. Furthermore, we assessed whether the effect of nicotine on such unattended stimuli depends upon the use of exogenous or endogenous cues. In both experiments, the electroencephalogram was recorded while non-smokers completed discrimination tasks in Posner-type paradigms after chewing a nicotine polacrilex gum (Nicorette 2 mg) in one session and a placebo gum in another session. Nicotine reduced reaction times to invalidly cued targets when cueing was endogenous. In contrast, no differential effect of nicotine on reaction times was observed when exogenous cues were used. Electrophysiologically, we found a similar attentional modulation of the P1 and N1 components under placebo and nicotine but a differential modulation of later event-related potential components at a frontocentral site. The lack of a drug-dependent modulation of P1 and N1 in the presence of a behavioral effect suggests that the effect of nicotine in endogenous visuo-spatial cueing tasks is not due to an alteration of perceptual processes. Rather, the differential modulation of frontocentral event-related potentials suggests that nicotine acts at later stages of target processing.

The left parietal cortex and motor intention: an event-related functional magnetic resonance imaging study.

Traditionally the posterior parietal cortex was believed to be a sensory structure. More recently, however, its important role in sensory-motor integration has been recognized. One of its functions suggested in this context is the forming of intentions, i.e. high-level cognitive plans for movements. The selection and planning of a specific movement defines motor intention. In this study we used rapid event-related functional magnetic resonance imaging of healthy human subjects to investigate the involvement of posterior parietal cortex in motor intention in response to valid imperative cues. Subjects were provided with either neutral, motor or spatial cues. Neutral cues simply alerted, motor cues indicated which hand to use for response, and spatial cues indicated on which side the target would appear. Importantly, identical targets and responses followed these cues. Therefore any differential neural effects observed are independent from the actual movement performed. Differential blood oxygen level dependent signal changes for motor vs. neutral as well as motor vs. spatial cue trials were found in the left supramarginal gyrus, as hypothesized. The results demonstrate that neural activity in the left supramarginal gyrus underlies motor plans independent from the execution of the movement and thus extend previous neuropsychological and functional imaging data on the role of the left supramarginal gyrus in higher motor cognition.

The modulatory effects of nicotine on parietal cortex activity in a cued target detection task depend on cue reliability.

This functional magnetic resonance imaging study investigates the effects of nicotine in a cued target detection task when changing cue reliability. Fifteen non-smoking volunteers were studied under placebo and nicotine (Nicorette polacrilex gum 1 and 2 mg). Validly and invalidly cued trials were arranged in blocks with high, middle and low cue reliability. Two effects of nicotine were investigated: its influence on i) parietal cortex activity underlying the processing of invalid vs. valid trials (i.e. validity effect) and ii) neural activity in the context of low, middle and high informative value of the cue (i.e. cue reliability effect). Nicotine did not affect behavioral performance. However, nicotine reduced the difference in the blood oxygenation level dependent (BOLD) signal between invalid and valid trials in the right intraparietal sulcus. The reduction of parietal activity in invalid trials was smaller in the low cue reliability condition. The same posterior parietal region exhibited a nicotinic modulation of BOLD activity in valid trials which was dependent on cue reliability: Nicotine specifically enhanced the neural activity during valid trials in the context of low cue reliability, i.e. when subjects are already in a state of low certainty. We speculate that the right intraparietal sulcus might be part of two networks working in parallel: one responsible for reorienting attention and the other for the cholinergic modulation of cue reliability. By reducing the use of the cue, nicotine modulates parietal activity related to reorienting attention in conditions with higher cue certainty. On the other hand, nicotine increases parietal activity in states of low certainty. This enhanced activation might influence brain regions, such as the posterior cingulate, directly involved in the processing of cue reliability.

Neuronal correlates of familiarity-driven decisions in artificial grammar learning.

It has been proposed on the basis of behavioural data that grammaticality judgments in implicit artificial grammar learning paradigms are largely driven by priming based on fragment familiarity. A prediction that follows from this account is that neural deactivation, a common correlate of repetition priming, should be observed for grammatical compared to ungrammatical stimuli. We conducted an event-related fMRI study to investigate neuronal correlates of such fragment-based priming. In a study phase, participants performed a short-term memory task on a series of strings of pseudofont characters. Scanning was performed in a subsequent test phase in which participants classified new strings as either grammatical or ungrammatical. Test strings differed systematically from training strings in terms of exemplar and fragment similarity. Behaviourally, participants classified strings as grammatical based on fragment familiarity. Differential activity was evident during string classification as reduced activity in left lateral occipital complex and bilateral lingual gyri for strings with high fragment familiarity compared to strings with low fragment familiarity. Thus, consistent with the hypothesis, neuronal facilitation in extrastriate occipital regions may constitute one basis of implicit grammaticality decisions based on fragment priming.

Effects of cholinergic enhancement on conditioning-related responses in human auditory cortex.

It has previously been shown that cholinergic blockade attenuates conditioning-related neuronal responses in human auditory cortex. The present study was conducted to investigate the effect of cholinergic enhancement on such experience-dependent cortical responses. The cholinesterase inhibitor physostigmine, or a placebo control, were continuously infused into healthy young volunteers, during differential aversive conditioning whilst brain activity was measured using event-related functional magnetic resonance imaging (fMRI). Volunteers were presented with two tones, one of which (CS+) was conditioned by pairing with an electrical shock whereas the other was always presented without the shock (CS-). Conditioning-related activations, expressed as an enhanced blood oxygenation level dependent (BOLD) response to the salient CS+, were evident in left auditory cortex under placebo but not under physostigmine. This absence of conditioning-related activations under physostigmine was due to enhanced responses to the CS- under physostigmine as compared to placebo. We suggest that an overactive cholinergic system leads to increased processing of behaviourally irrelevant stimuli and thus attenuates differential conditioning-related cortical activations.

Pharmacological modulation of behavioral and neuronal correlates of repetition priming.

In this experiment we address the pharmacological modulation of repetition priming, a basic form of learning, using event-related functional magnetic resonance imaging. We measured brain activity in a word-stem completion paradigm in which, before study, volunteers were given either placebo, lorazepam (2 mg orally), or scopolamine (0.4 mg, i.v.). Relative to placebo, both drugs attenuated the behavioral expression of priming. Repetition was associated with a decreased neuronal response in left extrastriate, left middle frontal, and left inferior frontal cortices in the placebo group. Both drugs abolished these "repetition suppression" effects. By showing a concurrence of behavioral and neuronal modulations, the results suggest that GABAergic and cholinergic systems influence the neuronal plasticity necessary for repetition priming.

Dopaminergic lateralisation in the forebrain: relations to behavioural asymmetries and anxiety in male Wistar rats.

Neurochemical lateralisation has been demonstrated in dopaminergic systems in the rat brain, and it has been suggested that such lateralisation might contribute to asymmetric and emotional behaviour. Here, we investigated dopaminergic brain lateralisation in relation to spontaneous and drug-induced behavioural asymmetries, and to emotional behaviour in a sample of 24 male Wistar rats. Asymmetric behaviour was measured in the open field in the undrugged state and after a systemic challenge with the muscarinic receptor antagonist scopolamine (0.5 mg/kg). Emotional behaviour was measured in the elevated plus-maze. Dopaminergic lateralisation was assessed by means of a post-mortem analysis of tissue dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) content. We found higher DOPAC/DA ratios in the neostriatum, ventral striatum, frontal cortex and amygdala of the right hemisphere. In the open field, the complete sample of rats did not show a left/right asymmetry in spontaneous behaviour, whereas systemic scopolamine induced a left-sided preference in thigmotactic scanning. A correlational analysis yielded individual relationships between behaviour and post-mortem neurochemistry, since lateralisation of DOPAC/DA ratios in favour of the right ventral striatum was related to right-side thigmotaxis. Furthermore, a right dopaminergic lateralisation in the frontal cortex was associated with lower anxiety. The study indicates that asymmetries in ventral striatal dopamine might contribute to side preferences in thigmotactic scanning while frontal dopaminergic lateralisation might influence emotional processing.

Auditory noise can prevent increased extracellular acetylcholine levels in the hippocampus in response to aversive stimulation.

The intent of this study was to investigate neurochemical and behavioural effects of aversive stimulation and the impact of auditory background noise. Using in vivo microdialysis, hippocampal acetylcholine was extracted and subjected to HPLC analysis while male Wistar rats were exposed to aversive stimulation similar to that used in conventional procedures for aversive conditioning. Three groups of animals were used. Animals in the first group were exposed to a single tone/footshock pairing followed by a tone alone 2 h later. Animals in the second group served as controls and were only exposed to the tone without shock. A third group was exposed to the same tone/shock pairing and tone as the first group while being exposed to constant background noise during the whole experiment. The results showed, that the tone/shock combination led to pronounced behavioral and cholinergic activation. In contrast, exposure to background noise prevented the increase in hippocampal ACh levels to tone/shock stimulation. The unconditioned behavioural response, however, was not prevented suggesting that hippocampal ACh is not a necessary correlate of behavioural activation or arousal. A second experiment intended to investigate the effects of background noise in a shuttle box avoidance learning paradigm where rats were trained to avoid an aversive footshock, which was signalled by a tone. There, one group of rats was exposed to background noise during avoidance learning, and the other group was not exposed to noise. Whereas both groups learned to avoid the shock to some degree over training, the noise exposed animals did not show improvement in escape performance over the course of training, indicating that the noise hindered development of an adaptive response to the shock. In summary, our data indicate that background noise can prevent increased extracellular hippocampal ACh levels in response to an aversive stimulus, and can also lead to deficits in learning to escape from shock.

High versus low reactivity to a novel environment: behavioural, pharmacological and neurochemical assessments.

Based on their rearing response to a novel open field, male Wistar rats were divided into two sub-groups with either high or low behavioural activity (high rearings, versus low rearings). These sub-groups were repeatedly exposed to the same open field and tested for behavioural habituation. Since we previously found neurochemical evidence for different cholinergic reactivities in such high rearing and low rearing rats, their behavioural responses to the muscarinic antagonist scopolamine (0.5 mg/kg) were also investigated in the open field. Additionally, they were exposed to the elevated plus-maze to test for possible differences in measures of anxiety. After behavioural testing, tissue concentrations of biogenic amines were determined in the ventral striatum (nucleus accumbens, olfactory tubercle), frontal cortex, striatum, hippocampus and amygdala. The results show that the higher rearing responses of high rearing rats in the novel open field were paralleled by higher locomotor activity. These behavioural differences between groups decreased with repeated open field exposure, an effect which was largely due to between-session habituation in high rearing rats. Thereby, high rearing rats approached the lower levels of low rearing rats, in which locomotor activity and rearings did not habituate between testing. Nevertheless, habituation was also observed in low rearing rats, especially in the measure of thigmotactic scanning, since the levels of scanning declined both between and within test sessions. The anticholinergic challenge with scopolamine induced a general pattern of behavioural activation. Furthermore, scopolamine partly reinstated the behavioural differences between high and low rearing rats that had been observed in the novel open field, since high rearing rats showed more rearing behaviour than low rearing rats under scopolamine. In contrast to the open field, there were no significant differences between high and low rearing rats in the plus-maze. The neurochemical analysis revealed, among others, higher dopamine levels in the ventral striatum of high rearing rats together with lower serotonin levels in the medial frontal cortex. The current findings thus indicate that high and low rearing rats not only differ in their behavioural response to a novel environment, but also in their patterns of behavioural habituation, and with respect to behaviour induced by an anti-cholinergic challenge. These differential behavioural profiles of high and low rearing animals are discussed with respect to the role of dopaminergic mechanisms in the forebrain, and the potential impact of cholinergic mechanisms.

Cholinergic activation in frontal cortex and nucleus accumbens related to basic behavioral manipulations: handling, and the role of post-handling experience.

The present experiment is part of a series of studies designed to investigate cerebral cholinergic activity during basic behavioral testing procedures. Using in vivo microdialysis, we monitored extracellular acetylcholine levels in rats which were picked up manually (termed handling) and exposed to an open field, or animals which were picked up and returned to their home cage. These procedures were repeated on two consecutive days. In the lateral precentral area of the frontal cortex, both procedures increased cholinergic activity. However, on the 1 st day of testing, the degree of cholinergic activation was of even greater magnitude in animals which were returned to the home cage after handling than in animals which were exposed to a novel open field. This neurochemical pattern was dissociated from behavioral indices of activation, since rearing and locomotor activity were more pronounced in the open field than in the home cage. In the nucleus accumbens core and shell, where extracellular acetylcholine is provided by cholinergic interneurons, we also found cholinergic activation on both days of testing. However, unlike the frontal cortex, there were no substantial neurochemical differences between animals which were exposed to the open field after handling vs. those which were returned to their home cage. Together, our data suggest that a simple interaction like handling provides a significant stimulus for the animal to which cholinergic activity responds in several forebrain areas. Here, frontal cortical acetylcholine appears to be especially sensitive, with a pattern of activation which is dependent on post-handling experience. These results are discussed with respect to their possible functional implications, and the role of handling as an experimental factor. Since handling is part of many neurobehavioral procedures, handling-induced changes can interact with the imposed independent variables under investigation, such as post-trial pharmacological manipulations, requiring consideration in the interpretation of any experiment employing handling of the subjects.

Hippocampal acetylcholine and habituation learning.

Acetylcholine neurotransmission is considered to play a critical role in processes underlying behavioural activity, arousal, attention, learning, and memory. These functional attributions have largely been based on pharmacological findings. or data from brain damaged animals, and humans with neurodegenerative diseases, such as Alzheimer's disease. With the introduction of the in vivo microdialysis method it has recently become possible to monitor acetylcholine in the brain of the behaving animal, which allows to investigate its activity in specific behavioural tasks. With respect to learning and memory, one of the most elementary experimental paradigms is that of behavioural habituation, where the decrease of exploratory activity as a function of repeated exposure to the same environment is taken as an index of memory. We have used this paradigm to monitor hippocampal acetylcholine levels by means of in vivo microdialysis in rats, which were exposed to a novel open field and which were re-exposed to it on the following day (10 min each). The results show that exposure of rats to the novel environment led to increased extracellular levels of hippocampal acetylcholine which were positively correlated with exploratory behaviour. These cholinergic activations were larger than those of control animals which were handled like the experimental animals but which were not exposed to the open field. When re-exposing the experimental animals to the same environment, exploratory behaviour, but not cholinergic activation, was decreased. indicating habituation. In the subsequent 10 min, that is, when the animals where back in their home cages, cholinergic activity was still increased. The magnitude of increase was larger after re-exposure than after exposure to the novel open field. Finally, we differentiated the animals into "superior" vs "inferior" learners and found that the "superior" learners showed higher behavioural activation in the novel environment and stronger neurochemical responses, both. in the novel and familiar environment. Our data show that extracellular levels of hippocampal acetylcholine are not only elevated in relation to novelty and behavioural activation. but also during behavioural habituation. Furthermore, an inter-individual variability of cholinergic activation seems to exist which is related to individual differences in behavioural responsiveness to novelty. Such differences in cholinergic activity may be related to other known differences in hippocampal structure and function and may be important for previously reported inter-individual variabilities in sensation-seeking and related mnestic functions.

Relationship between anxiety and serotonin in the ventral striatum.

Rats were tested in an elevated plus-maze on two consecutive days. Based on the percentage of time spent in the open arms on the 1st day, they were divided into two subgroups with either low or high anxiety levels. A post-mortem neurochemical analysis showed that animals with high anxiety had lower ventral striatal tissue levels of 5-HT. No such differences were found for 5-HT in other brain areas or in dopamine and norepinephrine levels. The ventral striatal 5-HT levels correlated with plus-maze behavior on the 2nd but not 1st day. These data suggest that individual differences in ventral striatal 5-HT interact with plus-maze behavior, which may help to explain why serotonergic drugs can have inconsistent effects in this paradigm.