Central Striatum Research Articles

Crym-positive striatal astrocytes gate perseverative behaviour

Astrocytes are heterogeneous glial cells of the central nervous system1–3. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders4–7. In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR–Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory–inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex–striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics8, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders9–12. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte–neuron interaction mechanisms that could be targeted in treatments for perseveration.

NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2 Receptor Stimulation: Involvement in Behavioral Repetition.

Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or β-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.SIGNIFICANCE STATEMENT Behavioral repetition is a form of compulsivity, which is one of the core symptoms of psychiatric disorders, such as obsessive-compulsive disorder. Perseveration is also a hallmark of such disorders. Both clinical and animal studies suggest important roles of abnormal dopaminergic signaling and striatal hyperactivity in compulsivity; however, the precise molecular link between them remains unclear. Here, we demonstrated the contribution of NOX1 to behavioral repetition induced by repeated stimulation of D2 receptors. Repeated stimulation of D2 receptors upregulated Nox1 mRNA in a striatal subregion-specific manner. The upregulated NOX1 promoted striatal synaptic facilitation in iMSNs by enhancing phosphorylation signaling. These results provide a novel mechanism for D2 receptor-mediated excitatory synaptic facilitation and indicate the therapeutic potential of NOX1 inhibition in compulsivity.

Investigating the Role of Striatal Neuron Subtypes in Compulsive Behavior and Treatment Response

Convergent OCD neuroimaging studies demonstrate symptom-associated striatal hyperactivity resolved by effective treatment. However, the roles of spiny projection neuron (SPN) subtypes in compulsive behavior are unclear. Here we dissected contributions of D1- and D2-SPNs using a model system that displays hyperactivity in central striatum (CS) and OCD-relevant behaviors: Sapap3-KO mice.

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior.

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (∼3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (∼6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.SIGNIFICANCE STATEMENT These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessive-compulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

An Adenosine A2A Receptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, response rates to SSRI treatment vary between symptom dimensions. In this study, to find a therapeutic target for SSRI-resilient OCD symptoms, we evaluated treatment responses of quinpirole (QNP) sensitization-induced OCD-related behaviors in mice. SSRI administration rescued the cognitive inflexibility, as well as hyperactivity in the lateral orbitofrontal cortex (lOFC), while no improvement was observed for the repetitive behavior. D2 receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A2A antagonist, istradefylline, which rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons (MSNs) of sensitized mice, alleviated both of the QNP-induced abnormal behaviors with only short-term administration. These results provide a new insight into therapeutic strategies for SSRI-resistant OCD symptoms and indicate the potential of A2A antagonists as a rapid-acting anti-OCD drug.

Aripiprazole and Riluzole treatment alters behavior and neurometabolites in young ADHD rats: a longitudinal 1H-NMR spectroscopy study at 11.7T

Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive compulsive disorder (OCD) are co-occurring neurodevelopmental diseases that share alterations of frontocortical neurometabolites. In this longitudinal study we investigated the behavioral and neurochemical effects of aripiprazole and riluzole treatment in juvenile spontaneously hypertensive rats (SHR), a model for ADHD. For neurochemical analysis we employed in vivo magnetic resonance spectroscopy (MRS). Spectra from voxels located at the central striatum and prefrontal cortex were acquired postnatally from day 35 to 50. In the SHR strain only, treatments reduced repetitive grooming and climbing behavior. The absolute quantification of cerebral metabolites in vivo using localized 1H-MRS at 11.7T showed significant alterations in SHR rats compared to controls (including glutamine, aspartate and total NAA). In addition, drug treatment reduced the majority of the detected metabolites (glutamate and glutamine) in the SHR brain. Our results indicate that the drug treatments might influence the hypothesized ‘hyperactive’ state of the cortico-striatal-thalamo-cortical circuitries of the SHR strain. Furthermore, we could show that behavioral changes correlate with brain region-specific alterations in neurometabolite levels in vivo. These findings should serve as reference for animal studies and for the analysis of neurometabolites in selected human brain regions to further define neurochemical alterations in neuropsychiatric diseases.

Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common and devastating disease affecting millions of people worldwide annually. Exaggerated inflammation and apoptosis are two pivotal pathological processes for secondary brain injury after ICH. Quercetin, a flavonoid widely distributed in various herbs, fruits and vegetables, has been proved to improve neuronal functional recovery in spinal cord injury rats. However, the efficacy of quercetin in caring for post-ICH brain injury has not been investigated. In the present study, we established an ICH model by injecting type VII bacterial collagenase (0.5U) into the central striatum of male Sprague-Dawley rats. The animals were randomized to four groups: sham-operation group; ICH + vehicle group; ICH + 5 mg/kg quercetin group; and ICH + 50 mg/kg quercetin group. The expression levels of IL-1β, IL-4, IL-6 and TNF-α in the brain tissue were assayed by Real-time PCR, ELISA and Western Blot, and cell apoptosis was assayed by TUNEL and caspase-3 staining 3 days after model establishment. It was found that the lesion volume, the brain water content, the expression levels of the four inflammation markers and the number of apoptotic cells were reduced significantly in ICH rats receiving quercetin, especially in 50 mg/kg quercetin group. These results confirmed the therapeutic efficacy of quercetin in repairing brain injury, probably by inhibiting inflammatory response and apoptosis, thus promoting nerve functional restoration.

Amphetamine-elicited striatal Fos expression is attenuated in neurotensin null mutant mice

Neurotensin (NT) has been suggested to interact with dopamine systems in different forebrain sites to exert both antipsychotic- and psychostimulant-like effects. We previously found that genetic or pharmacological manipulations that disrupt endogenous NT signaling attenuate antipsychotic drug-induced Fos expression in the dorsolateral and central striatum but not other striatal regions. To assess the role of NT in psychostimulant responses, we examined the ability of d-amphetamine (AMP) to induce Fos in wild-type and NT null mutant mice. AMP-elicited Fos expression was significantly attenuated in the medial striatum of NT null mutant mice, but was unaffected in other striatal territories. Similar results were obtained in rats and mice pretreated with the high affinity neurotensin receptor (NTR1) antagonist SR 48692. The effect of the NTR1 antagonist was particularly apparent in the striatal patch (striosome) compartment, as defined by μ-opioid receptor immunoreactivity. These data suggest that NT is required for the full activation by AMP of medial striatal neurons.

Inhibition of methylphenidate-induced gene expression in the striatum by local blockade of D1 dopamine receptors: Interhemispheric effects

Psychostimulants change the function of cortico-basal ganglia circuits. Some of these effects are mediated by altered gene regulation in projection neurons of the striatum which participate in these circuits. Psychostimulant-induced changes in gene expression in these neurons are a consequence of excessive stimulation of G-protein-coupled receptors, particularly the D1 dopamine receptor subtype. Recent findings show that the psychostimulant methylphenidate, which causes dopamine overflow in the striatum, produces changes in striatal gene regulation similar, but not identical, to those induced by psychostimulants such as cocaine and amphetamine. We investigated, in rats, the role of striatal D1 receptors in methylphenidate-induced gene expression, by intrastriatal administration of the D1 receptor antagonist SCH-23390. Effects on the expression of two plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a, in the striatum and cortex were assessed. Intrastriatal infusion of SCH-23390 (2–10 μg) attenuated zif 268 and Homer 1a mRNA expression induced by methylphenidate (10 mg/kg, i.p.) in a dose-dependent manner. Moreover, this unilateral SCH-23390 infusion not only inhibited gene induction at the infusion site in the central striatum, but also in distant striatal regions including the nucleus accumbens, as well as throughout the entire contralateral striatum. These results indicate that striatal D1 receptors are critical for gene induction by methylphenidate. Moreover, the ipsilateral and contralateral effects of local SCH-23390 administration suggest that D1 receptor-stimulated striatal output exerts robust control over widespread striatal activities/gene expression via regulation of input to the striatum.

Behavioral and anatomical effects of quinolinic acid in the striatum of the hemiparkinsonian rat

Parkinson's disease (PD), a hypokinetic disorder, and Huntington's disease (HD), a hyperkinetic disorder, share the fact that in the motor pathways the dysfunction starts in the striatum. In PD the projection neurons are overactive due to decreased inhibitory regulation by lost dopamine afferents, while in HD the output from the striatum is insufficient due to loss of projection neurons. This study aimed to determine whether the introduction of a mild HD condition in the PD striatum can counter the hypokinetic condition. The experiment was carried out in the 6-OHDA rat model for PD in which amphetamine, 5 mg/kg, evokes an asymmetric rotation response toward the side of the 6-OHDA lesion (ipsilateral rotation). The response to amphetamine in this study was fractionated into multiple components and measured automatically. After baseline measurements, the subjects were divided into four groups. Group I was unilaterally sham-lesioned in medial, central, and lateral striatum. Group II was injected quinolinic acid (QA) 20 nM in medial, central, and lateral striatum. Group III was injected QA 60 nM in central striatum. Group IV was injected QA 120 nM in central striatum. The effects of QA were measured weekly. The sham lesions in Group I had no effects. In Group II, ipsilateral rotation was reduced and replaced by oral stereotypy, a competitive behavior. In Group III, ipsilateral rotation decreased, but to a lesser degree than in Group II. In Group IV, QA had no effects. Histological findings show a unilateral loss of tyrosine immunoreactive (TH) neurons in substantia nigra and of fibers in striatum in all subjects. In addition, in Group II the striatum was atrophied. These findings suggest that the shift in Group II from ipsilateral rotation to oral stereotypy after QA was due to reduced striatal output caused by a loss of projection neurons, a loss insufficient to induce HD symptoms, but sufficient to counter the PD condition.

Infusion of apomorphine into the dorsocentral striatum produces acute drug-induced recovery from neglect produced by unilateral medial agranular cortex lesions in rats

Previous studies have shown that systemic administration of apomorphine is effective in producing acute drug-induced recovery from neglect induced by unilateral medial agranular cortex (AGm) lesions. More recent studies have demonstrated that recovery from neglect may be due to plastic changes occurring in the dorsal central striatum (DCS). Further, lesions of the DCS produce neglect that does not respond to systemic administration of apomorphine, suggesting that this area may be crucial for the therapeutic effects of apomorphine. In the present study, the behavioral effects of apomorphine infused into the DCS of animals with AGm lesion-induced neglect were examined to determine whether the DCS is a site of drug action. An infusion of 0.375 μg of apomorphine into the DCS, but not a lateral striatal control area, was effective in producing acute recovery from neglect. The results of this study support the crucial role of the DCS in recovery from neglect induced by unilateral AGm lesions and suggest that the DCS may be an important site of action for the therapeutic effects of apomorphine. Because dopamine agonist therapy has been shown to be effective in humans with neglect, the results of the current study may represent an important step in the development of future pharmacotherapies.

Increase in accumbal dopaminergic transmission correlates with response cost not reward of hypothalamic stimulation

Rats were trained to lever-press for intracranial self-stimulation (ICSS) of the lateral hypothalamus on either a fixed ratio (FR) 1 or 10 schedule. Their brains were removed after a 20 min session and tissue punches taken from the nucleus accumbens, olfactory tubercle, anterior striatum, or central striatum. These punches were assayed for content of dopamine (DA) and the major DA metabolite DOPAC. Compared with implanted controls, only the FR10 group showed significantly elevated DOPAC/DA ratios. These elevations were statistically significant in nucleus accumbens and central striatum and near significance in anterior striatum. They occurred to similar degrees in each hemisphere. In contrast, we found that stimulation of the ventral tegmental area of anesthetized rats asymmetrically increased the DOPAC/DA ratio, being most prominent in the ipsilateral accumbens. Because the FR10 group made only 58% of the responses of the FR1 group and received only 6% of the stimulations of the FR1 group, yet unlike the FR1 group showed a significant increase in the DOPAC/DA ratio, we suggest that the DA release was primarily influenced by the schedule, not the stimulation or the reward of the stimulation. These results were interpreted in terms of a model in which hypothalamic ICSS reward is largely dependent on non-dopaminergic mechanisms, with accumbal DA transmission being strongly dependent on the costs versus benefits of ongoing behavior.

Acute methamphetamine administration upregulates NGFI-B mRNA expression in the striatum: co-localization with c-Fos immunoreactivity.

In this study, the effects of acute methamphetamine administration on expression of the nuclear transcription factor NGFI-B mRNA and its co-localization with c-Fos immunoreactivity in the striatum were evaluated in animals receiving a single dose of methamphetamine (4 mg/kg) given at 2 or 6 h prior to perfusion. All animals received a daily saline injection for 6 days prior to methamphetamine treatment. We have found that, similar to c-fos activation, NGFI-B mRNA levels were significantly increased 2 h after methamphetamine treatment and returned to basal levels 6 h later. Induction of NGFI-B mRNA levels by methamphetamine was highest in central striatum as compared to the dorsomedial distribution pattern observed in control animals. After acute methamphetamine treatment, the distribution pattern of NGFI-B mRNA upregulation was very similar to that of methamphetamine induced c-Fos immunoreactivity. However, co-localization studies with c-Fos immunoreactivity showed that not all NGFI-B-positive cells contained c-Fos after methamphetamine treatment. Forty-five percent of all NGFI-B mRNA expressing neurons contained c-Fos immunoreactivity in the dorsomedial striatum as compared to 60% in central and 35% in ventrolateral striatum. This study provides a detailed description of the differential spatial and temporal modulation of NGFI-B and c-Fos expression in the striatum by acute methamphetamine treatment over time.

Amygdaloid projections to ventromedial striatal subterritories in the primate

The ventral striatum is the part of the striatum associated with reward and goal-directed behaviors, which are mediated in part by inputs from the amygdala. The ventral striatum is divided into ‘shell’ and ‘core’ subterritories which have different connectional, histochemical and pharmacological properties. Behavioral studies also indicate that subterritories of the ventral striatum are differentially involved in specific goal-directed behaviors. The amygdala is a heterogeneous structure which has multiple nuclei involved in processing emotional information. While the existence of an amygdalostriatal pathway has long been established, the relationship between amygdaloid afferents and specific subterritories of the ventral striatum is not known. In this study we operationally defined the ventromedial striatum as the region receiving cortical inputs primarily from the orbital and medial prefrontal cortex. We placed retrograde tracer injections into subregions of the ventromedial striatum of macaques monkeys to determine the relative contribution of specific amygdaloid inputs to each region. Calbindin-D28k immunostaining was used to further define the shell subterritory of the ventromedial striatum. Based on these definitions, the amygdala innervates the entire ventromedial striatum, and has few to no inputs to the central striatum. The basal and accessory basal nuclei are the major source of input to the ventromedial striatum, innervating both the shell and ventromedial striatum outside the shell. However, a restricted portion of the dorsomedial shell receives few basal nucleus inputs. Afferent inputs from the basal nucleus subdivisions are arranged such that the parvicellular subdivision projects mainly to the ventral shell and core, and the magnocellular subdivision targets the ventral shell and ventromedial putamen. In contrast, the intermediate subdivision of the basal nucleus projects broadly across the ventromedial striatum avoiding only the dorsomedial shell. The shell has a specific set of connections derived from the medial part of the central nucleus and periamygdaloid cortex. Within the shell, the dorsomedial region is distinguished by additional inputs from the medial nucleus. The ventromedial caudate nucleus forms a unique transition zone with the shell, based on inputs from the periamygdaloid cortex. Together, these results indicate that subterritories of the ventromedial striatum are differentially modulated by amygdaloid nuclei which play roles in processing olfactory, visual/gustatory, multimodal sensory, and ‘drive’-related stimuli.

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation.

Motor stereotypies are abnormally repetitive behaviors that can develop with excessive dopaminergic stimulation and are features of some neurologic disorders. To investigate the mechanisms required for the induction of stereotypy, we examined the responses of dopamine-deficient (DD) mice to increasing doses of the dopamine precursor L-DOPA. DD mice lack the ability to synthesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robust hyperlocomotion relative to wild-type (WT) mice when treated with L-DOPA, which restores striatal DA tissue content to approximately 10% of WT levels. To further elevate brain DA content in DD mice, we administered the peripheral L-amino acid decarboxylase inhibitor carbidopa along with L-DOPA (C/l-DOPA). When striatal DA levels reached >50% of WT levels, a transition from hyperlocomotion to intense, focused stereotypy was observed that was correlated with an induction of c-fos mRNA in the ventrolateral and central striatum as well as the somatosensory cortex. WT mice were unaffected by C/L-DOPA treatments. A D1, but not a D2, receptor antagonist attenuated both the C/L-DOPA-induced stereotypy and the c-fos induction. Consistent with these results, stereotypy could be induced in DD mice by a D1, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereotypy and c-fos induction by C/L-DOPA. These results indicate that activation of D1 receptors on a specific population of striatal neurons is required for the induction of stereotypy in DD mice.

The neurotensin antagonist SR 48692 attenuates haloperidol-induced striatal Fos expression in the rat

Neurotensin interacts with central dopamine systems and has been suggested to exert antipsychotic drug-like actions. Antipsychotic drugs such as haloperidol induce striatal immediate-early gene expression. In order to study neurotensin's role in antipsychotic drug actions, rats were pretreated with the neurotensin antagonist SR 48692 and then injected with haloperidol. SR 48692 dose-dependently decreased haloperidol-elicited immediate-early gene expression in the dorsolateral and central striatum but not other striatal areas. SR 48692 reduced Fos expression in the striatal patch (striosome) and matrix compartments, with a significantly greater effect in the patch. These data suggest that neurotensin may play a role in the actions of haloperidol. In view of proposed functional roles of the striatal patch and matrix, we suggest that neurotensin may be important in the therapeutic rather than side effects of antipsychotic drugs.

Striatonigrostriatal Pathways in Primates Form an Ascending Spiral from the Shell to the Dorsolateral Striatum

Clinical manifestations in diseases affecting the dopamine system include deficits in emotional, cognitive, and motor function. Although the parallel organization of specific corticostriatal pathways is well documented, mechanisms by which dopamine might integrate information across different cortical/basal ganglia circuits are less well understood. We analyzed a collection of retrograde and anterograde tracing studies to understand how the striatonigrostriatal (SNS) subcircuit directs information flow between ventromedial (limbic), central (associative), and dorsolateral (motor) striatal regions. When viewed as a whole, the ventromedial striatum projects to a wide range of the dopamine cells and receives a relatively small dopamine input. In contrast, the dorsolateral striatum (DLS) receives input from a broad expanse of dopamine cells and has a confined input to the substantia nigra (SN). The central striatum (CS) receives input from and projects to a relatively wide range of the SN. The SNS projection from each striatal region contains three substantia nigra components: a dorsal group of nigrostriatal projecting cells, a central region containing both nigrostriatal projecting cells and its reciprocal striatonigral terminal fields, and a ventral region that receives a specific striatonigral projection but does not contain its reciprocal nigrostriatal projection. Examination of results from multiple tracing experiments simultaneously demonstrates an interface between different striatal regions via the midbrain dopamine cells that forms an ascending spiral between regions. The shell influences the core, the core influences the central striatum, and the central striatum influences the dorsolateral striatum. This anatomical arrangement creates a hierarchy of information flow and provides an anatomical basis for the limbic/cognitive/motor interface via the ventral midbrain.

Acute injection of drugs with low addictive potential (Δ9-tetrahydrocannabinol, 3,4-methylenedioxymethamphetamine, lysergic acid diamide) causes a much higher c-fos expression in limbic brain areas than highly addicting drugs (cocaine and morphine)

It is regarded as a common pharmacological property responsible for the addictive potential of drugs of abuse that they are able to activate brain areas involved in the sensation of pleasure, especially the nucleus accumbens. To investigate the connection between addictive potential and stimulation of critical brain areas in more detail, we studied c-fos accumulation in response to various addicting drugs in direct comparison. The substances were injected into drug-naive rats, and c-fos mRNA levels were measured throughout the brain by in situ hybridization. Cocaine in a high dose of 50 mg/kg yielded only a discrete c-fos expression in the medial and central striatum. Morphine (50 mg/kg) caused a weak c-fos synthesis in the lateral septum. THC (Δ9-tetrahydrocannabinol), 25 mg/kg, induced c-fos mRNA again in the lateral septum and furthermore in large parts of the striatum including the nucleus accumbens. LSD (lysergic acid diamide), 1 mg/kg, elicited a similar c-fos expression pattern as THC, but there was additionally a very strong hybridization signal in the cerebral cortex, especially in the upper layers, and in the ventral part of the periaqueductal gray. The widest range of brain areas was activated by MDMA (3,4-methylenedioxymethamphetamine, `ecstasy'), 6 mg/kg. In addition to the regions that responded to LSD, there was a very pronounced c-fos signal in the nucleus accumbens core and shell and in the mammillary nuclei. Taken together, our study revealed that the drugs with the highest addictive potential, cocaine and morphine, yielded a very low c-fos synthesis throughout the brain whereas the brain regions closely linked to pleasure (especially the nucleus accumbens) responded strongly to drugs with an apparently lower addictive potential (THC, LSD, MDMA).

Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors.

Several non-physiological stimuli (i.e. pharmacological or electrical stimuli) have been shown to induce Fos expression in striatal neurons. In this work, striatal Fos (i.e. Fos-like) expression was studied after physiological stimulation, i.e. motor activity (treadmill running at 36 m/min for 20 min). In rats killed 2 h after the treadmill session, Fos expression was observed in the medial region of the rostral and central striatum, and in the dorsal region of the caudal striatum. Fos expression was prevented by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg) or the D1 dopamine receptor antagonist SCH-23390 (0.1 mg/kg), but not by pretreatment with the D2 receptor antagonist eticlopride (0.5 mg/kg). Thirty-six hours after 6-hydroxydopamine lesion, a considerable reduction in treadmill-induced Fos expression was observed in both sides; however, Fos expression in the lesioned striatum was higher than in the contralateral intact striatum. Several weeks after unilateral 6-hydroxydopamine lesion of the nigrostriatal system, treadmill-induced Fos expression was significantly, but not totally, reduced in the lesioned striatum. Corticostriatal deafferentation also led to considerable reduction in treadmill-induced Fos expression. The present results indicate that exercise induces striatal Fos expression and that, under physiological stimulation, concurrent activation of D1 and NMDA receptors is necessary for such expression to occur. Reduction of Fos expression is practically absolute after acute blockage of these receptors, but not after lesions, possibly due partially to compensatory changes.

3-Nitropropionic acid produces striatum selective lesions accompanied by iNOS expression

Systemically administered 3-nitropropionic acid (3-NPA) that inhibits the mitochondrial oxidative phosphorylation induces selective lesions in the striatum. To investigate the nature of these selective lesions, we administered 3-NPA (20 mg/kg, s.c. daily for 2 or 3 days) to Wistar rats and investigated the behavioral disturbance, striatal lesions and their variations after modulating the activity of nitric oxide synthase (NOS). On the second or third day of 3-NPA administration, half the animals manifested behavioral disturbances (paddling, rolling, tremor, abnormal gait, and recumbence). A strong extravasation of immunoglobulin G (IgG) and a decrease in immunoreaction for glial fibrillary acidic protein (GFAP) were detected, and iNOS-like (iNOS-L) immunoreactive small cells appeared in the lateral and central striatum especially around the vessels. A week later, lesions lacking GFAP-immunoreaction were detected in the striatum in survived animals. Pretreatment with N-nitro- l-arginine methyl ester ( l-NAME) along with each injection of 3-NPA did not improve the behavioral disturbances nor the survival rate, but attenuated the extravasation of IgG and iNOS-L immunoreaction. Pretreatment with aminoguanidine or FK506 improved the behavioral symptoms and survival rate. Extravasation of IgG and expression of iNOS-L immunoreactivity were attenuated, and the striatal lesion was reduced. Data indicate the involvement of NO in the high vulnerability of the striatum, and that iNOS, one of inflammatory markers, is induced following exposure to 3-NPA.