Risk scores for transient ischemic attack.

The risk of recurrent ischemic stroke after a transient ischemic attack (TIA) has been reported to be 5-10%, and is elevated especially within the first days after the index event. Since TIA primarily has a good outcome without persisting new deficits, interest has been growing to predict stroke recurrence after TIA. This has led to the development of scores, initially for long-term prognosis such as the Stroke Prognosis Instrument (SPI) or the Hankey score, which both have shown a good predictive value at 1 or 2 years after TIA. Risk factors such as age, hypertension or cardiovascular disease were integrated in these systems. Since the early risk prediction for stroke in patients presenting within 24 h after onset of symptoms became clinically more and more relevant in emergency stroke units, the ABCD score (for the predictive factors Age, Blood pressure, Clinical symptoms, Duration of symptoms) was developed. Validation was promising, and hence further scores were developed, which entailed a large number of studies trying to validate these systems or to improve them (e.g. ABCD(2), ABCD(2)I, ABCD(3), ABCD(3)I, CIP model, ASPIRE approach, ABCDE+ etc.). The main approaches were to include imaging results (such as DWI positivity) or etiologic considerations (e.g. carotid stenosis or atrial fibrillation). However, these new scores necessitate an extensive diagnostic workup, and therefore can only be used in large stroke centers. Currently, for acute TIA management, the use of ABCD(2) is recommended in several guidelines.

Antithrombotic therapy in transient ischemic attack patients.

Historically, studies of antithrombotic therapy in ischemic cerebrovascular disease have included both stroke and transient ischemic attack (TIA). Thus, therapy regimes are very similar. Aspirin (75-325 mg within 48 h after onset of symptoms) is still the standard antithrombotic treatment because other agents have performed similarly (or worse). Combinations of agents have shown mixed results. Aspirin combined with clopidogrel has failed to show a significant reduction of stroke/TIA recurrences but increased the bleeding risk if taken for more than several months. The combination of aspirin and dipyridamole is slightly better than aspirin alone and in particular reduced nonfatal stroke/TIA - hence it is recommended as an alternative and may be used in patients with recurrent events while on regular aspirin. In contrast, combined treatment is regularly recommended after endovascular interventions and if both cardio- and cerebrovascular diseases are present. Warfarin and similar compounds have long been the standard treatment for most patients with permanent, paroxysmal or intermittent non-valvular atrial fibrillation, for which there is excellent evidence in most patients (CHADS-VASc score >1). New compounds have been approved in recent years and shown to reduce either ischemic events, intracranial bleeding complications or both when compared with warfarin. None of them requires regular therapy monitoring. Because there are no head-to-head comparisons of these newer agents, definite recommendations as to which to choose, and when, are hard to make. However, there are some notable differences as well as new approved entities.

The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping).

ASCO phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) assigns a degree of likelihood of causal relationship to every potential disease (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but the disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke describing all underlying diseases in every patient. In this new evolution of ASCO called ASCOD, we have added a 'D' for dissection, recognizing that dissection is a very frequent disease in young stroke patients. We have also simplified the system by leaving out the 'levels of diagnostic evidence', which has been integrated into grades 9 and 0. Moreover, we have also changed the cutoff for significant carotid or intracranial stenosis from 70% to more commonly used 50% luminal stenosis, and added a cardiogenic stroke pattern using neuroimaging. ASCOD captures and weights the overlap between all underlying diseases present in ischemic stroke patients.

Continuous magnetic resonance perfusion imaging acquisition during systemic thrombolysis in acute stroke.

BACKGROUND: Early recanalization and increase in collateral blood supply are powerful predictors of favourable outcome in acute ischaemic stroke. The factors contributing to the heterogeneous response to intravenous thrombolysis therapy in individual patients, however, are not fully understood. The on-going single-centre 'MR perfusion imaging during thrombolysis' study uses repetitive arterial spin labelling (ASL) measurements to characterize the haemodynamic processes in acute stroke during therapy. The first milestone was to develop an appropriate infrastructure for thrombolysis in the magnetic resonance imaging (MRI) scanner without time delay and ensuring optimal patient safety and care. METHODS: Between February and December 2011, 16 patients with acute neurological symptoms suggestive of hemispheric stroke within 4.5 h after symptom onset were included. In addition to clinical data, we documented the time from onset to arrival at the hospital, start and duration of MRI examination, start of thrombolytic therapy, and complications. The decision to thrombolyse was made after a routine stroke MRI protocol. During the 60-min systemic thrombolysis, repetitive ASL perfusion imaging was acquired, providing non-invasive information on cerebral perfusion. Continuous ECG monitoring, pulse oximetry, blood pressure measurements every 5 min, and short neurological assessments every 15 min were performed in every patient. RESULTS: The median initial NIHSS score of the patients presenting with a mean of 84 min after onset was 4 (range 2-18). MRI examination was initiated within a mean of 45 min after arrival at the hospital. Five patients identified as stroke mimics were not treated with recombinant tissue plasminogen activator (rt-PA), and in 1 case with basilar artery occlusion bridging therapy was performed outside the scanner. In the remaining 10 patients, rt-PA therapy was started in the scanner directly after decision making on the basis of clinical information and baseline MRI. The mean door-to-needle time was 60 min (range 44-115) including approximately 10 min needed for acquiring informed consent. While 4 patients required antihypertensive treatment, no relevant complications were encountered. CONCLUSIONS: Fast and safe medical care in patients during systemic thrombolysis in the MRI scanner is feasible. Despite the process of obtaining informed consent, with a dedicated and experienced stroke team the door-to-needle time can be kept in a range recommended by current guidelines. Continuous real-time information about the dynamics of cerebral perfusion from ASL perfusion in acute stroke patients undergoing thrombolysis may provide additional information for the understanding of the events following acute arterial obstruction and its course.

Characterization of patients with recurrent ischaemic stroke using the ASCO classification.

BACKGROUND AND PURPOSE: The ASCO score has the advantage of allowing a more comprehensive characterization of ischaemic stroke patients and their risk factors, as reflected in different grades of evidence of atherosclerotic changes (A), small vessel disease (S), potential cardiac (C) or other (O) sources. It might also help to characterize patients with recurrent ischaemic stroke and document the etiology of stroke recurrence as well as the further development of risk factor constellations. METHODS: We prospectively screened our stroke database for patients with recurrent ischaemic stroke between 2004 and 2011, and classified each stroke using ASCO. The distribution of etiologies was analysed, and changes in the ASCO score were documented for each patient. RESULTS: We identified 131 patients with recurrence of ischaemic stroke. At the first event, the distribution of etiologies and their grade of evidence was 97 grade 1 (A = 18/S = 32/C = 44/O = 3), six grade 2 (A = 2/S = 1/C = 3/O = 0), 199 grade 3 (A = 85/S = 83/C = 23/O = 8), 204 grade 0 (A = 26/S = 14/C = 44/O = 120) and 18 grade 9 (A = 0/S = 1/C = 17/O = 0). At stroke recurrence, 98 grade 1 (A = 16/S = 24/C = 55/O = 3), 11 grade 2 (A = 2/S = 5/C = 4/O = 0), 210 grade 3 (A = 94/S = 92/C = 13/O = 11), 171 grade 0 (A = 16/S = 9/C = 26/O = 117) and 34 grade 9 (A = 0/S = 1/C = 33/O = 0) were identified. Analysis of each individual showed a modification of the score in 85 patients (64.9%). CONCLUSIONS: Recurrent ischaemic stroke does not always have the same etiology as the previous one(s). Among variable changes of grade 1 etiologies, an increasing prevalence of cardioembolism--often insufficiently treated--at stroke recurrence was a major finding. ASCO proved to be highly useful to monitor risk factor constellations.

Multiple subcortical acute ischemic lesions reflect small vessel disease rather than cardiogenic embolism.

Multiple acute ischemic lesions in different hemispheres or vascular territories are mainly considered to be of proximal embolic origin. However, despite careful diagnostic work-up, the etiological classification often stays undetermined. We propose that multiple acute ischemic lesions can sometimes be a phenomenon observed in small vessel disease (SVD). From a prospectively collected database of more than 7,000 stroke patients, 173 patients with acute bihemispheric infarction were identified. We analyzed those subjects with multiple small (< 15 mm Ø) subcortical acute ischemic lesions on diffusion-weighted MRI (DWI) and concomitant severe small vessel disease (Fazekas grades II-III) without a proximal embolic source as evaluated by cardiological investigations. Twenty patients (mean age 66 ± 12 years, 12 men) with a mean number of 2.95 ± 1.24 acute lesions on DWI (range of 2-7 lesions per patient) were identified (n = 5 Fazekas II°, n = 15 Fazekas III°). Most of the lesions were located in typical areas of lacunar infarction. The mean NIHSS score on admission was 2.95 ± 2.0 (range 0-8). Multiple acute ischemic lesions in different vascular territories might not always be of proximal cardiovascular embolic origin. Simultaneous small subcortical ischemic lesions may reflect remote ischemia due to small vessel disease reflecting simultaneous hemorheological dysfunction.

How to identify stroke mimics in patients eligible for intravenous thrombolysis?

Since decision-making for thrombolysis in acute stroke settings is restricted to a limited time window and based on clinical assessment and CT findings only, thrombolysis is sometimes applied to patients with a final diagnosis other than a stroke. From a prospectively collected stroke/MRI data bank (2004-2010) with 648 suspected ischemic stroke patients treated with rtPA, we identified patients without evidence of acute infarction on follow-up MRI and a final diagnosis other than a stroke or acute cerebrovascular event. We compared demographics, symptoms, complications, and outcome of patients with stroke mimics (SM) to those with acute infarction. In 42 patients, an SM was diagnosed: seizures in 20, conversion disorder in seven, dementia in six, migraine in three, brain tumor in two, and others in four patients. Patients with SM less often had typical stroke symptoms like dysarthria (p < 0.01), facial palsy (p < 0.001), hemiparesis (p < 0.001), horizontal gaze palsy (p < 0.001), and visuospatial neglect (p = 0.03), while aphasia (p = 0.004) and accompanying convulsions (p = 0.01) occurred more often. Independent predictors of SM were known cognitive impairment, aphasia, and accompanying convulsions. Thrombolysis-related complications (orolingual angioedema) occurred in one SM patient and none of the SM patients deteriorated clinically. Stroke mimics comprise neurological/psychiatric disorders and differ from ischemic stroke patients with regard to the clinical presentation at onset. This might be helpful in deciding which patients should undergo acute stroke MRI to rule out SM, facilitate treatment decisions, and reduce the risk of unnecessary therapy.

Comparison of the new ASCO classification with the TOAST classification in a population with acute ischemic stroke.

Precise analysis of stroke subtypes is important for clinical treatment decisions, the prognostic evaluation of patients, as well as defining stroke populations in clinical studies. The TOAST classification is the most widely used and approved form for etiologic subtyping. Increasing knowledge about stroke mechanisms and the introduction of new diagnostic techniques have supported the promotion of the new ASCO phenotypic classification, which aims to characterize patients using different grades of evidence for stroke subtypes. We prospectively assigned 103 consecutive patients from our stroke center for subtype classification using ASCO and TOAST. Clinical features and complementary investigations were recorded according to our standardized acute stroke care protocol. Evidence grade 1 with ASCO was assessed in 12.62% for large artery disease (A), 23.30% small-vessel disease (S), 36.89% cardiac source (C) and 1.94% another cause (O). Evidence grades 1-3 were identified in 60.19% A, 75.73% S, 49.51% C, and 3.88% O. A total of 68.93% of the patients were classified in more than one category, and only 3.88% remained completely undetermined. The κ value for inter-rater agreement was 0.92-1. Using TOAST, the distribution was 9.71% A, 23.30% S, 34.95% C, 1.94% O, and 30.10% undetermined. The ASCO classification showed a good concordance with TOAST. The inter-rater agreement was high. The comprehensive character of ASCO allows the recording of important additional information. This may be helpful for a specific treatment adaptation in each individual patient and creation of different etiological profiles in view of adapted clinical trials.

Clinical and MRI characteristics of acute migrainous infarction.

OBJECTIVE: Migrainous infarction is considered a rare complication of migraine. Although several studies reported silent brain lesions on neuroimaging in patients with migraine with aura, knowledge about lesion patterns in acute migrainous infarction is scarce. We investigated clinical and MRI characteristics in a series of patients with migraine-associated acute cerebral ischemia. METHODS: Seventeen patients among 8,137 stroke patients over an 11-year period were included. All had undergone a dedicated stroke workup including diffusion-weighted imaging (DWI) and a detailed assessment of clinical features and of vascular risk factors. RESULTS: The majority of patients presented with prolonged aura symptoms (visual aura 82.3%, sensory dysfunction 41.2%, and aphasia 5.9%; median NIH Stroke Scale score 2). Presentation at hospital was significantly delayed after symptom onset (mean 33 hours). A total of 70.6% had acute ischemic lesions in the posterior circulation; the middle cerebral artery territory was affected in 29.4%. Small lesions were present in 64.7%; multiple lesions were found in 41.2%. No overlapping ischemic lesions of different vascular territories were found. The prevalence of a patent foramen ovale was high (64.7%). CONCLUSIONS: This study supports previous observations that migrainous infarction mostly occurs in the posterior circulation, and in younger women with a history of migraine with aura. Acute ischemic lesions were often multiple and located in distinct arterial territories. As there were no overlapping ischemic lesions, hemodynamic compromise during the development of migraine is unlikely the cause of infarction. Differentiation between migrainous infarction and prolonged migraine aura is difficult and associated with delayed admission of patients.

MR imaging-guided intravenous thrombolysis in posterior cerebral artery stroke.

PCA stroke was under-represented in or excluded from the clinical trials examining thrombolysis based on the PWI-DWI mismatch concept. We present 6 patients with PCA stroke treated with thrombolysis in an extended time window by using MR imaging criteria. Symptoms included aphasia, sensorimotor hemiparesis, hemineglect, and homonymous hemianopia. Initial MR imaging demonstrated circumscribed ischemic lesions in the thalamus or hippocampus; MR angiography showed PCA occlusion with corresponding hypoperfusion. Follow-up MR imaging showed partial/complete recanalization in 4 patients with minor infarction growth, while in 1 patient, PCA occlusion persisted, resulting in a large PCA infarction. Three patients improved within 2 hours; at discharge, homonymous hemianopia had resolved in 3 patients. At 3-month follow-up, 4 patients had an mRS score of 0 or 1. These results support the approach to treat patients with PCA stroke with thrombolysis based on the mismatch concept. Because rehabilitation options for hemianopia are limited, thrombolysis may enhance the chance of a favorable outcome.

Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration.

Dopamine receptors (DARs) in the nucleus accumbens (NAc) are critical for cocaine's actions but the nature of adaptations in DAR function after repeated cocaine exposure remains controversial. This may be due in part to the fact that different methods used in previous studies measured different DAR pools. In the present study, we used a protein crosslinking assay to make the first measurements of DAR surface expression in the NAc of cocaine-experienced rats. Intracellular and total receptor levels were also quantified. Rats self-administered saline or cocaine for 10 days. The entire NAc, or core and shell subregions, were collected one or 45 days later, when rats are known to exhibit low and high levels of cue-induced drug seeking, respectively. We found increased cell surface D1 DARs in the NAc shell on the first day after discontinuing cocaine self-administration (designated withdrawal day 1, or WD1) but this normalized by WD45. Decreased intracellular and surface D2 DAR levels were observed in the cocaine group. In shell, both measures decreased on WD1 and WD45. In core, decreased D2 DAR surface expression was only observed on WD45. Similarly, WD45 but not WD1 was associated with increased D3 DAR surface expression in the core. Taking into account many other studies, we suggest that decreased D2 DAR and increased D3 DAR surface expression on WD45 may contribute to enhanced cocaine-seeking after prolonged withdrawal, although this is likely to be a modulatory effect, in light of the mediating effect previously demonstrated for AMPA-type glutamate receptors.

Changes in functional vasomotor reactivity in migraine with aura.

Migraine with aura (MA) is associated with cerebral hyper- and hypoperfusion during and after the attacks. Several attempts to estimate individual perfusion changes and asymmetries in patients with MA using transcranial Doppler (TCD) have not been consistent. In 70 patients with MA and 40 controls with migraine without aura (MoA) or without any history of migraine, interictally recorded TCD sequences were prospectively analysed. Formal curve analysis of the visually evoked flow response (VEFR) was performed semiautomatically. As a main parameter for functional vasomotor reactivity (fVMR), the visually evoked flow rate (VEFR%) was calculated. The VEFR% showed a significantly higher mean difference of 14.7 +/- 12% in MA patients vs. 5.8 +/- 4.4% (P < 0.001) in controls. The significant asymmetry of fVMR in MA patients is suggested to reflect interattack persisting vasomotor changes which are of pathophysiological interest and may be used as a monitoring tool under prophylactic medication.

Visual evoked potential-based acuity assessment in normal vision, artificially degraded vision, and in patients.

AIMS: To assess visual acuity (VA) objectively using visual evoked potentials (VEPs), avoiding subjective trace evaluation and providing an acuity estimate with associated confidence limits. METHODS: 40 normal subjects and 24 patients (with corneal and retinal diseases, decimal VA range 0.15-1.1 (= 0.8(logMAR) to -0.04(logMAR))) participated in the study. Checkerboard stimuli with six check sizes covering 0.05-0.4 degrees (or 0.09-0.8 degrees for visual acuities below 0.35 (= 0.46(logMAR)) were presented in brief-onset mode (40 ms on, 93 ms off) at 7.5 Hz. In normal subjects, the stimuli were also optically degraded by frosted occluders resulting in a decimal VA range of 0.13-2.8 (= 0.9(logMAR) to -0.45(logMAR)). Altogether, 108 steady-state VEPs were recorded with a Laplacian montage (2xOz-(RO+LO)). Fourier analysis yielded the magnitude (A) at the stimulus frequency, and the average of the two neighboring frequencies as noise estimate (N). A and N determine the significance level p of the response, and from their ratio the non-noise-contaminated response (A*) can be calculated. Tuning curves were obtained by plotting A* vs the dominant spatial frequency of the corresponding checkerboard. A fully automatic algorithm used the significance level (p<5%) and A* to automatically select an appropriate region in the high spatial-frequency range on which a linear regression was performed, yielding a zero-amplitude extrapolated spatial frequency SF0. Subjective VA was obtained with the automated "Freiburg Acuity Test". RESULTS: The brief-onset presentation evoked high VEP amplitudes; however, many tuning curves displayed the well-known "notch" at intermediate check sizes. The fully automated analysis algorithm succeeded in 107 of 108 cases and effectively ignored the notch, if present. The relation between logVA and log(SF0) was a constant factor throughout the range tested: logVA = log(SF0)/17.6 cpd. In more than 95% of all cases, the acuity predicted from SF0 coincided within a factor of two (up and down, or +/-0.3 logMAR) with subjective VA with a coefficient of correlation of 0.90. CONCLUSION: The fully automated analysis avoided subjective problems in peak-trough assessment. The results provide quantitative limits to assess patients with possible malingering.

The laterodorsal tegmentum contributes to behavioral sensitization to amphetamine.

A critical event in the development of behavioral sensitization is a transient increase in excitatory drive to dopamine neurons of the ventral tegmental area (VTA). This is likely to be due, in part, to the ability of drugs of abuse to produce long-term potentiation, expressed as increased AMPA receptor transmission, at excitatory synapses onto VTA dopamine neurons. We investigated the role of the laterodorsal tegmentum (LDT) in behavioral sensitization because LDT neurons provide an important source of excitatory drive to VTA dopamine neurons, through mixed glutamate and cholinergic inputs. To test the role of the LDT in amphetamine sensitization, ibotenic acid or sham lesions of the LDT were performed 1 week before the first of six daily amphetamine injections. When challenged with amphetamine 13 days after the last injection, sham rats expressed sensitization of stereotypy and post-stereotypy locomotor hyperactivity, whereas the latter was attenuated by ibotenic acid lesions of the LDT. To determine whether plasticity occurs in the LDT during amphetamine sensitization, we used a previously developed microdialysis assay in which increased ability of AMPA to activate a pathway serves as a marker for long-term potentiation. Two days after discontinuing repeated saline or amphetamine injections, the responsiveness of LDT-VTA neurons to AMPA was determined by microinjecting AMPA (0.4 nmol) into the LDT and measuring glutamate efflux in the ipsilateral VTA. Glutamate efflux was transiently increased in both groups but a delayed group difference was apparent with relatively higher glutamate efflux in amphetamine rats 30-60 min after AMPA injection. In parallel experiments, dopamine efflux in the nucleus accumbens (NAc) following intra-LDT AMPA declined in saline rats but remained relatively stable in amphetamine rats. Both results suggest relatively greater excitability of the LDT-VTA-NAc pathway after repeated amphetamine treatment. Our results provide the first evidence that neuronal plasticity in the LDT contributes to behavioral sensitization.

Matrix metalloproteinase profile in patients with Creuztfeldt-Jakob disease.

Preliminary findings suggest that abnormalities in matrix metalloproteinase (MMP) activity may be found in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD). In this study of 16 subjects with CJD and 16 age-, and sex-matched controls, we determined the presence of MMP-2 and MMP-9 in their active and proenzyme forms, the relative levels of MMP-3 and four inhibitors of MMP activity (TIMP-1, TIMP-2, TIMP-3 and TIMP-4), and the concentration of 4-3-3 protein. The methodology used involved zymography and immunological techniques. The results indicate that, compared with controls, CJD patients have a significantly higher positive frequency of pro-MMP-9 and of the active form of MMP-2, along with significantly higher levels of TIMP-1 and TIMP-2, classical inhibitors of MMP-9 and MMP-2, respectively. We also found a positive correlation between 14-3-3 protein concentration and that of TIMP-1 and TIMP-2 levels (correlation coefficients of 0.793 and 0.798, respectively). These results suggest that abnormalities in MMP and TIMP profiles may be helpful in the biochemical characterisation of CJD.

Baclofen attenuates conditioned locomotion to cues associated with cocaine administration and stabilizes extracellular glutamate levels in rat nucleus accumbens.

We have used cocaine-conditioned locomotion in rats as an animal model for cocaine-conditioned responses that contribute to drug craving and relapse in human addicts. The purpose of the present study was to examine the ability of the GABA(B) agonist, baclofen, to attenuate such associative responses. First, experiments were conducted to identify a dose range of baclofen that did not impede exploratory or spontaneous behavior. This dose range was used during testing for conditioned locomotion specific to a flashing light and metronome, which were previously associated with administration of cocaine (PAIRED group) or saline (UNPAIRED group). At 2.0 mg/kg, baclofen attenuated conditioned locomotion in PAIRED subjects to the level of UNPAIRED subjects receiving saline or 2.0 mg/kg baclofen. Considering the importance of glutamate transmission in the nucleus accumbens (NAc) during associative responses to reward-related stimuli, the effect of baclofen on extracellular levels of glutamate in the NAc was tested with microdialysis. Baclofen (2.0 mg/kg) did not alter basal glutamate levels. However, baclofen pretreatment prevented the predatory odor, 2,5-dihydro-2,4,5-trimethylthiazoline, from increasing glutamate levels. This is the first report of baclofen modulating extracellular levels of glutamate in the NAc. Baclofen may prove to have general utility for suppressing stimulus-evoked increases in NAc glutamate levels. This could explain its ability to prevent cocaine-conditioned responses. In summary, our results suggest that enhancing GABA(B) transmission inhibits cocaine-conditioned responses, possibly by suppressing glutamate transmission in the NAc. A better understanding of interactions between GABA and glutamate transmission in the NAc may lead to the development of pharmacotherapies for cocaine craving.

Amphetamine and cocaine do not increase Narp expression in rat ventral tegmental area, nucleus accumbens or prefrontal cortex, but Narp may contribute to individual differences in responding to a novel environment.

Narp is an immediate early gene product that acts extracellularly to cluster AMPA receptors at excitatory synapses. The present study tested the hypothesis that drugs of abuse alter Narp expression and thereby influence AMPA receptor transmission in addiction-related circuits. Immunohistochemical studies demonstrated the existence of Narp-positive cells in hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc), with lower levels of staining in the ventral tegmental area (VTA). To study the effects of psychomotor stimulants, Narp levels were quantified by Western blotting and normalized to actin. There were no differences in Narp levels in any brain region between rats treated with repeated saline injections, a single amphetamine injection (5 mg/kg), repeated amphetamine injections (5 mg/kg x 5 days), or repeated cocaine injections (20 mg/kg twice daily x 7 days). We also examined the possible role of Narp in individual differences in responding to a novel environment, a predictor of behavioural responses to psychomotor stimulant drugs including the propensity to acquire drug self-administration. Narp levels in the PFC, but not other regions, were significantly correlated with locomotor activity in a novel environment. These findings suggest that differential Narp expression in the PFC may be involved in determining individual vulnerability to drugs of abuse, perhaps by influencing the activity of its excitatory projections.

In vivo modulation of ventral tegmental area dopamine and glutamate efflux by local GABA(B) receptors is altered after repeated amphetamine treatment.

The activity of dopamine neurons in the ventral tegmental area is modulated by excitatory (glutamatergic) and inhibitory (GABAergic) afferents. GABA, released by intrinsic neurons and by projection neurons originating in the nucleus accumbens and other regions, inhibits dopamine neurons via activation of GABA(A) and GABA(B) receptor subtypes. Using in vivo microdialysis in freely moving rats, we investigated the role of ventral tegmental area GABA(B) receptors in modulating levels of dopamine and glutamate within the ventral tegmental area, both in naive rats and in rats treated repeatedly with saline or amphetamine (5 mg/kg i.p., for 5 days). In naive rats, administration of a potent and selective GABA(B) receptor antagonist (CGP 55845A) into the ventral tegmental area elicited a concentration-dependent increase in dopamine levels, but did not alter glutamate levels. In rats tested 3 days after discontinuing repeated amphetamine administration, 50 microM CGP 55845A increased dopamine levels to a greater extent than in saline controls. This difference was no longer present in rats tested 10-14 days after discontinuing repeated amphetamine injections. CGP 55845A (50 microM) had no effect on glutamate levels in the ventral tegmental area of saline-treated rats. However, it produced a robust increase in glutamate levels in rats tested 3 days, but not 10-14 days, after discontinuing repeated amphetamine injections. These results suggest that somatodendritic dopamine release is normally under strong tonic inhibitory control by GABA(B) receptors. Repeated amphetamine administration enhances GABA(B) receptor transmission in the ventral tegmental area during the early withdrawal period, increasing inhibitory tone on both dopamine and glutamate levels. This is the first demonstration, in an intact animal, that drugs of abuse alter GABA(B) receptor transmission in the ventral tegmental area.