Intrastriatal injection of [3H]dopamine through a chronic cannula to produce rotation: Distribution and concentration of the tracer in specific brain regions

As others have shown, rats rotated contralaterally following unilateral intrastriatal injections of dopamine. However, the concentration of the injection solution necessary to elicit rotation in our and others' studies was high, 50 μg/0.5 μl (10,000 times endogenous concentration) and the latency to turn was 20–60 min. Thus, we injected [³H]dopamine ([³H]DA) to determine the concentration of the injected DA in the striatum and to determine if the long latency to turn was related to spread of DA over time to distal nuclei such as the globus pallidus, subthalamic nucleus and substantia nigra. Microinjections (0.5 μl) of [³H]DA were made through a chronic striatal cannula in pargyline-treated freely moving rats. Determinations of [³H]DA concentrations in individual brain areas were made at 20 min and 60 min following intrastriatal injection. The major accumulation of [³H]DA and its metabolites was in the dorsal striatum, near the cannula tip, and in the sensorimotor cortex where the cannula passed through to the striatum. The concentration of [³H]DA in the dorsal striatum was only 10–100 times the endogenous concentration, depending upon the cannula injection system used. The 60 min latency to rotate could not be attributed to spread of DA to the subthalamic n., entopeduncular n. and substantia nigra. Rotation following an intrastriatal injection of DA was dependent upon the dorsal striatal tissue concentration of DA. The ventral striatum and globus pallidus were also possibly involved. The highest striatal [³H]DA concentrations were, at most, 10 times greater than the concentrations of systemically injectedl-[³H]DOPA, and, at the lower concentrations which produced twisting and weak rotation, the DA concentration was similar to that seen with systemicl-DOPA.     

Long-term effects of amygdaloid kindling on striatal dopaminergic terminals

The present study assessed the effects of kindling on striatal DA terminals. Kindled and control rats were tested for DA transporter density using [³H]GBR-12935 binding to striatal membranes and for amphetamine and KCI-induced [³H]DA release from striatal slices. Kindling decreased the maximal number of [³H]GBR-12935 binding sites in the dorsal striatum of rats sacrificed either 2 h or 4 weeks after the last seizure but had no effect on stimulated fractional [³H]DA release. These findings suggest a minor damage to DA terminals in the dorsal striatum. At the same postseizure time points, kindling augmented the hyperlocomotion associated with novel environment. Explanation of this effect requires in vivo measures of striatal DA functioning.     

Effects of para-chlorophenylalanine on amphetamine and haloperidol-induced changes in striatal dopamine turnover

Para-chlorophenylalanine (PCPA) was administered to rats, and the animals were sacrificed 48 h later. Animals received various doses of S(+)-amphetamine (AMPH) 31 min before sacrifice or of haloperidol (HAL) 46 min before sacrifcie and an intracerebral injection of [³H]tyrosine 15 min prior to sacrifice. PCPA pretreatment potentiated the increased accumulation of striatal [³H]dopamine (DA) induced by doses of AMPH to 1.5 mg/kg, and inhibited the decrease in striatal [³H]DA accumulation observed at higher doses (> 2.5 mg/kg) of AMPH. Furtherm the AMPH-induced increase in endogeneous levels of striatal DA was inhibited by PCPA pretreatment. Similarily, PCPA pretreatment potentiated the HAL-induced increase in striatal [³H]DA accumulation. The data are discussed with respect to an inhibitory serotonergic influence on nigrostriatal DA function, and the relationship of nigrostriatal biochemical events to AMPH-induced behavioral changes.     

A continuous striatal infusion of 6-hydroxydopamine produces a terminal axotomy and delayed behavioral effects

Rat models of Parkinson's disease typically employ a rapid nigral injection of 6-hydroxydopamine (6-OHDA) to produce a near-complete loss of nigrostriatal dopamine neurons, and thus model end stage disease. The present report describes the use of a continuous, low dose infusion of 6-OHDA into the striatum which produces a terminal axotomy of nigrostriatal dopamine neurons and protracted behavioral response. A solution of 6-OHDA in 0.4% ascorbate, delivered at 37°C from osmotic minipumps, was stable for 8 days as determined by its retained toxicity to a dopaminergic neuroblastoma cell line. The continuous infusion of 0.2 μg 6-OHDA per h did not affect the striatal uptake of [³H]GABA, [³H]choline, or [³H]glutamate but reduced [³H]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal infusion of 6-OHDA produced a dose-dependent reduction of striatal dopamine and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increase in amphetamine-induced ipsiversive rotations occurred within 1.5 days after the acute striatal injection of 20 μg or 30 μg of 6-OHDA but required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [³H]mazindol binding showed that, begining by 1.5 days, a diffuse depletion of terminals encompassed much of the striatum in the 30 μg acute injection group, whereas in the continuously infused rats, the lesion was apparent only by 4 days and was restricted to a smaller and more completely lesioned area. Unlike acutely lesioned animals, continuously infused rats revealed no obvious loss of dopamine neurons in the pars compacta by 5 weeks after 6-OHDA. The continuous striatal infusion of 6-OHDA can produce a topographically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.     

Footshock treatment activates catecholamine synthesis in slices of mouse brain regions

Synthesis of catecholamines was measured in slices of frontal cortex, hypothalamus, striatum, hippocampus and brainstem by the accumulation of [³H]norepinephrine (NE) and [³H]dopamine (DA) following incubation with [³H]tyrosine.Following acute footshock (60 shocks, 0.3 mA 30 min), consistent increases in [³H]DA accumulation were seen in frontal cortex slices, but no significant effect was seen in striatal slices. The accumulation of [³H]NE was not altered consistently in frontal cortex, hypothalamus, hippocampus or brainstem. Brain slices from mice adrenalectomized 24–48 h before footshock showed similar results. However, in hypophysectomized mice, footshock did not increase the [³H]DA accumulation in slices of frontal cortex. Administration of dexamethasone before footshock prevented the footshock-induced increase in frontal cortex [³H]DA accumulation, but footshock then significantly increased [³H]NE accumulation in the hypothalamus and brainstem. Chronic footshock (5 days) had little effect on frontal cortex [³H]catecholamine accumulation but produced a consistent elevation of [³H]NE accumulation in slices from the hypothalamus.In confirmation that the slices data reflected in vivo metabolism, both dihydroxyphenylacetic acid and homovanillic acid were significantly elevated in the frontal cortex but not the striatum of mice receiving acute footshock.Since previous studies have shown that ACTH administered intracerebroventricularly also accelerated [³H]DA accumulation in frontal cortex slices, these results are consistent with the involvement of ACTH in the effects of footshock on frontal cortex DA. The effects of chronic footshock are consistent with the activation of hypothalamic tyrosine hydroxylase by corticosterone.     

Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum

GR-113808, a potent and selective 5-HT₄ receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 μM GR-113808 did not effect the extracellular concentrations of DA in either region and 100 μM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 μM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 μg/0.5 μl) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 μg but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT₄ receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.     

Enhancement of [H]dopamine release and its [H]metabolites in rat striatum by nicotinic drugs

Recent evidence has identified directly muscarinic acetylcholine receptor (m-ACh R) and nicotinic acetylcholine receptor (n-ACh R) in the brain utilizing receptor binding assay. Several studies suggest that release of dopamine (DA) in the striatum is regulated by presynaptic receptors present on dopaminergic terminals. In the present study, the effects of cholinergic drugs on [³H]DA release were examined using micropunched tissue and synaptosomes obtained from rat striatum. ACh (5 × 10⁻⁴M) significantly increased spontaneous [³H]DA release, and the overflow was partially inhibited by d-tubocurarine (1 mM) but not atropine. Nicotine, lobeline, coniine and spartein, nicotinic agonists, significantly increased spontaneous and 25 mM K⁺ evoked [³H]DA release almost in a dose-dependent manner. In contrast, oxotremorine (2 × 10⁻⁴M), muscarinic agonist, did not any change in [³H]DA efflux. Furthermore, the metabolites of [³H]DA were separated by column chromatography. The main metabolite of [³H]DA in the spontaneous release from rat striatal synaptosomes was [³H]DOPAC (3,4-dihydroxyphenylacetic acid). Lobeline (5 × 10⁻⁵M) accelerated the outflow of [³H]DOPAC and [³H]OMDA metabolites (O-methylated and deaminated metabolites).These results could give rise to the suggestion that there was n-ACh R on the dopaminergic nerve terminals in the striatum and n-ACh R might have related to a directly excitatory effect on the DA release.     

Evidence for a dopaminergic innervation of the cat lateral habenula: its role in controlling serotonin transmission in the Basal ganglia

The presence of a dopaminergic innervation of the cat lateral habenula and its possible role in modulating serotonin transmission within the basal ganglia were investigated using both in vitro and in vivo approaches. A high density of [³H]spiroperidol binding sites with similar affinities for domperidone and apomorphine as those present in the cat striatum were found in the habenula. By means of the push-pull cannula technique, a substantial release of [³H]dopamine continuously formed from [³H]tyrosine was detected in the lateral habenula of halothane-anesthetized cats since the amount of [³H]catecholamines was enhanced in the presence of benztropine, an inhibitor of dopamine uptake into dopaminergic nerve terminals. Furthermore, in anesthetized animals with a push-pull cannula implanted in each caudate nucleus and substantia nigra habenular applications of dopamine (10⁻⁷ M) reduced nigral but not striatal release of [³H]serotonin continuously formed from [³H]tryptophan. This change was prevented either by the delivery of domperidone to the lateral habenula or by the blockade of GABAergic transmission (picrotoxin 10⁻⁵ M) in the dorsal raphe. These data support the involvement of habenula-raphe pathways in the regulation of serotonin transmission in the cat basal ganglia and indicate that dopaminergic inputs to the lateral habenula participate in such a control.     

Chronic ethanol changes opiate receptor function in rat striatum

Ethanol produces supersensitivity of striatal σ-opiate receptor sites labeled by [³H]DADLE and [³H]etorphine. The impairment may be ascribed to the diminished enkephalin release detected in rat striatum after chronic ethanol consumption. On the contrary, a lower affinity of striatal μ-opiate receptors results after same ethanol exposure. In fact, the K_d values of [³H]Met-enkephalin and [³H]DHM are enhanced when measured in striata of ethanol-dependent rats. The diverse sensitivity of the various classes of opiate receptors to ethanol may be ascribed to different ethanol effects on enekephalinergic transmission.     

The effect of repeated amphetamine treatment on striatal DA transporter and rotation in rats

The effect of repeated amphetamine treatment on the involvement of the striatal DA transporters in rotation was tested in rats. Repeated amphetamine treatment had no effect on [³H]DA uptake or [³H]GBR-12935 binding density. However, unlike the naive rats who rotated away from the striatum with a lower density of DA transporters, rats sensitized to amphetamine rotated toward the striatum with a lower density of DA transporters. These findings imply that repeated amphetamine augments the subcortical involvement in behavioral output.     

Stimulation of dopamine release by GABA in rat striatal slices

The effect of GABA on the release of dopamine (DA) from dopaminergic terminals was examined in striatal slices of the rat. The slices were continuously superfused withL-[³H]tyrosine and [³H]DA released was estimated in serial 2.5 min superfusate fractions. GABA from 10⁻⁵ M to 10⁻³ M stimulated the spontaneous release of [³H]DA. The intensity of the effect appeared to be concentration dependent. The GABA stimulatory effect on [³H]DA release persisted during the entire application of GABA for periods as long as 50 min. At a much higher concentration (10⁻¹ M) GABA inhibited the spontaneous release of [³H]DA.At a concentration (10⁻⁴ M) which stimulated [³H]DA release, GABA had no effect on [³H]DA uptake or [³H]tyrosine initial transport in striatal sucrose homogenates. Furthermore it did not affect DA synthesis as indicated by the estimation of the conversion index of tyrosine into DOPA (³H₂O formed fromL-[3,5-³H]tyrosine/tyrosine specific activity in tissues).The stimulatory effect of GABA (5 × 10⁻⁵ M) on the spontaneous release of [³H]DA was not detectable when slices were superfused in the absence of calcium or in the presence of tetrodotoxin (5 × 10⁻⁷ M). It was markedly reduced in the presence of picrotoxin (10⁻⁵ M), a GABA antagonist. Finally, like GABA, GABA agonists such as muscimol and compounds structurally related to GABA such as lioresaal and gammahydroxybutyrate stimulated [³H]DA spontaneous release. Gamma-hydroxylioresal, an inactive metabolite of lioresal, was without effect.These various results suggest that GABA stimulates specifically the release of DA endogenously synthesized in dopaminergic terminals. The blockade of the GABA stimulatory effect by tetrodotoxin (5 × 10⁻⁷ M) suggests that the GABA receptors mediating the action of GABA are not located presynaptically on dopaminergic terminals but on neurons or neuronal afferences within the striatum.     

A dopamine-sensitive striatal efferent system mapped with [C]deoxyglucose in the rat

Rats which had exhibited contralateral rotation following unilateral injection of dopamine (DA) through a striatal cannula were given 0.5–50 μg DA intrastriatally and then were injected with [¹⁴C]deoxyglucose peripherally to measure glucose utilization in the striatum and its projection nuclei. Quantitative autoradiographic techniques were used to measure glucose utilization. Brain areas which showed L-R asymmetries and changes in glucose utilization different from vehicle-injected animals were: the substantia nigra (pars compacta and pars reticulata), the subthalamic n., entopeduncular n., lateral habenula, and deep layers of the superior colliculus. The globus pallidus was affected also, but only in one group for which the injected DA may have spread and affected it directly. Each of these areas receives projections from the striatum or is one additional synapse away. Intrastriatal injections of norepinephrine, isoproterenol, and procaine did not produce changes in glucose utilization in the striatal projection nuclei. The results support the existence of a DA-sensitive strionigral system to both the reticulata and compacta regions of the nigra, and suggest that this activity is paralleled by a strio-subthalamic and strio-entopeduncular-habenular system. The onset of changes in glucose utilization in the entopeduncular-habenular system was later than in the strio-subthalamic and strionigral systems and correlated with the onset of rotation. However, data from 4 animals which did not rotate suggest that each of these systems is necessary but not sufficient for rotation. It is concluded that DA receptors in the striatum play a significant role in the effects of peripherally administered DA agonists on other nuclei, even though most of these other nuclei also have their own DA receptors.     

Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 μCi (10 μg) of [³H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere. The concentrations of dopamine and its metabolites (DOPAC, HVA and 3-MT) were quantified by gas chromatography-mass spectrometry in the right and left striata at 5 and 15 min after unilateral intracarotid infusion of 1 μg apomorphine. At both time intervals and regardless of the side infused, the metabolites of dopamine increased ipsilateral to the side of infusion. Moreover, 3-MT levels were significantly decreased in the contralateral striatum. After direct intrastriatal injection of either 0.1 or 1.0 μg apomorphine into the right striatum, the levels of dopamine metabolites were again increased in the ipsilateral striatum. 3-MT levels were also decreased significantly in the left striatum. In contrast to the effects observed after systemic administration of apomorphine, these results demonstrate that dopamine release in the striatum is increased by selectively delivering higher concentrations of apomorphine to the nerve terminals of the nigrostriatal neurons. The effects of unilateral apomorphine on dopamine metabolism in the contralateral striatum are most likely the effect of interhemispheric communication.     

ACTH1–24 and lysine vasopressin selectively activate dopamine synthesis in frontal cortex

The accumulation of [³H]catecholamines from [³H]tyrosine in frontal cortical, septal, striatal and hippocampal slices was examined following intracerebroventrcular (i.c.v.) injections of ACTH₁₋₂₄, lysine vasopressin (LVP) and saline. Both ACTH₁₋₂₄ and LVP (1 μg) selectively increased the accumulation of [³H]dopamine (DA) in frontal cortical slices, but did not affect that of [³H]norepinephrine (NE). LVP but not ACTH₁₋₂₄ also inhibited the accumulation of [³H]DA in striatal slices. ACTH₁₋₂₄ did not alter the accumulation of [³H]NE in hippocampal slices, nor did LVP alter the accumulation of either catecholamine (CA) in septal slices. In vitro incubations with ACTH analogs or LVP failed to alter the rate of accumulation of [³H]CAs in striatal, substantia nigral and frontal cortical slices, except for an inhibitory effect at high doses. This effect is believed to be an artifact of precursor dilution caused by release of tyrosine following degradation of the peptides. Neither peptide modified the increased [³H]CA accumulation stimulated by 26 mM K⁺, nor did ACTH_1–24 modify the inhibition of [³H]CA accumulation caused by 3 × 10⁻⁶ M haloperidol or 3 × 10⁻⁷ M apomorphine. Selective activation of the mesocortical DA system has also been reported to occur in response to footshock, suggesting the possibility that endogenous ACTH and/or LVP might mediate the stress-induced activation of mesocortical DA synthesis. Alternatively, i.c.v. injections of these peptides may themselves be stressful and thus indirectly elicit the response.     

Influence of prelimbic and sensorimotor cortices on striatal neurons in the rat: electrophysiological evidence for converging inputs and the effects of 6-OHDA-induced degeneration of the substantia nigra

These studies were designed to investigate whether there are convergent prelimbic and sensorimotor cortical inputs onto striatal neurons in the rat and whether dopaminergic (DA) nigrostriatal fibers regulate these inputs. The influence of the nigrostriatal DA system was assessed in rats with either small or large 6-hydroxydopamine-induced lesions of the substantia nigra. In normal rats 39 out of 74 neurons (52.7%) were excited by stimulation of both the prelimbic and the sensorimotor cortex. No marked change in corticostriatal transmission was evident in rats with small 6-OHDA-induced lesions (defined as 10–35% decrease in [³H]DA uptake in striatal synaptosomes). In rats with large lesions (75–85% decrease in striatal [³H]DA uptake), however, a complete rearrangement of the corticostriatal transmission occurred. This was evident in a decrease of thresholds to obtain cortical responses, by modifications of the discharge properties of striatal neurons receiving input from cortices and by an increase in the number of neurons responding to cortical stimulation. In addition, a significantly higher percentage of striatal neurons responded to stimulation of both prelimbic and sensorimotor cortices in rats with large lesions than in rats with small lesions or in control rats. This data suggests that: (1) no functional separation of prelimbic and sensorimotor cortical inputs occurs in the rat striatum, (2) the nigrostriatal DA system exerts a focusing effect on these inputs, (3) the striatum is actively involved in the integrative processing of descending cortical information.     

Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse

Summary In the striatum of the homozygous weaver mutant mouse (wv/wv), dopamine content, uptake and tyrosine hydroxylase activity are decreased compared to wild-type (+/+) mice. In mice heterozygous for the weaver gene (wv/+), these dopaminergic parameters exhibit only minor reductions compared to +/+ mice. Thewv/wv striatum has recently been shown to have an increase in serotonin content. In the present study, the serotonin uptake system of the weaver striatum was investigated. Synaptosomal uptake of [³H] serotonin was determined in the dorsal portion ofwv/wv and +/+ striatum, and serotonin uptake sites were examined by the binding of [³H] citalopram in the striatum ofwv/wv, wv/+ and +/+ mice. The dopamine uptake system was also investigated in all three genotypes via the binding of [³H] mazindol. Synaptosomal uptake of [³H] serotonin was increased by 79% in the dorsal portion of thewv/wv striatum compared to that seen in the +/+ striatum. The binding of [³H] citalopram was increased by 62% in the dorsolateral and by 111% in the dorsomedial portions of thewv/wv striatum compared to +/+. [³H] Citalopram binding in thewv/+ striatum was also higher than +/+, but this increase did not reach statistical significance. Within thewv/wv striatum, [³H] mazindol binding was almost completely absent (88–89% reduction) in the dorsal portion and severely reduced in the other striatal areas. These data support the notion that the dorsal portion of thewv/wv striatum, which has the severest reduction in dopamine uptake, is hyperinnervated by serotonin fibers.     

NMDA regulation of dopamine release from proximal and distal dendrites in the cat substantia nigra

The NMDA regulation of the dendritic release of [³H]dopamine ([³H]DA) synthesized from [³H]tyrosine was investigated in vitro using a microsuperfusion procedure in the pars compacta (SNC) and the pars reticulata (SNR) of the cat substantia nigra. The spontaneous release of [³H]DA was threefold higher in the SNC than in the SNR and amphetamine (1 μM) enhanced similarly [³H]DA release in both nigral areas. In the absence of magnesium, NMDA (50 μM) stimulated markedly the release of [³H]DA in the SNC and SNR, these effects being completely prevented by MK 801 (1 μM), the NMDA receptor antagonist. The DA uptake inhibitor, nomifensine (5 μM), increased the amount of [³H]DA recovered in SNC (×2) and SNR (×3) superfusates but did not significantly modify the NMDA-evoked responses. The effects of NMDA seen in the absence or presence of nomifensine persisted when the two nigral areas were continuously superfused with tetrodotoxin (1 μM). These results are in favor of the presence of NMDA receptors on dopaminergic dendritic arborizations and indicate that the stimulation of these receptors facilitates in a similar way the release of DA from proximal and distal dendrites.     

The antidopaminergic action of S-20098 is mediated by benzodiazepine/GABAA receptors in the striatum

The naphthalenic compound S-20098, which is a melatonergic agonist, inhibits [³H]diazepam binding in striatal membranes. S-20098 also inhibits apomorphine-induced turning in 6-hydroxydopamine lesioned rats. This antidopaminergic effect is blocked by either intraperitoneal injection of the central-type benzodiazepine (BZ) antagonist, flumazenil, or intrastriatal injection of the GABA_A antagonist, bicuculline. These findings indicate that S-20098 can activate central-type BZ receptors, and its antidopaminergic action, like that of melatonin, involves a GABAergic mechanism in the striatum.     

Development of a micromethod to study the Na-independentl-[H]glutamic acid binding to rat striatal membranes. II. Effects of selective striatal lesions and deafferentations

An apparent single class of Na⁺-independentl-[³H]glutamate (l-[³H]Glu) binding sites was biochemically and pharmacologically identified on rat striatal tissue. The K_d value was 1.75 μM and the B_max3.89 nmol/g protein. In order to further elucidate the putative physiological role of these binding sites and to valid our binding assay, experiments were conducted to determine the anatomical location of thel-[³H]Glu binding sites in the striatum. Local injection of the neurotoxin, kainic acid into the striatum caused degeneration of target cells in the structure followed by an important decrease (-37%) in the number of these binding sites, with no significant change in the affinity constant. Lesions of the cortical frontal and parietal areas projecting to the striatum via putative glutamatergic fibers led, on the other hand, after 3 weeks to one month, to a significant increase (+23%) in the number ofl-[³H]Glu binding sites. The K_d value does not significantly change after decortication. Finally, suppression either of the nigrostriatal dopaminergic input or of the partially cholinergic thalamostriatal tract do not affect [³H]Glu binding to striatal tissue. These results suggest that about 40% of our [³H]Glu binding sites are located on striatal target cell sensitive to the neurotoxic effect of kainic acid. Therefore, they seem to be partly postsynaptic. The existence of a relation between these binding sites and the corticostriatal glutamatergic input was shown by the development of a supersensitivity response after suppression of this cortical input. These sites might therefore constitute one of the receptor subclass for Glu linked to the excitatory action of the corticostriatal afferent. Since degeneration of either the nigrostriatal dopaminergic or the thalamostriatal fibres did not affect the binding ofl-[³H]Glu characterized in our study, the binding sites will probably not occur at the presynaptic level on these nerve terminals in the striatum.     

Striatal and cortical NMDA receptors are altered by a neurotoxic regimen of methamphetamine

Methamphetamine (m-AMPH) treatment produces long-lasting damage to striatal and cortical monoaminergic terminals and may also injure nonmonoaminergic cortical neurons. Evidence suggests that both dopamine (DA) and glutamate (GLU) play crucial roles in producing this damage. We used quantitative autoradiography to examine [³H]mazindol ([³H]MAZ) binding to striatal DA transporters and [³H]GLU binding to N-methyl-D-aspartate (NMDA) receptors in the striatum and cortex 1 week and 1 month after a neurotoxic regimen of m-AMPH. Rats received m-AMPH (4 mg/kg) or saline (SAL) (1 ml/kg) in four s.c. injections separated by 2 h intervals. One week after m-AMPH, the ventral and lateral sectors of the striatum showed the greatest decreases in both [³H]MAZ and [³H]GLU binding, while the nucleus accumbens (NA) showed no significant decreases. One month after m-AMPH, striatal [³H]MAZ binding was still significantly decreased, while NMDA receptor binding had recovered. Surprisingly, the parietal cortex showed a m-AMPH-induced increase in NMDA receptor binding in layers II/III and IV 1 week after m-AMPH and only in layers II/III 1 month after m-AMPH. The prefrontal cortex showed no m-AMPH-induced changes in NMDA receptor binding at either time point. This is the first demonstration that a regimen of m-AMPH that results in long-lasting damage to DA terminals can alter forebrain NMDA receptor binding. Thus, repeated m-AMPH treatments may produce changes in glutamatergic transmission in selected striatal and cortical regions. © 1996 Wiley-Liss, Inc.