Dtsz Hamster Research Articles

Short- and long-term outcomes of chronic pallidal deep brain stimulation in the dystonic dtsz hamster

Short- and long-term outcomes of chronic pallidal deep brain stimulation in the dystonic dtsz hamster

Mechanisms of pallidal deep brain stimulation: Alteration of cortico-striatal synaptic communication in a dystonia animal model

Pallidal deep brain stimulation (DBS) is an important option for patients with severe dystonias, which are thought to arise from a disturbance in striatal control of the globus pallidus internus (GPi). The mechanisms of GPi-DBS are far from understood. Although a disturbance of striatal function is thought to play a key role in dystonia, the effects of DBS on cortico-striatal function are unknown.We hypothesised that DBS, via axonal backfiring, or indirectly via thalamic and cortical coupling, alters striatal function. We tested this hypothesis in the dtsz hamster, an animal model of inherited generalised, paroxysmal dystonia.Hamsters (dystonic and non-dystonic controls) were bilaterally implanted with stimulation electrodes in the GPi. DBS (130 Hz), and sham DBS, were performed in unanaesthetised animals for 3 h. Synaptic cortico-striatal field potentials, as well as miniature excitatory postsynaptic currents (mEPSC) and firing properties of medium spiny striatal neurones were recorded in brain slice preparations obtained immediately after EPN-DBS.The main findings were as follows: a. DBS increased cortico-striatal evoked responses in healthy, but not in dystonic tissue. b. Commensurate with this, DBS increased inhibitory control of these evoked responses in dystonic, and decreased inhibitory control in healthy tissue. c. Further, DBS reduced mEPSC frequency strongly in dystonic, and less prominently in healthy tissue, showing that also a modulation of presynaptic mechanisms is likely involved. d. Cellular properties of medium-spiny neurones remained unchanged.We conclude that DBS leads to dampening of cortico-striatal communication, and restores intrastriatal inhibitory tone.

Expression of metabotropic glutamate 5 receptors in the striatum and cortex and effects of modulators on the severity of dystonia in the phenotypic dtsz model

The metabotropic glutamate 5 (mGlu5) receptor has been suggested as therapeutic target for L-Dopa-induced dyskinesia which is often associated with dystonic symptoms. Therefore, we investigated the acute effects of the non-competitive mGlu5 receptor antagonist fenobam as well as the positive modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the severity of inherited dystonia in the mutant dtsz hamster, a phenotypic model with age-dependent episodes of dystonia. Fenobam did not exert significant antidystonic effects (20-50 mg/kg intraperinoneal, i.p.). CDPPB (10, 20 mg/kg i.p.) which was expected to worsen dystonia also failed to show any effects on the severity of dystonia. Interestingly, CDPPB caused axial dyskinesia in addition to the dystonic symptoms in mutant hamsters. This adverse effect could not be observed in non-dystonic control hamsters, indicating possible changes in the expression of mGlu5 receptors in dystonic hamsters. The mGlu5 receptor mRNA did not differ between the dtsz mutant and control hamsters, while immunohistochemical studies indicated that the mGlu5 receptor expression was about 35% higher in striatum and cortex of mutant hamsters at the age of high dystonia severity scores, notably not after spontaneous remission of dystonia, compared to age-matched controls. This difference in mGlu5 receptor protein may be due to altered protein conformation instead of protein level, as western blots revealed similar amounts of monomeric and dimeric protein in mutant hamsters versus control. Thus, the present data do not provide clear evidence for an important role of the mGlu5 receptor in the pathophysiology and as a therapeutic target for types of inherited dystonia.

P 76 Maturation deficits in striatal interneurons in a phenotypic model of dystonia

GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common incurable movement disorder characterized by involuntary muscle contractions resulting in abnormal movements and/or postures. Previous studies have shown a deficit of striatal GABAergic interneurons (IN) in the dtsz mutant hamster, one of the few phenotypic animal models of dystonia. The resulting lack of inhibition of striatal projection neurons is likely involved in development of dystonic episodes which is corroborated by antidystonic effects of GABA potentiating drugs in the animal model and in dystonia patients. However, mechanisms underlying this deficit in striatal IN are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18 days of age) and at age of highest severity of dystonia (33 days of age) in the dtsz hamster by immunohistochemistry and real time PCR. In line with previous findings, the density of GAD67 positive IN and the level of parvalbumin mRNA, a marker for fast spiking GABAergic IN, were lower in mutant hamsters than in controls. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level indicated that the migration of GABAergic IN into the striatum was not retarded. KCC2 cation/chloride transporter and cytosolic carboanhydrase VII mRNA expression, used as markers for maturation of striatal GABAergic signaling, as well as expression of BDNF were unaltered. However, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dtsz hamsters at an age of 33 days, but not after spontaneous remission of dystonia at an age of 90 days. Since IN shift expression from alpha2 to alpha1 subunits during postnatal maturation, this result together with a decreased parvalbumin mRNA expression suggest a delayed maturation of striatal GABAergic IN in this animal model, which might underlie abnormal neuronal activity and striatal plasticity. The potential link between alterations in GABAA receptor subunits and GABAergic disinhibition in dystonia deserves further attention in research on the pathophysiology and therapeutic targets.

Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dtsz) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics

Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dtsz hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry. Tropicamide retarded the onset of dystonic attacks, as previously observed after acute systemic administration of trihexyphenidyl. Combined systemic administration of trihexyphenidyl (30mg/kg) and tropicamide (15mg/kg) reduced the severity in acute trials and delayed the onset of dystonia during long-term treatment. In contrast, acute striatal microinjections of trihexyphenidyl, tropicamid or the positive allosteric M4 receptor modulator VU0152100 did not exert significant effects. Receptor analyses revealed changes of M1 receptors in the dorsomedial striatum, suggesting that the cholinergic system is involved in abnormal striatal plasticity in dtsz hamsters, but the pharmacological data argue against a crucial role on the phenotype in this animal model. However, antidystonic effects of tropicamide after systemic administration point to a novel therapeutic potential of M4 preferring anticholinergics for the treatment of dystonia.

Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.

Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.

Pharmacological and autoradiographic studies on the pathophysiological role of GABA B receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections

The GABA B receptor (GABA BR) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt sz hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA A receptor (GABA AR) binding in several brain regions. In order to clarify the pathophysiological role of central GABA BRs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA BR agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt sz hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 μg/0.5 μl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA BR antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 μg/0.5 μl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt sz hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt sz hamsters. In view of the absence of striatal changes in GABA B binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.

Extracellular amino acid levels in the striatum of the dtsz mutant, a model of paroxysmal dystonia

The pathophysiology of idiopathic dystonia is still unknown, but it is regarded as a basal ganglia disorder. Previous studies indicated an involvement of a striatal GABAergic disinhibition and a cortico-striatal glutamatergic overactivity in the manifestation of stress-inducible dystonic episodes in the dt sz hamster, a model of idiopathic paroxysmal dystonia. These investigations were carried out postmortem or in anesthetized animals. In the present study, in vivo microdialysis in conscious, freely-moving dt sz and non-dystonic control hamsters was used to examine the levels of GABA, aspartate, glutamate, glutamine, glycine and taurine in each animal during following conditions: (1) at baseline in the absence of dystonia, (2) during an episode of paroxysmal dystonia precipitated by stressful stimuli, (3) during a recovery period and (4) at baseline after complete recovery. In comparison to non-dystonic controls, which were treated in the same manner as the dystonic animals, no differences could be detected under basal conditions. The induction of a dystonic episode in mutant hamsters led to higher contents of glycine in these animals in comparison to stressed but non-dystonic controls. Significant changes of glycine levels within the animal groups were not detected. The levels of the excitatory amino acids glutamate, glutamine and aspartate as well as the levels of the inhibitory amino acids GABA and taurine did not differ between the animal groups or between the periods of measurement. The higher levels of glycine might contribute to the manifestation of paroxysmal dystonia in dt sz hamsters, although unaltered glutamate, glutamine and aspartate levels do not support the hypothesis of a critical involvement of a cortico-striatal overactivity. It seems that a deficiency of GABAergic interneurons, found by previous immunohistochemical examinations, does not lead to reduced extracellular GABA levels in the striatum.

Decreased density of amygdaloid parvalbumin-positive interneurons and behavioral changes in dystonic hamsters (Mesocricetus auratus).

The dtsz hamster represents a model of primary paroxysmal nonkinesiogenic dyskinesia in which dystonic episodes can be induced by stress and anxious stimuli. This disease is regarded as a basal ganglia disorder. In fact, a deficit of striatal interneurons could play a key role in the pathophysiology in dystonic hamsters. Because the involvement of limbic structures cannot be excluded so far, the density of parvalbumin-immunoreactive (PV+) interneurons was determined in the basolateral amygdala in the present study. Compared with nondystonic hamsters, the density of PV+ interneurons was moderately decreased in the dtsz mutant. The functional consequence of this finding was examined by behavioral analyses. Examinations in the elevated plus maze and in a modified open field failed to disclose an enhanced anxiety-related behavior in dtsz hamsters (Mesocricetus auratus). A lower acoustic startle response and a stronger habituation in mutant hamsters than in controls correlated with a decreased body weight. Interestingly, prepulse inhibition was absent in mutant hamsters. The latter finding suggests a disturbed sensorimotor gating that can be related to alterations in both the basal ganglia nuclei and in limbic structures.

Acute effects of neurosteroids in a rodent model of primary paroxysmal dystonia

The pathophysiology of various types of dyskinesias, including dystonias, is poorly understood. Clinical and epidemiological studies in humans revealed that the severity of dyskinesias and the frequency of paroxysmal forms of the disease are altered by factors such as the onset of puberty, pregnancy, cyclical changes and stress, indicating an underlying hormonal component. The dystonic phenotype in the dt sz hamster, a genetic animal model of paroxysmal dystonia, has been suggested to be based on a deficit of striatal γ-aminobutyric acid (GABA)ergic interneurons and changes in the GABA A receptor complex. In this animal model, hormonal influences seem to be also involved in the pathophysiology, but an influence of peripheral sex hormones has already been excluded. Possibly, neurosteroids as endogenous regulators of the GABA A receptor may be critically involved in the pathophysiology of dystonia in this animal model. Therefore, in the present study, the effects of the neurosteroids allopregnanolone acetate and allotetrahydrodeoxycorticosterone (THDOC), representing positive modulators of the GABA A receptor, as well as of the negative GABA A receptor modulators pregnenolone sulfate and dehydroepiandrosterone (DHEA), on severity of dystonia were examined in dt sz hamsters after acute intraperitoneal injections. Allopregnanolone acetate and THDOC exerted a moderate reduction of dystonia, whereas pregnenolone sulfate and DHEA had no significant effects. Although the effects of allopregnanolone acetate and THDOC were moderate and short-lasting, the present results suggest that changes in neurosteroid levels might be involved in the initiation of dystonic episodes. Future studies have to include measurements of brain neurosteroid levels as well as of chronic neurosteroid administrations to clarify the pathophysiological role and therapeutic potential of neurosteroids in dystonia.

Age-related changes in parvalbumin-positive interneurons in the striatum, but not in the sensorimotor cortex in dystonic brains of the dtsz mutant hamster

In the dt sz hamster, a model of paroxysmal dystonia, an age-dependent increase in the activity of striatal projection neurons has been hypothesized to be based on a deficit of striatal parvalbumin-immunoreactive (PV +) interneurons at an age of most marked expression of dystonia (30–40 days of life). In the present study, the spontaneous age-dependent remission of paroxysmal dystonia in older dt sz hamsters (age > 90 days) was found to coincide with a normalization of the density of striatal PV + interneurons. Furthermore, the arborization of these interneurons was lower in 31 day old dt sz hamsters, but was even higher in dt sz mutant at an age of > 90 days than in control animals. Double-labeling with bromodeoxyuridine failed to show a retarded proliferation, while the number of interneurons with strong expression of PV mRNA was lower in young mutant hamsters. As shown by unaltered density of PV + interneurons in sensorimotor cortex of 31 day old dt sz hamsters, PV containing interneurons are not reduced throughout the whole brain at the sensitive age. The present data suggest that a retarded postnatal maturation of striatal PV + interneurons plays a critical role in paroxysmal dystonia.

Effects of intrastriatal injections of glutamate receptor antagonists on the severity of paroxysmal dystonia in the dtsz mutant

Imbalances of the glutamatergic system are implicated in the pathophysiology of various basal ganglia disorders, but few is known about their role in dystonia, a common neurological syndrome in which involuntary muscle co-contractions lead to twisting movements and abnormal postures. Previous systemic administrations of glutamate receptor antagonists in dt sz hamsters, an animal model of primary paroxysmal dystonia, exerted antidystonic effects and electrophysiological experiments pointed to an enhanced corticostriatal glutamatergic activity. In order to examine the pathophysiological relevance of these findings, we performed striatal microinjections of the α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) and the N-methyl- d-aspartate (NMDA) receptor antagonists d(−)-2-amino-5-phosphopentanoic acid (AP-5), ( R)-(+)-3-amino-1-hydroxypyrrolidin-2-one (HA-966) and dizocilpine (MK-801). The striatal application of NBQX reduced the severity and increased the latency to onset of dystonia significantly only at a dosage of 0.08 μg per hemisphere, lower (0.03 μg) and higher dosages (0.16 μg and 0.32 μg) failed to exert comparable effects on the severity. None of the striatal injected NMDA receptor antagonists influenced the severity of the dystonic attacks in the mutant hamster. The combined application of NBQX (0.08 μg) with AP-5 (1.0 μg) failed to exert synergistic antidystonic effects, but the beneficial effect on the severity of dystonia of the single application of NBQX was reproduced. Therefore, corticostriatal glutamatergic overactivity mediated by AMPA receptors, but not by NMDA receptors, is possibly important for the manifestation of dystonic attacks in the dt sz hamster mutant.

Striatal microinjections of nitric oxide synthase inhibitors and l-arginine fail to exert effects on paroxysmal dystonia in the dtsz mutant

Primary dystonia is a common movement disorder with an unknown pathophysiology, but basal ganglia dysfunctions seem to play a critical role. Previous studies in the dt sz mutant hamster, an animal model of primary paroxysmal dystonia, demonstrated a deficit of striatal γ-amino-butyric acid (GABA) containing interneurons, which normalized at the age of the spontaneous remission of the symptoms. Whereas the reduction of striatal parvalbumin-reactive interneurons is thought to be critically involved in the pathogenesis of dystonia in the hamster mutant, the impact of a reduced density of nitric oxide synthase (NOS) reactive interneurons within the striatum is still unclear. Beside GABA, these interneurons contain somatostatin, neuropeptide Y, nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and neuronal NOS, an enzyme which produces NO after the activation of the interneurons. In order to clarify if the reduced density of NOS-reactive interneurons contributes by an altered striatal production of nitric oxide (NO) to the occurrence of dystonic attacks in the hamster mutant, we performed microinjections of the NOS inhibitors 7-nitroindazole (7-NI) and N ω-propyl- l-arginine (NPLA) and of the precursor of NO, l-arginine, into the striata of dt sz hamsters. Neither 7-NI (0.1 and 0.4 μg per hemisphere) and NPLA (2.5, 5 and 7.5 μg per hemisphere) nor l-arginine (9 and 18 μg per hemisphere) exerted any effects on the severity of dystonic movements in the dt sz mutant. Therefore, a critical involvement of striatal changes of NO in the pathophysiology of dystonic attacks in the dt sz hamster cannot be confirmed by the results of these pharmacological examinations. In view of the ontogenetic reduction of the other types of GABAergic interneurons, the deficit of NOS-reactive interneurons is possibly due to the same underlying unknown mechanism, but is less important for the pathophysiology of primary paroxysmal dystonia in the dt sz hamster mutant.

High-frequency stimulation of the entopeduncular nucleus improves dystonia in dtsz hamsters.

High-frequency stimulation (HFS) of the internal pallidum (GPi) has been reported to improve generalized dystonia in patients. Currently, dystonia is thought to be associated with disturbed neuronal activity of GPi neurons. Similar findings have been observed in the dtsz hamster, a model of idiopathic paroxysmal non-kinesiogenic dystonia. For this reason, we investigated the effect of bilateral HFS of the entopeduncular nucleus (EPN, rodent homologue of GPi) on the severity of dystonia. Bilateral EPN-HFS resulted in a reversible decrease of dystonia severity up to 50% when compared to both pre- and post-HFS scores, and controls. Our results underline the pathophysiological role of the EPN in the dtsz hamster and suggest the suitability of this model to further investigate mechanisms of HFS in dystonia.

The NMDA receptor NR2B subtype selective antagonist Ro 25-6981 aggravates paroxysmal dyskinesia in the dt sz mutant

Previously, enhanced levels of spermine which stimulates N-methyl- d-aspartate (NMDA) receptors, particularly those containing the NR2B subunit, were found in brains of dt sz mutant hamsters, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. Therefore, the effects of the NR2B selective NMDA receptor antagonist Ro 25-6981 ([ R-( R, S)]-α-(4-hydroxyphenyl)-β-methyl-4-phenyl-methyl)-1-piperidine-propanol] on severity of dystonia were investigated in the dt sz hamster. Ro 25-6981 failed to exert antidystonic effects, but even caused a moderate aggravation at higher doses (10.0, 12.5 mg/kg). This result indicates that overstimulation of receptors that include the NR2B subunit by polyamines is not involved in the dystonic syndrome. NR2B-selective NMDA receptor antagonists seem not to provide a novel approach in the treatment of hereditary paroxysmal dyskinesias.

Effects of locally administered pentylenetetrazole on nigral single unit activity and severity of dystonia in a genetic model of paroxysmal dystonia.

The dt(sz) hamster is a well-established animal model of idiopathic paroxysmal dystonia. Previous investigations of this mutant have indicated dysfunctions of the gamma-aminobutyric acid (GABA)-ergic system within the basal ganglia. Systemic administration of the central stimulant pentylenetetrazole (PTZ) aggravated dystonia at subconvulsant doses, whereas GABA-mimetic drugs have beneficial effects in dt(sz) hamsters. GABA mimetics also provide clinical benefit in humans with idiopathic paroxysmal dystonia. The spontaneous discharge rates of substantia nigra pars reticulata (SNr) neurons was unaltered in anesthetized dt(sz) hamsters, but systemic application of subconvulsant doses of PTZ caused significantly greater increases of discharge rates in dystonic hamsters compared with nondystonic controls. The present study tested the hypothesis that SNr neurons are more sensitive to local application of PTZ in dt(sz) hamsters than in nondystonic hamsters. PTZ applied locally by pressure injection at 2, 3, and 5 mM to the SNr during in vivo single unit recordings revealed a dose-dependent increase of SNr discharge rates in mutants and controls relative to predrug rates, with a significantly greater increase in mutants at 3 mM PTZ. To examine the functional relevance of the increased susceptibility of SNr neurons to PTZ in mutants, the effects of PTZ on severity of dystonia were investigated after microinjections into the SNr of freely moving dt(sz) hamsters. Bilateral nigral microinjection of 40 ng PTZ did not aggravate dystonia but exerted moderate antidystonic effects. Therefore, the previous findings of prodystonic effects of systemic administration of PTZ in dt(sz) hamsters are related to extranigral effects rather than to the elevation of nigral discharge rates in response to systemic, or locally applied, PTZ. The greater susceptibility of neurons within the SNr to PTZ suggests dysfunctions of the GABA(A) receptor in dt(sz) mutants.

Alterations in spontaneous single unit activity of striatal subdivisions during ontogenesis in mutant dystonic hamsters

The pathophysiology of idiopathic dystonia, characterized by sustained twisting movements and postures, is still unknown. Clinically, however, the basal ganglia are thought to be the main causative origin of idiopathic dystonia. In the dt sz hamster, a genetic animal model for idiopathic paroxysmal dystonia, the attacks occur in response to mild stress and the severity of dystonia is age-dependent. Previous autoradiographic studies in the dt sz hamster revealed a decreased dopamine D1 and D2 receptor binding and an increased [ 3 H ]-2-deoxyglucose uptake in the dorsomedial caudate–putamen (CPu), a region supposed to be critically involved in dystonia. Therefore, we were interested whether the spontaneous firing rate of dorsomedial striatal neurons is age-dependently altered in comparison to age-matched non-dystonic control hamsters. Extracellular recordings of spontaneous single unit activity of dorsomedial and ventromedial Type II striatal neurons, i.e., biphasic positive–negative action potentials, from fentanyl anesthetized animals revealed a drastically increased firing rate in the dorsomedial CPu of mutants during age of maximum severity of dystonia. In post-dystonic dt sz hamsters, i.e., after remission of stress-inducible dystonia, no significant differences regarding the dorsomedial CPu could be obtained. We conclude that the dorsomedial subregion of the CPu seems to be critically involved in the dystonic syndrome of dt sz hamsters and that a transiently reduced inhibitory control over excitatory cortico-striatal processes, possibly due to an altered development of GABAergic inhibition, occurs during ontogenesis in dt sz hamsters.