Search

Stereotypy can be characterized as inflexible, repetitive behaviors that occur following repeated exposure to psychostimulants, such as cocaine (COC). Stereotypy may be related to preferential activation of the patch (striosome) compartment of striatum, as enhanced relative activation of the patch compartment has been shown to positively correlate with the emergence of stereotypy following repeated psychostimulant treatment. However, the specific contribution of the patch compartment to COC-induced stereotypy following repeated exposure is unknown. To elucidate the involvement of the patch compartment to the development of stereotypy following repeated COC exposure, we determined if destruction of this sub-region altered COC-induced behaviors. The neurons of the patch compartment were ablated by bilateral infusion of the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/μl) into the striatum. Animals were allowed to recover for eight days following the infusion, and then were given daily injections of COC (25 mg/kg) or saline for one week, followed by a weeklong drug-free period. Animals were then given a challenge dose of saline or COC, observed for 2 h in activity chambers and sacrificed. The number of mu-labeled patches in the striatum were reduced by DERM-SAP pretreatment. In COC-treated animals DERM-SAP pretreatment significantly reduced the immobilization and intensity of stereotypy but increased locomotor activity. DERM-SAP pretreatment attenuated COC-induced c-Fos expression in the patch compartment, while enhancing COC-induced c-Fos expression in the matrix compartment. These data indicate that the patch compartment contributes to repetitive behavior and suggests that alterations in activity in the patch vs matrix compartments may underlie to this phenomenon.

To investigate whether differences in vulnerability to free radicals might underlie differences among striatal neurons in their vulnerability to neurodegenerative processes such as occur in ischemia and Huntington's disease, we have analyzed the localization of superoxide free radical scavengers in different striatal neuron types in normal rhesus monkey. Single- and double-label immunohistochemical experiments were carried out using antibodies against the enzymes copper, zinc superoxide dismutase (SOD1), or manganese superoxide dismutase (SOD2), and against markers of various striatal cell types. Our results indicate that the striatal cholinergic and parvalbumin interneurons are enriched in SOD1 and/or SOD2, whereas striatal projection neurons and neuropeptide Y/somatostatin (NPY+/SS+) interneurons express only low levels of both SOD1 and SOD2. We also found that projection neurons of the matrix compartment express significantly higher levels of SOD than those in the striosome compartment. Since projection neurons have been reported to be more vulnerable than interneurons and striosome neurons more vulnerable than matrix neurons to neurodegenerative processes, our results are consistent with the notion that superoxide free radicals are at least partly involved in producing the differential neuron loss observed in the striatum following global brain ischemia or in Huntington's disease.

Striatal neurons can be classified as movement- and nonmovement-related depending on their ability to change firing rate in close temporal association with spontaneous movement in an open-field arena. The present study assessed the location of these cell types within the compartmental organization of the striatum by combining single-unit recording techniques in freely moving rats with calbindin immunohistochemistry. Movement-related neurons were found predominately either in the matrix or along the matrix-striosome border. Most of these neurons were nonselective in that they increased activity whenever the animals changed from a quiet resting posture to any form of behavioral activation (e.g., grooming, locomotion, rearing). The remaining neurons in this group responded exclusively to movements of the head. Nonselective units discharged at a significantly slower rate than head-movement units during both quiet rest and periods of actual movement. Nonmovement-related neurons, which failed to show a reliable change in activity to overt behavior, comprised a relatively small portion of the neuronal sample but were also located in either the matrix or along the matrix-striosome border. Collectively, these results suggest that even though striatal neurons can be distinguished on the basis of their responsiveness to ongoing behavior in an open-field paradigm, such distinctions are not clearly linked to sites within the matrix or its striosomal borders.

Chronic administration of dopaminergic agonists to rats with unilateral 6-OH-dopamine (6-OHDA) lesions of nigrostriatal pathway produces behavioral sensitization to subsequent agonist challenges and may serve as a model for DOPA-induced dyskinesias. In order to understand striatal mechanisms behind this long-term behavioral change we examined striatal c-Fos and FosB immunoreactivity induced by apomorphine challenge (5 mg/kg, s.c.) after 3 days of withdrawal following a 2-week administration (5 mg/kg, b.i.d., s.c.) both in intact and 6-OHDA-lesioned animals. In intact rats, c-Fos induction by acute apomorphine exposure showed a striosomal pattern, whereas FosB immunopositivity was diffusely distributed. Following chronic administration, FosB induction turned to a clear striosome dominant pattern similar to c-Fos expression. In denervated striatum, expression of both proteins was profoundly augmented in a homogeneous pattern after a single dose of apomorphine. A distinct striosomal patterning appeared after chronic apomorphine administration in ventromedial part of the denervated striatum with a down-regulation in the matrix and relative enhancement in striosomes. These results suggest that compartmental reorganization of striatal neuronal activity may play a role in long-term behavioral changes induced by chronic dopaminergic treatments both under normal and dopamine-depleted conditions.

Injections of the full D1-agonist A-77636 (1.45 mg/kg) were found to induce clear Fos-like immunoreactivity (FLI) in the striatum of neurologically intact rats. Pretreatment with the D2-like agonist quinpirole (3 mg/kg) potentiated staining in the lateral striatum, but actually decreased the number of immunoreactive cells observed in the medial portion of the rostral striatum. Comparison with adjacent sections processed for the calcium binding protein calbindin, indicated that quinpirole pretreatment specifically suppressed staining in the matrix compartment of the striatum while tending to potentiate it in the striosomes, resulting in an extremely patchy pattern of labeling. These results suggest that exogenous stimulation of D2-receptors, although not essential for the induction of FLI, may play an important role in the compartmental patterning of neuronal activity within the striatum.

Injections of D-amphetamine (5 mg/kg) three hours before sacrifice were found to elicit robust Fos-like immunoreactivity in the striatum of cynomolgus monkeys and of the common marmoset. Labeled cells were most frequently observed in the medial portion of the caudate nucleus and were distributed in a patchy fashion. Comparison with adjacent sections stained for the calcium binding protein calbindin indicated that the patches of amphetamine induced labeling corresponded to the calbindin-poor striosomes. These results are consistent with those reported in rats and thus suggest similarities in the basic organization of striatal mechanisms underlying the response to amphetamine in rodents and primates.

The effects of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA; 10(-3) M), N-methyl-D-aspartate (10(-3) M, in the absence of magnesium or presence of AMPA) and carbachol (10(-3) M) on the release of preloaded [3H]gamma-aminobutyric acid ([3H]GABA) from microdiscs of tissue punched out from sagittal brain slices in striosome- or matrix-enriched areas of the rat striatum have been compared. Although AMPA stimulated similarly the release of [3H]GABA in both striatal compartments, the release of [3H]GABA evoked by either N-methyl-D-aspartate (in the presence of AMPA) or carbachol was more pronounced in matrix- than in striosome-enriched areas. AMPA- and N-methyl-D-aspartate- (in the absence of magnesium) evoked responses were reduced but not abolished in the presence of tetrodotoxin (10(-6) M) in both compartments while the carbachol-evoked release of [3H]GABA was decreased by tetrodotoxin only in the matrix. The interruption of cholinergic transmission by the combined application of atropine (10(-5) M) and pempidine (10(-4) M) was without effect on the AMPA-evoked release of [3H]GABA, but it reduced the N-methyl-D-aspartate- (in the absence of magnesium or presence of AMPA) evoked release of [3H]GABA in both compartments, these reductions being of similar amplitude than those observed with tetrodotoxin.

In two areas of the rat striatum, the in vitro N-methyl-D-aspartate (NMDA, 50 microM)-evoked release of [3H]dopamine was studied in the presence of bicuculline (5 and 50 microM), an antagonist of GABAA receptors. The responses observed with the higher concentration (50 microM) is compatible with an antagonistic activity of bicuculline on NMDA receptor, as recently reported by Wright and Nowak.

The catecholamine selective neurotoxin, 6-hydroxydopamine, was injected into the ventral mesencephalon of rats and the distribution of tyrosine hydroxylase immunoreactivity in the striatum was compared to that of substance P and calbindin immunoreactivities, recognized histochemical markers of striatal compartments. Two components of the TH-IR mesostriatal innervation were identified. A more vulnerable component, present in the core of the nucleus accumbens and matrix of the caudate-putamen, excepting its ventrolateral part, was eliminated rapidly, unmasking a less vulnerable component which was present primarily in the shell of the nucleus accumbens and patch(striosome) compartment of the caudate-putamen. The TH-IR innervation in the ventrolateral caudate-putamen also was patchy following these lesions but the patches corresponded consistently to neither patch nor matrix compartments.

The distribution of cholinergic pre- and postsynaptic markers and dopaminergic presynaptic markers was analyzed in the adult human striatum, using quantitative receptor autoradiography. The distribution of the different binding sites indicates that cholinergic and dopaminergic uptake sites display a striosomal organization, with a higher binding site density in the striatal matrix. M1 muscarinic cholinergic receptor distribution parallels the distribution of cholinergic presynaptic markers. Our data show that cholinergic and dopaminergic terminals, and M1 receptors are enriched in the matrix of the adult human striatum.

The development of dopamine D1-receptors in rat striatum during the early postnatal period is examined, using autoradiography and [3H]SCH 23390 as ligand. Dopamine D1-receptors are present in striatum at birth and are more dense than in any adjacent region. The receptors are preferentially localized in striosomes and to some extent in a subcallosal streak. The density of D1-receptors in the matrix increases with age so that by two weeks postnatally the striosomal pattern is no longer evident, and the overall dense labelling is the same as seen in adults. Dopamine D1-receptor development seems to take place earlier than that of dopamine terminals but at the same time as or somewhat later than that of acetylcholinesterase. The D1-defined striosomes move from ventrolateral towards dorso-medial striatum with increasing age and from anterior to posterior striatum. This direction is nearly perpendicular to the direction of development of several other markers, including dopamine terminals and D2-receptors. The present studies indicate that for markers appearing in the striosomal compartment there are different patterns of development with respect to time and spatial pattern. Regulation of striatal development by interaction of neuronal systems with one another and with other factors is complex and will require extensive study to clarify the mechanisms involved.

The distribution of dopamine receptors in rat neostriatum was determined by means of light microscopic autoradiography of in vivo labeled binding sites for [3H]N-n-propylnorapomorphine and compared with the distribution of acetylcholinesterase histochemical staining. The distribution of dopamine receptors was non-homogeneous and patches of low receptor density were in register with acetylcholinesterase-poor striosomes. This suggests that the distribution pattern of dopamine receptors is specifically related to various input systems.

In situ hybridization histochemistry using cDNA oligonucleotide probes for the neuropeptides dynorphin, enkephalin and substance P was used to map the distribution of peptidergic neurons in the striatal patch and matrix compartments in the rat. Striatal neurons containing message for each of these peptides were distributed in both striatal compartments in the following proportions: dynorphin, in 52% of patch neurons and 45% of matrix neurons; enkephalin, in 65% of patch neurons and 58% of matrix neurons and substance P, in 61% of patch neurons of 54% matrix neurons. Fluorescent retrograde axonal tracing combined with in situ hybridization histochemistry demonstrated that the majority of neurons expressing enkephalin project to the globus pallidus and few project to the substantia nigra, whereas the reverse obtains for neurons expressing dynorphin and substance P.

Comparisons were made of the distribution of acetylcholinesterase (AChE) staining and [3H]hemicholinium-3 binding in adjacent tissue sections through the rabbit striatum. The distribution of these two markers matched closely in all regions examined. Circumscribed AChE-poor zones (striosomes) were visible throughout the rostral one-third of the caudate nucleus and were aligned with areas of low [3H]hemicholinium-3 binding in adjacent sections. Quantitative analysis of the [3H]hemicholinium-3 film autoradiographs revealed a 2- to 3-fold lower binding of [3H]hemicholinium-3 to sites within the striosome compartment compared with the darker background (matrix). Further analysis revealed at least 3 distinct levels of binding throughout the striatum. The results suggest a novel autoradiographic approach for identifying and quantifying striatal heterogeneties. Because [3H]hemicholinium-3 apparently labels the high-affinity choline transport complex associated with cholinergic neurons, the patchy striatal distribution of AChE/[3H]hemicholinium-3 apparently marks zones with differing densities of cholinergic neuron processes.

The distribution of neurotensin receptors in the human caudate nucleus was studied using autoradiographic methods following in vitro labelling of cryostat sections with [3H]neurotensin, and the pattern of receptor labelling was compared to the distribution of acetylcholinesterase (AChE) staining in adjacent sections. A heterogeneous pattern of neurotensin receptors was found in the caudate nucleus. Patches of low receptor density aligned with the AChE-poor striosomes, regions of moderate receptor density corresponded with the AChE-rich matrix zone, and annular regions of high receptor density aligned with the AChE-negative border zone lying between the AChE-poor striosome and the AChE-rich matrix compartments. These results suggest the existence of 3 neurochemical compartments within the human caudate nucleus.

The distribution of cortico-striatal fibers from the frontal cortex was studied by autoradiography in cat and monkey and compared with the patterns of striatal acetylcholinesterase activity observed in the same brains. The clustering patterns of labeled fronto-caudate fibers were found to correspond to a large extent to the inhomogeneities in enzyme activity identified by the acetylthiocholinesterase staining method.

The distribution of benzodiazepine receptors in the human striatum was studied by quantitative autoradiography following in vitro labelling of cryostat sections with [ 3 H]flunitrazepam, and the pattern of receptor-labelling was compared to the distribution of a acetylcholinesterase (AChE) staining in adjacent sections. A heterogeneous pattern of benzodiazepine receptors was found in all regions of the striatum. The highest densities of receptors were seen in the ventral striatum (nucleus accumbens and olfactory tubercle), where very dense receptor patches aligned with both AChE-poor and AChE-rich regions. The dorsal striatum (caudate nucleus and putamen) contained lower concentrations of benzodiazepine receptors, but dense receptor patches were still evident (especially in the caudate nucleus) and these aligned with AChE-poor strisomes.

Mesostriatal projections were labeled in 11 squirrel monkeys by injecting the anterograde tracer, [35S]methionine, into different parts of the dopamine-containing A8-A9-A10 cell complex of the midbrain. Two strikingly different compartmental patterns of mesostriatal projection were found. Fields of dense labeling in both the caudate nucleus and the putamen, interrupted by pockets of sparse labeling, were observed with deposits involving cell group A8, cell group A10 and/or the dorsally situated 'pars mixta' of the substantia nigra. Where striosomes could be identified as such in adjoining histochemically stained sections, the sparsely labeled zones were aligned with them. By contrast, a pattern of focally dense labeling in the caudate nucleus and putamen, with much weaker labeling surrounding the densely labeled zones, was found with injection sites centered in the horizontal band and associated ventrally extending fingers of the substantia nigra pars compacta. Many of the pockets of heightened labeling could be shown to correspond to histochemically defined striosomes. These compartmental patterns were identified both in the caudate nucleus and in the putamen. We conclude that the A8-A9-A10 cell complex of the primate contains spatially distinct subdivisions with preferential projections directed, respectively, toward the striosome and matrix compartments of the striatum.

A number of recent studies have demonstrated two chemically distinct compartments in the neostriatum: opiate receptor-rich patches and a surrounding matrix. Using axonal transport and receptor localization techniques in the rat brain, we have found that striatal projections from architectonically distinct cortical fields conform to this compartmentalized plan. The prelimbic cortex has bilateral projections that concentrate within the striatal patches. In contrast, the agranular motor cortex and cingulate cortex have bilateral projections to the matrix, while the somatic sensory cortex and visual cortex have ipsilateral matrix projections. Each matrix input occupies a characteristic striatal district. The projection to the patches distributes prelimbic input throughout the striatum, which may allow for prelimbic interactions with input from all other cortical areas.

The striatum of the mammalian forebrain is composed of two complementary functional compartments, the patches and the matrix. By injecting [3H]thymidine at different embryonic times and sacrificing the rats as young adults, we found that the earliest neurons to leave the mitotic cycle were restricted to the patch compartment. Neurons that became postmitotic at later times preferentially joined the matrix compartment. Distinctive periods of cell proliferation may underlie pattern formation throughout the developing forebrain.