Opposing effects of 5,7-DHT lesions to the core and shell of the nucleus accumbens on the processing of irrelevant stimuli.

There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7-DHT lesions to the shell produced the opposite effect and potentiated LI.

Blockade of dopamine D3 but not D2 receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment.

Dopamine D3 receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D3 vs. D2 receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D3 selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D3 antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D2 antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D3 receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D3 receptor antagonists to treat schizophrenia.

Depolarizing and calcium-mobilizing stimuli fail to enhance synthesis and release of endocannabinoids from rat brain cerebral cortex slices.

The concentrations of the endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolamine (anandamide) were examined in rat brain cerebral cortex slices and surrounding medium. Basal concentrations of endocannabinoids were similar to those identified previously in rat brain, with anandamide content being much lower (19 pmol/g) than that of 2-AG (7300 pmol/g). In contrast, basal concentrations in the surrounding medium were proportionally much lower for 2-arachidonoylglycerol (16 pmol/mL) compared to anandamide (0.6 pmol/mL). Incubation of slices with glutamate receptor agonists, depolarizing concentrations of KCl, or ionomycin failed to alter tissue concentrations of endocannabinoids, while endocannabinoids in the medium were unaltered by elevated KCl. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester, an inhibitor of fatty acid amide hydrolase, significantly enhanced tissue concentrations of anandamide (and related N-acylethanolamines), without altering 2-AG, while evoking proportional elevations of anandamide in the medium. Removal of extracellular calcium ions failed to alter tissue concentrations of anandamide, but significantly reduced 2-AG in the tissue by 90% and levels in the medium to below the detection limit. Supplementation of the medium with 50 µM N-oleoylethanolamine only raised tissue concentrations of N-oleoylethanolamine in the presence of cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester and failed to alter either tissue or medium anandamide or 2-AG concentrations. These results highlight the ongoing turnover of endocannabinoids, and the importance of calcium ions in maintaining 2-AG concentrations in this tissue.

Acute effects of bergamot oil on anxiety-related behaviour and corticosterone level in rats.

Bergamot essential oil (BEO), Citrus aurantium subsp. bergamia (Risso) Wright & Arn. (Rutaceae), is used widely in aromatherapy to reduce stress and anxiety despite limited scientific evidence. A previous study showed that BEO significantly increased gamma-aminobutyric acid levels in rat hippocampus, suggesting potential anxiolytic properties. The aim of this study was to investigate the effect of BEO (1.0%, 2.5% and 5.0% w/w) administered to rats on both anxiety-related behaviours (the elevated plus-maze (EPM) and hole-board tests) and stress-induced levels of plasma corticosterone in comparison with the effects of diazepam. Inhalation of BEO (1% and 2.5%) and injection of diazepam (1 mg/kg, i.p.) significantly increased the percentage of open arm entries on the EPM. The percentage time spent in the open arms was also significantly enhanced following administration of either BEO (2.5% and 5%) or diazepam. Total arm entries were significantly increased with the highest dose (5%), suggesting an increase in locomotor activity. In the hole-board test, 2.5% BEO and diazepam significantly increased the number of head dips. 2.5% BEO and diazepam attenuated the corticosterone response to acute stress caused by exposure to the EPM. In conclusion, both BEO and diazepam exhibited anxiolytic-like behaviours and attenuated HPA axis activity by reducing the corticosterone response to stress.

A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory.

The serotonergic system is implicated in the neurobiological control of learning and memory, both in healthy individuals and pathological disorders, although the underlying mechanisms remain elusive. After the cloning and characterization of serotonin, or 5-hydroxytryptamine (5-HT), receptors and the resultant development of selective agonist and antagonist compounds and transgenic receptor-knockout mice, our understanding of the role of various serotonin receptors in learning and memory has improved. 5-HT(1A), 5-HT4 and 5-HT6 receptors are densely expressed in brain regions innervated by serotonergic projections from the raphe nuclei and are associated with learning and memory. Here, we review the evidence that compounds acting on these receptors can have positive effects on learning and memory, and we discuss the potential mechanisms involved. This information raises the possibility that such compounds could be developed as adjunct therapeutics with existing treatments to improve learning and memory deficits, which are core symptoms of Alzheimer's disease, schizophrenia and depression.

The Serotonin Club: coming of age.

This special issue of Trends in Pharmacological Sciences devoted to serotonin, or 5-hydroxytryptamine (5-HT), celebrates the 21st anniversary of the Serotonin Club, an event also marked by a major international meeting on serotonin held 17-20 July 2008, in Oxford (U.K.).

Increased dopamine D2High receptors in rats reared in social isolation.

Postweaning social isolation in the rat induces lasting alterations that parallel several of the core symptoms seen in human schizophrenics, including hyperreactivity to novel environments, cognitive impairment, and deficits in sensorimotor gating. The current study determined whether these changes are accompanied by any elevation in the proportion of striatal dopamine receptors in the functional high affinity state (D(2) (High)), as observed in other preclinical models of psychosis. Male Lister hooded rats (20-24 days) were housed in groups of three or alone. On Day 36 postweaning locomotor activity was monitored for 60 min in a novel arena, and on Day 37 novel object discrimination was assessed using a 2 h intertrial interval. Three days later striata were collected, homogenized, washed three times to remove endogenous dopamine, and the proportion of D(2) (High) determined by competition between dopamine and 2.27 nM [(3)H]domperidone. Isolates were significantly more active than group housed controls for both ambulation and rears. Although both groups exhibited comparable levels of familiarization trial object exploration, group housed animals were able to discriminate between novel and familiar objects during the choice trial while isolates were not. Social isolation was associated with a highly significant elevation in the proportion of striatal D(2) (High), equivalent to a 3.3-fold increase (group 15.2% +/- 1.4%, isolate 49.8% +/- 4.8%; P < 0.0001, Student's unpaired t-test). These findings support both the hypothesis that elevated D(2) (High) is a common feature of multiple animal models of psychosis, and the validity of isolation rearing as a neurodevelopmental model of a "schizophrenia-like" state.

Fluoxetine administration modulates the cytoskeletal microtubular system in the rat hippocampus.

A number of studies suggest that stressful conditions can induce structural alterations in the hippocampus and that antidepressant drugs may prevent such deficits. In particular, the selective serotonin reuptake inhibitor (SSRI) fluoxetine was more effective in modulating different neuronal plasticity phenomena and related molecules in rat hippocampus. Cytoskeletal microtubule dynamics are fundamental to dendrites and axons remodeling, leading to the hypothesis that fluoxetine may affect the microtubular system. However, despite reports of stress-induced alterations in microtubule dynamics by different stressors, only few studies investigated the in vivo effects of antidepressants on microtubules in specific rat brain regions. The present study investigated the dose-related (1, 5, or 10 mg/kg i.p.) effects of acute and chronic (21 days) treatments with fluoxetine on the ratio of hippocampal alpha-tubulin isoforms which is thought to reflect microtubule dynamics. Western Blot analysis was used to quantify alpha-tubulin isoforms, high-performance liquid chromatography and fluorescence detection was used to measure ex vivo monoamine metabolism. The results showed that acute fluoxetine increased the stable forms acetylated and detyrosinated alpha-tubulin. Conversely, chronic fluoxetine decreased acetylated alpha-tubulin, indicative of increased microtubule dynamics. The neuron-specific Delta2-Tubulin was increased by chronic fluoxetine indicating neuronal involvement in the observed cytoskeletal changes. Although acute and chronic fluoxetine similarly altered serotonin metabolism by inhibition of serotonin reuptake, this showed no apparent correlation to the cytoskeletal perturbations. Our findings demonstrate that fluoxetine administration modulates microtubule dynamics in rat hippocampus. The cytoskeletal effect exerted by fluoxetine may eventually culminate in promoting events of structural neuronal remodeling.

Auditory gating in rat hippocampus and medial prefrontal cortex: effect of the cannabinoid agonist WIN55,212-2.

Sensory gating can be assessed in rodents and humans using an auditory conditioning (C)-test (T) paradigm, with schizophrenic patients exhibiting a loss of gating. Dysregulation of the endocannabinoid system has been proposed to be involved in the pathogenesis of schizophrenia. We studied auditory gating and the effects of the cannabinoid agonist WIN55,212-22 on gating in CA3 and dentate gyrus (DG) of the hippocampus and medial prefrontal cortex (mPFC) in male Lister hooded rats using in vivo electrophysiology. The effects of a single dose of WIN55,212-2 on the N2 local field potential (LFP) test/conditioning amplitude ratios (T/C ratio) and response latencies were examined. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. WIN55,212-2 disrupted auditory gating in all three areas with a significant increase in test amplitudes in the gating rats. A group of non-gating rats demonstrated higher test amplitudes and higher T/C ratios compared to gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A prevented WIN55,212-2 induced disruption of gating. This study demonstrates gated auditory-evoked responses in CA3, DG and mPFC. The mPFC showed an early phase of gating which may later be modulated by CA3 and DG activity. Furthermore, cannabinoid receptor activation disrupted auditory gating in CA3, DG and mPFC, an effect which was prevented by CB1 receptor antagonism. The results further demonstrate the presence of a non-gating rat population which responded differently to cannabinoid agonists.

Early life stress causes FG-7142-induced corticolimbic dysfunction in adulthood.

Maternal separation (MS) during the neonatal period enhances stress responsivity in adulthood. The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are involved in coordinating various stress responses. Evidence indicates that MS reduces benzodiazepine and GABA(A) receptor expression in these regions, although their effects on neuronal function in the mPFC and the BLA remain unknown. The present study was conducted to assess the effects of MS on neuronal activity in the mPFC and BLA in response to the benzodiazepine receptor partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142). Rat pups were subjected to MS (360 min), brief handling (H; 15 min) or standard animal facility rearing (AFR) on postnatal days 2-14. In adult males, in vivo electrophysiology under isoflurane anesthesia was used to conduct acute recordings of extracellular unit activity in response to systemic FG-7142 administration. Animals subjected to H showed significantly increased basal mPFC activity compared to MS and AFR animals. There were no differences in basal BLA activity between the early rearing groups. In response to FG-7142, MS animals showed significantly attenuated mPFC activity compared to H animals and a nonsignificant trend towards attenuated mPFC activity compared to AFR animals. In contrast to mPFC, MS animals showed significantly potentiated FG-7142-induced activity in the BLA, compared to both H and AFR animals. These findings indicate that MS induces functionally relevant alterations in corticolimbic GABA(A) receptor signaling. Given that FG-7142 mimics several behavioral and physiological effects of stress, these results may also model stress-induced corticolimbic dysfunction caused by early life stress.

Differential effects of the D- and L- isomers of amphetamine on pharmacological MRI BOLD contrast in the rat.

RATIONALE: The D - and L-amphetamine sulphate isomers are used in the formulation of Adderall XR(R), which is effective in the treatment of attention-deficit hyperactivity disorder (ADHD). The effects of these isomers on brain activity has not been examined using neuroimaging. OBJECTIVES: This study determines the pharmacological magnetic resonance imaging blood-oxygenation-level-dependent (BOLD) response in rat brain regions after administration of each isomer. MATERIALS AND METHODS: Rats were individually placed into a 2.35 T Bruker magnet for 60 min to achieve basal recording of variation in signal intensity. Either saline (n = 9), D-amphetamine sulphate (2 mg/kg, i.p.; n = 9) or L: -amphetamine sulphate (4 mg/kg, i.p.; n = 9) were administered, and recording continued for a further 90 min. Data were analysed for BOLD effects using statistical parametric maps. Blood pressure, blood gases and respiratory rate were monitored during scanning. RESULTS: The isomers show overlapping effects on the BOLD responses in areas including nucleus accumbens, medial entorhinal cortex, colliculi, field CA1 of hippocampus and thalamic nuclei. The L-isomer produced greater global changes in the positive BOLD response than the D-isomer, including the somatosensory and motor cortices and frontal brain regions such as the orbitofrontal cortices, prelimbic and infralimbic cortex which were not observed with the D-isomer. CONCLUSIONS: The amphetamine isomers produce different BOLD responses in brain areas related to cognition, pleasure, pain processing and motor control probably because of variations on brain amine systems such as dopamine and noradrenaline. The isomers may, therefore, have distinct actions on brain regions affected in ADHD patients.

The effects of pharmacological blockade of the 5-HT(6) receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo-pituitary-adrenal axis activity in rats.

5-hydroxytryptamine (5-HT) mediates behavioural and neuroendocrine responses to noxious or stressful stimuli. 5-HT(6) receptors are expressed in brain regions involved in nociceptive processing, however, their role in nociception is unknown. Here we demonstrate that acute, systemic administration of the 5-HT(6) receptor antagonist, 5-chloro-N-(4-methoxy-3-benzothio-phenesulfonamide (SB-271046), reduces formalin-evoked nociceptive behaviour and increases plasma corticosterone. SB-271046 dose-dependently reduced pre-formalin distance moved, rearing, grooming and defecation. These data provide the first evidence for 5-HT(6) receptor-mediated regulation of nociception and hypothalamo-pituitary-adrenal axis activity in a model of persistent pain although effects on locomotor activity demand that the putative antinociceptive effect of SB-271046 be interpreted with some caution.

Dopamine: the rewarding years.

Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine.

Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast.

RATIONALE: Guanfacine (an alpha-(2A) adrenoreceptor agonist) is a drug of benefit in the treatment of attention deficit hyperactivity disorder (ADHD) (Taylor FB, Russo J, J Clin Psychopharmacol 21:223-228, 2001). Assessment of this drug using neuroimaging will provide information about the brain regions involved in its effects. OBJECTIVES: The pharmacological magnetic resonance imaging blood oxygenation level dependent (BOLD) response was determined in rat brain regions following administration of guanfacine. METHODS: Male rats were individually placed into a 2.35 T Bruker magnet for 60 min to achieve basal recording of changes in signal intensity. Either saline (n = 9) or guanfacine (0.3 mg/kg, i.p.; n = 9) was then administered and recording was continued for a further 90 min. Data were analysed for BOLD effects using statistical parametric maps. Respiration rate, blood pressure and blood gases were monitored and remained constant throughout scanning. RESULTS: The main changes observed were negative BOLD effects in the caudate putamen and nucleus accumbens with positive BOLD effects in frontal association, prelimbic and motor cortex areas. CONCLUSIONS: These data suggest that guanfacine can decrease neuronal activity in the caudate while increasing frontal cortex activity. This ability to change neuronal activity in specific areas of rat brain that are known to be impaired in ADHD (Solanto MV, Behav Brain Res 130:65-71, 2002) may contribute to guanfacine's beneficial effects.

Treatment with olanzapine increases cell proliferation in the subventricular zone and prefrontal cortex.

The present study examines the effect of chronic treatment with two atypical neuroleptics, commonly used to treat schizophrenia. Adult rats were given either risperidone or olanzapine in their drinking water for 21 days. Memory was assessed on the first and last day of treatment using an object discrimination test, and the rate of cell proliferation in the subventricular zone (SVZ), dentate gyrus (DG) and prefrontal cortex (PFC) was quantified by immuno staining for Ki-67. The results show that both risperidone and olanzapine significantly improved performance in object discrimination after 21 days, and additionally, olanzapine significantly increased cell proliferation in the SVZ and PFC but not the DG.

Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects.

Neonatal maternal separation (MS) has been used to model long-term changes in neurochemistry and behaviour associated with exposure to early-life stress. This study characterises changes in behavioural and neuroendocrine parameters following MS. On postnatal days (PND) 3-15, male and female Long-Evans rats underwent 3 h daily MS. Non-handled (NH) control offspring remained with the dams. Starting at PND 90, behaviour was assessed at weekly intervals in the elevated plus-maze, elevated T-maze, and locomotor activity boxes, and body weight monitored throughout. At the end of the study, adrenals were weighed and blood collected for analysis of plasma corticosterone and adrenocorticotropic hormone (ACTH) under basal conditions and following restraint stress. As adults, MS weighed more than NH animals. Activity on the open arms of the plus-maze was similar between MS and NH animals. In the T-maze, MS males had shorter emergence latencies than their NH counterparts. Spontaneous ambulation in a novel environment was significantly higher in MS than in NH animals, and males exhibited overall lower activity than females. Basal plasma corticosterone was lower in MS than in NH females, but no rearing condition difference was observed following restraint stress. Females had higher corticosterone and ACTH levels than males, whereas adrenal glands of MS animals weighed less than those of NH controls. The MS paradigm caused long-term gender dependent effects on behaviour and HPA axis status. The consistent gender differences confirm and expand existing results showing altered anxiety and stress reactivity in male and female rats.

Ecstasy: are animal data consistent between species and can they translate to humans?

The number of 3,4-methylenedioxymethamphetamine (ecstasy or MDMA) animal research articles is rapidly increasing and yet studies which place emphasis on the clinical significance are limited due to a lack of reliable human data. MDMA produces an acute, rapid release of brain serotonin and dopamine in experimental animals and in the rat this is associated with increased locomotor activity and the serotonin behavioural syndrome in rats. MDMA causes dose-dependent hyperthermia, which is potentially fatal, in humans, primates and rodents. Subsequent serotonergic neurotoxicity has been demonstrated by biochemical and histological studies and is reported to last for months in rats and years in non-human primates. Relating human data to findings in animals is complicated by reports that MDMA exposure in mice produces selective long-term dopaminergic impairment with no effect on serotonin. This review compares data obtained from animal and human studies and examines the acute physiological, behavioural and biochemical effects of MDMA as well as the long-term behavioural effects together with serotonergic and dopaminergic impairments. Consideration is also given to the role of neurotoxic metabolites and the influence of age, sex and user groups on the long-term actions of MDMA.

Effect of Thunbergia laurifolia, a Thai natural product used to treat drug addiction, on cerebral activity detected by functional magnetic resonance imaging in the rat.

RATIONALE: Thunbergia laurifolia Linn. (TL) is an herbal medicine used to treat alcohol and drug addiction in Thai traditional medicine. A previous study demonstrated that an extract of TL increases rat striatal dopamine release in vitro. OBJECTIVES: This study determined whether a methanol extract of TL altered rat brain region activity using in vivo functional nuclear magnetic resonance imaging (fMRI) in a manner consistent with the observed effects in vitro on dopamine release. METHODS: fMRI was performed on a 2.35-T Bruker MR system. MR images were acquired from rat brain using the rapid acquisition relaxation enhanced sequence (field of view 50 mm). The imaging parameters used for the anatomical scan yielded an in-plane spatial resolution of 0.2x0.2 mm. Consecutive single-slice functional imaging over the rat brain investigated the changes in signal intensity in various parts of the brains induced by TL (200 mg/kg, i.p.) or vehicle administration. RESULTS: These demonstrate that TL increased signal intensity in various brain areas such as nucleus accumbens, globus pallidus, amygdala, frontal cortex, caudate putamen and hippocampus. These are similar to those reported previously to show effects after either cocaine or amphetamine administration. Physiological variables were not affected by the injection of TL (200 mg/kg, i.p.), but there was a small decrease in arterial blood pressure. CONCLUSIONS: The results indicate that TL increases significant neuronal activity in specific brain regions responsible for reward and locomotor behaviour (fixed-effect analysis); however, there is no significant difference between TL and vehicle-treated groups with random-effect analysis (population statistic). The active compound(s) in TL responsible for the pharmacological effects of TL remain to be identified.

Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder.

RATIONALE: The psychomotor stimulant methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD). Whereas the mechanism is not fully understood it is suggested to involve restoration of impaired dopamine function found in ADHD. OBJECTIVES: The aim of this study was to determine the effects of methylphenidate on brain region activation in vivo using pharmacological magnetic resonance imaging (phMRI) in a potential rat model of ADHD. METHODS: Rats were treated bi-daily [from postnatal day (PND) 24] for 4 days with the dopamine re-uptake inhibitor GBR 12909 (30 mg/kg i.p) or vehicle (control). On PND 57 rats were administered methylphenidate (4 mg/kg i.p) and locomotor activity measured. In a separate group of animals, blood oxygen level dependent (BOLD) response was measured using phMRI to determine changes in brain region activation produced by methylphenidate (4 mg/kg i.p.) in GBR 12909-pretreated or control rats. RESULTS: Methylphenidate produced a greater locomotor-stimulant response in controls compared with GBR 12909 rats. Pretreatment with GBR 12909 reduced the BOLD response produced by methylphenidate compared with that in control animals. The main effects of methylphenidate on the BOLD response were seen in the caudate, frontal cortex, hippocampus and hypothalamus. CONCLUSIONS: Short-term treatment with GBR 12909 in young rats causes long-term changes in dopaminergic systems, altering the methylphenidate-induced behavioural response and brain region activation compared with that in vehicle-pretreated rats. The results further support the view that altered dopaminergic function may be an important factor in ADHD and the value of animal models with this functional neurochemical deficit.

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo.

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.