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.

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.

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.

Cocaine addiction: clues from Drosophila on drugs.

Recent studies have shown that the fruitfly Drosophila exhibits behavioral sensitization in response to repeated exposure to cocaine; the exploitation of this genetically tractable model system for studying cocaine addiction is already providing new clues that may help understand the process of drug addiction in man.

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.

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants.

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans. Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801. Life Sci., 45, 599-606]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors. While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons. The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.

Amphetamine-induced plasticity of AMPA receptors in the ventral tegmental area: effects on extracellular levels of dopamine and glutamate in freely moving rats.

Previous electrophysiological studies suggested that the initiation of behavioral sensitization to cocaine and amphetamine involves a transient increase in AMPA receptor responsiveness in the ventral tegmental area (VTA). To test this, we used in vivo microdialysis to examine the effects of intra-VTA administration of AMPA (10 microm) and NMDA (100 microm) on dopamine (DA) and glutamate efflux in the VTA and the nucleus accumbens (NAC), an important target of VTA DA neurons. We compared rats treated for 5 d with saline or 5 mg/kg amphetamine and withdrawn for 3 or 10-14 d. After 3 d of withdrawal, intra-VTA AMPA increased both NAC and VTA DA levels to a greater extent in the amphetamine group, whereas NMDA produced similar effects in the saline and amphetamine groups. This enhanced responsiveness to AMPA was no longer evident in rats tested 10-14 d after the last injection. In addition, intra-VTA AMPA but not NMDA increased both VTA and NAC glutamate levels in rats tested 3 d after the last injection of amphetamine but not in saline controls. After 10-14 d, the responsiveness of glutamate levels to AMPA was no longer evident in the NAC but persisted in the VTA. Additional studies indicated that the glutamate effect in the NAC may involve increased responsiveness of DA receptors within the NAC. These findings establish an in vivo animal model with which to explore the consequences of repeated drug administration for AMPA receptor plasticity in the VTA. They also indicate that repeated amphetamine leads to potentiated interactions between DA and glutamate transmission.

Reduced monoamine oxidase activity in blood platelets from insulin-dependent diabetic subjects.

Insulin-dependent diabetics show a significant reduction in blood platelets' monoamine oxidase (MAO) activity when compared with age-matched and sex-matched controls. This does not appear to be the case for diabetics either on diet control or receiving oral hypoglycemic drugs. The important role of this enzyme in the regulation of the circulating levels of a number of monoamines known to have an inhibitory effect on insulin secretion may indicate the possible inclusion of the MAO/monoamine system in the pathophysiology of diabetes. The possibility of using platelets' MAO activity as a biologic marker for a subgroup of insulin-dependent diabetics is also discussed.

Tyramine-binding by synaptosomes from rat brain: effect of centrally active drugs.

Incubation of p-tyramine (TRM) with rat midbrain plus corpus striatum (MB+ CS) crude synaptosomal preparations, under conditions which reduce to a minimum amine uptake, results in appreciable binding of this amine by synaptosomes. This process is inhibited by preincubation with a number of drugs active in the CNS, e.g., chlorpromazine, desipramine, d-amphetamine, and diphenhydramine. Morphine, however, does not affect this binding. The Ki for each one of these compounds, as well as the K association constant and concentration of the binding sites of TRM, were determined. These results suggest a role for TRM in synaptic transmission mechanisms occurring in the nigrostriatal system, a function which could be regulated by a number of substances representing some of the major chemical classes of centrally active drugs (CD).

Oral asymmetries during verbal and non-verbal movements of the mouth.

Asymmetries in the amplitude and velocity of oral movements were studied in 24 right-handed subjects as they produced either syllables or non-verbal movements of the mouth. Single-frame analysis of the videotaped mouth movements revealed that the right side of the mouth opened wider and faster than the left for both verbal and non-verbal movements. Moreover, the size of the right bias increased as a function of the complexity of required movements. In addition, movements embedded within a series showed a greater right bias than movements at the beginning of a series. On the whole, females exhibited larger asymmetries than males. These results provide support for the suggestion that the left hemisphere plays an important role in the control of complex motor behaviour.

Expression of AMPA receptor flip and flop mRNAs in the nucleus accumbens and prefrontal cortex after neonatal ventral hippocampal lesions.

Many lines of evidence implicate dysfunctional excitatory amino acid (EAA) transmission in schizophrenia. The present study examined alpha-amino-3-hydroxy-5-methylisoxazole- 4-priopionate (AMPA) receptor expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using a rat model of schizophrenia in which excitotoxic lesions of ventral hippocampus (VH) on postnatal day (PD) 7 lead to the postpubertal emergence of behavioral abnormalities that resemble schizophrenic symptoms. In situ hybridization histochemistry with 35S-labeled oligonucleotide probes was used to quantify mRNA levels for GluR1-3 flip and flop variants at prepubertal and postpubertal time-points (PD 35 and 60, respectively). Comparisons of PD 35 and PD 60 groups suggested that there may be changes in the relative expression of flip and flop isoforms during normal development. The most pronounced change was an apparent increase in the flip/flop ratio for GluR1 from PD 35 to PD 60 in both the PFC and the NAc. Neonatal VH lesions did not significantly alter GluR1-3 flip and flop mRNA levels in the NAc at either time-point. However, in the PFC, GluR3 flop mRNA levels were significantly decreased in lesioned rats at PD 60. AMPA receptors incorporating flop variants exhibit faster desensitization, so a shift towards flip incorporation might lead to increased neuronal excitability in the PFC, thereby influencing subcortical DA systems regulated by PFC efferents. In summary, an early developmental injury can predispose rats to abnormal development of EAA transmission in the PFC. This may contribute to the postpubertal onset of symptoms after neonatal VH lesions.

Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors.

The ability of dopamine (DA) agonists and antagonists to modulate the K+-evoked overflow of radioactivity from superfused slices of prefrontal cortex of the rat, preincubated with [3H]DA in the presence of 1 microM desipramine, was examined. Apomorphine and the putative autoreceptor-selective DA agonist EMD 23 448 inhibited the K+-evoked overflow of radioactivity, while the DA antagonist sulpiride enhanced the evoked overflow in a dose-dependent and stereoselective manner. The latter effect was partially reversed by EMD 23 448. More than 95% of the radioactivity retained by the slices chromatographed with DA, while deaminated metabolites represented the majority of both the basal efflux (84% metabolites, 4-5% DA) and evoked overflow (84% metabolites, 14% DA) of radioactivity. These findings indicate that mesoprefrontal DA neurons possess release-modulating nerve terminal autoreceptors. Previous studies have shown that these neurons lack synthesis-modulating autoreceptors. Thus, autoreceptors on prefrontal DA terminals appear to be coupled to regulation of the release but not the synthesis of DA.

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.

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.

Effects of lesions of prefrontal cortex, amygdala, or fornix on behavioral sensitization to amphetamine: comparison with N-methyl-D-aspartate antagonists.

Behavioral sensitization to amphetamine involves the mesoaccumbens dopamine system and is accompanied by cellular changes in this system. Excitatory amino acid antagonists, when co-administered with amphetamine, prevent both behavioral sensitization and associated changes in the mesoaccumbens dopamine system. This suggests that excitatory amino acid-dependent events are critical to the initiation of sensitization. This study sought to identify excitatory amino acid projections required for sensitization, focusing on projections to the nucleus accumbens or ventral tegmental area. The major excitatory projections to the nucleus accumbens originate in the prefrontal cortex, amygdala and hippocampus. The prefrontal cortex and amygdala also send excitatory projections to the ventral tegmental area. Ibotenic acid lesions of the prefrontal cortex or amygdala and electrolytic lesions of the fornix were performed in rats. After one week of recovery, rats were treated with water or 2.5 mg/kg amphetamine for six days and challenged with amphetamine on day 8. Activity was tested in photobeam cages on days 1 and 8. On day 1, control and sham-lesioned rats exhibited stereotyped behaviors followed by a period of post-stereotypy locomotion. On day 8, sensitization was evident as an enhancement of both stereotypy and post-stereotypy locomotion. Co-administration of N-methyl-D-aspartate antagonists [MK-801 (dizocilpine maleate) or CGS 19755] with amphetamine prevented the development of sensitization of both stereotypy and post-stereotypy locomotion. Neither antagonist, however, prevented the expression of sensitization. None of the lesions completely mimicked these effects of N-methyl-D-aspartate antagonists. Lesions of hippocampal projections traveling in the fornix produced a general disinhibition of locomotor activity, but did not prevent sensitization of either stereotypy or post-stereotypy locomotion. Lesions of the prefrontal cortex failed to prevent sensitization of stereotypy was obtained following repeated amphetamine administration. However, like prefrontal cortical lesions, amygdala lesions prevented sensitization of post-stereotypy locomotion. When interpreted in the light of previous studies demonstrating the importance of the ventral tegmental area in the initiation of sensitization, the present results suggest a likely role for neuronal circuits involving the prefrontal cortex, amygdala and ventral tegmental area in the development of sensitization of post-stereotypy locomotion following repeated amphetamine administration. Such circuits may initiate sensitization through a mechanism involving excitatory amino acid regulation of the activity of mesoaccumbens dopamine neurons. Parallel circuits, involving other brain regions, may similarly contribute to sensitization of stereotyped behaviors.

Vulnerability to tardive dyskinesia.

Of 99 consecutive male patients studied at the North Chicago VA Tardive Dyskinesia Program, 58 had tardive dyskinesia and 41 did not. Factors that were significantly related, singly and in combinations, to tardive dyskinesia were 1) diagnosis of affective disorder with alcoholism and/or drug-induced parkinsonism, and 2) diagnosis of schizophrenia with advanced age (over 50) and/or prolonged hospitalization (over 14 years). A diagnosis of schizophrenia in patients under age 50 with short hospitalizations was not significantly associated with the presence of tardive dyskinesia.

Expression of dopamine transporter and vesicular monoamine transporter 2 mRNAs in rat midbrain after repeated amphetamine administration.

The dopamine transporter (DAT) in pre-synaptic membranes and the vesicular monoamine transporter 2 (VMAT2) in membranes of synaptic vesicles are involved in mediating the acute effects of amphetamine on dopamine transmission. Therefore, using a quantitative method of in situ hybridization and computerized image analysis, the expression of DAT and VMAT2 mRNAs was examined in rats treated for 5 days with amphetamine and killed 3 or 14 days after the last injection. We examined ventral tegmental area (VTA), substantia nigra (SN) and the transitional zone between VTA and SN. Each of these regions was further subdivided into rostral, intermediate and caudal portions. In control rats, autoradiographs revealed a gradient of both DAT and VMAT2 mRNA levels, decreasing gradually from rostral to caudal rat midbrain. After 3 days of withdrawal, a significant increase in DAT mRNA levels was found in rostral portions of VTA (117.9 + 5.8% of control group), SN (116.5 + 4.5%) and the transitional zone (119.6 + 5.6%) and in the intermediate portion of SN (113.5 + 4.3%). VMAT2 mRNA was significantly increased only in rostral and intermediate portions of the transitional zone (120.9 + 4.8 and 113.6 + 4.1%). After 14 days of withdrawal, there was a trend towards increased DAT mRNA levels in intermediate-caudal portions of midbrain, but a statistically significant increase was observed only in the intermediate portion of VTA (120.2 + 7.9%). No changes in VMAT2 mRNA levels were found. Thus, repeated amphetamine administration exerts modest and regionally selective effects on DAT and VMAT2 mRNA expression in subpopulations of midbrain dopamine neurons.

Amphetamine administration does not alter protein levels of the GLT-1 and EAAC1 glutamate transporter subtypes in rat midbrain, nucleus accumbens, striatum, or prefrontal cortex.

Our laboratory and others have previously shown that glutamate transmission is required for chronic amphetamine-induced neuroadaptations, and that glutamate transmission itself is altered by chronic amphetamine administration. For example, N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunit expression are altered in a region- and withdrawal-specific manner. The goal of this study was to determine whether repeated amphetamine administration influences the expression of two glutamate transporter subtypes, GLT-1 and EAAC1. Rats were treated with saline or 5 mg/kg amphetamine for 5 days (chronic saline and amphetamine groups, respectively), or saline for 4 days and 5 mg/kg amphetamine on day 5 (acute amphetamine group), and decapitated 24 h after the last injection. Tissue was dissected from brain regions involved in the psychomotor effects of amphetamine (nucleus accumbens, striatum, prefrontal cortex, ventral tegmental area, and substantia nigra). Levels of GLT-1 and EAAC1 were quantified by Western blotting and normalized to actin levels. We found no significant change in levels of GLT-1 or EAAC1 in response to either acute or chronic amphetamine treatment. These findings suggest that the transporter component of the glutamate system might not play a significant role in the alterations in glutamate transmission observed following repeated amphetamine administration.