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V M Pickel

Publications and source records attributed to V M Pickel.

At least 37 records · Page 2Linked to original sources
PubMed2001

Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus.

Cannabinoids and opioids are widely consumed drugs of abuse that produce motor depression, in part via respective activation of the cannabinoid subtype 1 receptor (CB1R) and the mu-opioid receptor (muOR), in the striatal circuitry originating in the caudate putamen nucleus (CPN). Thus, the CB1R and muOR may show similar targeting in the CPN. To test this hypothesis, we examined the electron microscopic immunocytochemical labeling of CB1R and muOR in CPN patches of rat brain. Of the CB1R-labeled profiles, 34% (588) were dendrites, presumably arising from spiny as well as aspiny-type somata, which also contained CB1R immunoreactivity. In dendrites, CB1R often was localized to nonsynaptic and synaptic plasma membranes, particularly near asymmetric excitatory-type junctions. Almost one-half of the CB1R-labeled dendrites contained muOR immunoreactivity, whereas only 20% of all muOR-labeled dendrites expressed CB1R. Axons and axon terminals as well as abundant glial processes also showed plasmalemmal CB1R and were mainly without muOR immunoreactivity. Many CB1R-labeled axon terminals were small and without recognizable synaptic junctions, but a few also formed asymmetric, or more rarely symmetric, synapses. The CB1R-labeled glial processes were often perivascular or perisynaptic, surrounding asymmetric excitatory-type axospinous synapses. Our results show that in CPN patches CB1R and muOR are targeted strategically to some of the same postsynaptic neurons, which may account for certain similarities in motor function. Furthermore, they also provide evidence that CB1R may play a major role in the modulation of presynaptic transmitter release and glial functions that are unaffected in large part by opioids active at muOR in CPN.

Animals↗
PubMed2001

FosB in rat striatum: normal regional distribution and enhanced expression after 6-month haloperidol administration.

Subcortical motor nuclei show differential expression of FosB immediate early gene products and specifically deltaFosB after short (8, 19, or 21 days) chronic exposure to typical and atypical neuroleptics represented by haloperidol and clozapine, respectively. We quantitatively examined whether there are light microscopic regional variations in area density of FosB or the truncated deltaFosB in several motor-related nuclei of adult rats receiving vehicle or long chronic (6 months) administration of either depot haloperidol or clozapine in their drinking water. In control animals the dorsomedial and ventromedial caudate-putamen nucleus (CPN) had a significantly higher density of FosB-immunoreactive cells than the dorsolateral and ventrolateral regions. The nucleus accumbens (NAc) core also serving motor functions had a higher basal expression than the limbic shell region in control animals. The mediolateral gradient in area density of FosB-labeled cells was maintained in animals receiving either haloperidol or clozapine. In animals receiving haloperidol, but not clozapine, however, there was a regionally selective increase in the area density of only FosB-immunoreactive neurons in the dorsolateral and ventrolateral CPN and in both the core and shell of the NAc. Only the animals receiving chronic haloperidol showed vacuous chewing movements, the animal equivalent of tardive dyskinesia in humans. Our results suggest that, whereas the medial striatal neurons are activated under basal conditions, long chronic haloperidol induced FosB expression more exclusively in the lateral CPN and NAc core, implicating these regions specifically in the motor side effects of this drug.

Animals↗
PubMed2001

Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration.

The frontal cortex (FrC) and cingulate cortex (CgC) are critical sites for normal cognitive function, as well as cognitive dysfunction in schizophrenia. Thus, modulation of synaptic transmission within these cortical areas may, in part, account for the therapeutic actions of antipsychotic drugs such as haloperidol and clozapine. FosB and DeltaFosB are immediate-early gene (IEG) products sensitive to changes in response to chronic neuroleptic drug administration. We quantitatively examine whether there are light microscopic regional and/or laminar variations in FosB or DeltaFosB in the FrC or CgC of normal adult rats, or animals receiving 6 months administration of either drinking water clozapine, or depot haloperidol. Only animals receiving chronic haloperidol developed vacuous chewing movements, the equivalent of tardive dyskinesia in humans. In control animals, the deep and superficial layers of the FrC showed a higher area density of FosB, but not DeltaFosB immunoreactive cells than the medial layers of FrC or any of the CgC layers. In animals receiving clozapine, but not haloperidol there was increase in the area density of FosB immunoreactive neurons in all FrC layers, but the major increase occurs in medial layers. These findings suggest that FosB expression identifies those FrC neurons that are most active during normal waking behaviors and are further activated following chronic administration of atypical neuroleptics without motor side effects. The results also indicate that the actions of clozapine are attributed in large part to modulation of the output of frontal cortical pyramidal neurons residing in the medial layers.

Animals↗
PubMed2001

Electrical stimulation of cerebellar fastigial nucleus protects rat brain, in vitro, from staurosporine-induced apoptosis.

Electrical stimulation of the cerebellar fastigial nucleus (FN) elicits a prolonged ( approximately 10 days) and substantial (50-80%) protection against ischemic and excitotoxic injuries. The mechanism(s) of protection are unknown. We investigated whether FN stimulation directly protects brain cells against apoptotic cell death in an in vitro rat brain slice culture model. Rats were electrically stimulated in FN or, as control, the cerebellar dentate nucleus (DN). Coronal slices through the forebrain were explanted, exposed to staurosporine, harvested, and analyzed for caspase-3 activity by a fluorescence assay. FN, but not DN, stimulation significantly reduced staurosporine-induced caspase-3 activity by 39 +/- 7% at 3 h, 31 +/- 3% at 6 h and 26 +/- 4% at 10 h of incubation. Immunocytochemistry revealed FN-specific reductions in activated caspase-3 mainly in glial-like cells throughout the forebrain. FN stimulation also results in a 56.5% reduction in cytochrome c release upon staurosporine incubation. We conclude that neuroprotection elicited from FN stimulation can directly modify the sensitivity of brain cells to apoptotic stimuli and thereby suppress staurosporine induced apoptosis in adult rat brain slices. This model indicates that neuroprotection can be studied in vitro and provides new insight into the potential role of glial cells in ischemic protection of neurons induced by FN stimulation.

Animals↗
PubMed2000

Neurokinin 1 receptor distribution in cholinergic neurons and targets of substance P terminals in the rat nucleus accumbens.

Substance P (SP) is the major endogenous ligand for neurokinin 1 (NK1) receptors and, together with acetylcholine, has an important role in motivated behaviors involving the limbic shell and motor core of the nucleus accumbens (NAc). To determine the functional sites for SP activation of NK-1 receptors and potential interactions with cholinergic neurons in these regions, the authors examined the electron microscopic immunocytochemical localization either of antisera against the NK1 receptor or of the NK1 receptor and either 1) SP or 2) the vesicular acetylcholine transporter (VAchT) in rat NAc. In both the NAc shell and core, NK1 receptor labeling was localized mainly to somatic and dendritic plasma membranes and nearby endosomal organelles in aspiny neurons. In sections through the ventromedial shell that were processed for NK1/SP labeling, 46% of the NK1-immunoreactive dendrites (n = 603 dendrites) showed symmetric or appositional contacts with SP-containing terminals. These terminals and several others that formed symmetric synapses also occasionally were immunoreactive for NK1 receptors. Analysis of the shell region for NK1/VAchT labeling showed that 61% of the total immunoreactive dendrites (n = 534 dendrites) contained NK1 receptors without VAchT, 29% contained both products, and 10% contained VAchT only. Many of the labeled somata and dendrites also received synaptic contact from VAchT-containing terminals. These findings suggest that, in the NAc, NK1 receptors are recycled through endosomal compartments and play a role in modulating mainly the postsynaptic responses, but also the presynaptic release, of SP and/or inhibitory neurotransmitters onto aspiny interneurons, some of which are cholinergic.

Animals↗
PubMed2000

Ultrastructural localization of nitrotyrosine within the caudate-putamen nucleus and the globus pallidus of normal rat brain.

Nitration of protein tyrosine residues by nitric oxide (NO)-derived reactive species results in the production of stable nitrotyrosine (NT) moieties that are immunochemically detectable in many regions of normal brain and enriched in those areas containing constitutive nitric oxide synthase (cNOS). These include the caudate-putamen nucleus (CPN) and the globus pallidus, which receives major inhibitory input from the CPN. To determine the functional sites for NT production in these critical motor nuclei, we examined the electron microscopic immunocytochemical localization of NT and cNOS in rat brain. In the CPN, NT was localized to the somata and dendrites of cNOS-containing interneurons and spiny neurons, some of which received input from cNOS-labeled terminals. The NT immunoreactivity was most prevalent on outer mitochondrial membranes and nearby segments of the plasma membranes in dendrites and within asymmetric synapses on dendritic spines. In the CPN and globus pallidus, there was also a prominent labeling of NT in astrocytic processes, small axons, and tubulovesicles and/or synaptic vesicles in axon terminals. These terminals formed mainly asymmetric synapses in the CPN and inhibitory-type synapses in the globus pallidus where they often apposed cNOS-containing terminals that also formed asymmetric, excitatory-type synapses. Our results suggest that NT is generated by mechanisms requiring the dual actions of excitatory transmitters and NO derived either from interneurons in the CPN or from excitatory afferents in the globus pallidus. The findings also implicate NT in the physiological actions of NO within the striatal circuitry and, particularly, in striatopallidal neurons severely affected in Huntington's disease.

Animals↗
PubMed2000

mu-opioid receptors are present in vagal afferents and their dendritic targets in the medial nucleus tractus solitarius.

Ligands of the mu-opiate receptor (MOR) are known to influence many functions that involve vagal afferent input to the nucleus tractus solitarius (NTS), including cardiopulmonary responses, gastrointestinal activity, and cortical arousal. The current study sought to determine whether a cellular substrate exists for direct modulation of vagal afferents and/or their neuronal targets in the NTS by ligands of the MOR. Anterograde tracing of vagal afferents arising from the nodose ganglion was achieved with biotinylated dextran amine (BDA), and the MOR was detected by using antipeptide MOR antiserum. The medial subdivision of the intermediate NTS was examined by electron microscopy for the presence of peroxidase-labeled, BDA-containing vagal afferents and immunogold MOR labeling. MOR was present in both presynaptic axon terminals and at postsynaptic sites, primarily dendrites. In dendrites, MOR immunogold particles usually were located along extrasynaptic portions of the plasma membrane. Of 173 observed BDA-labeled vagal afferent axon terminals, 33% contained immunogold labeling for MOR within the axon terminal. Many of these BDA-labeled terminals formed asymmetric, excitatory-type synapses with dendrites, some of which contained MOR immunogold labeling. MORs were present in 19% of the dendrites contacted by BDA-labeled terminals but were present rarely in both the vagal afferent and its dendritic target. Together, these results suggest that MOR ligands modulate either the presynaptic release from or the postsynaptic responses to largely separate populations of vagal afferents in the intermediate NTS. These results provide a cellular substrate for direct actions of MOR ligands on primary visceral afferents and their second-order neuronal targets in NTS.

Afferent Pathways↗
PubMed2000

Rostrocaudal variation in targeting of N-methyl-D-aspartate and mu-opioid receptors in the rat medial nucleus of the solitary tract.

N-methyl-D-aspartate (NMDA) receptors and mu-opioid receptors (MOR) have been implicated in gustatory and cardiorespiratory visceral reflexes, respectively involving second order sensory neurons in rostral and intermediate portions of the medial nucleus of the solitary tract (mNTS). To determine whether there are cellular sites suggesting functional interaction involving NMDA receptors and MOR in these regions, we examined their ultrastructural immunocytochemical localization by using antisera recognizing the functional subunit of NMDA receptors (NR1) or MOR in rat brain. In both mNTS subdivisions, NR1 labeling was prominently seen along membranes of cytoplasmic organelles in somata and large dendrites, as well as on asymmetric postsynaptic densities in small dendrites and dendritic spines. Many of these profiles also contained MOR immunoreactivity that was mainly distributed along extrasynaptic plasma membranes. Quantitative regional comparison showed that dendrites composed 64% (167 of 261) and 35% (137 of 390) of the dually labeled structures in the rostral and intermediate mNTS, respectively. In contrast, only 11% (28 of 261) of the total dually labeled profiles in the rostral, but 46% (180 of 390) of those in the intermediate mNTS were axon terminals. Many of the terminals containing NR1 and/or MOR were large and formed asymmetric synapses with multiple targets, resembling those features of known visceral afferents. Our results suggest that opioids, active at MOR in mNTS, modulate excitatory visceral reflexes involving mainly postsynaptic NMDA receptors in the rostral region. In addition, they suggest that similar mechanisms exist in the intermediate mNTS, where both NMDA receptors and MOR may differentially regulate the presynaptic release of glutamate from the visceral afferents.

Animals↗
PubMed2000

Presynaptic dopamine D(4) receptor localization in the rat nucleus accumbens shell.

Dopamine D(4) receptors in the nucleus accumbens shell (AcbSh) are thought to play a key role in mediating the locomotor and sensitizing affects of psychostimulants, as well as the therapeutic efficacy of atypical antipsychotic drugs. We used electron microscopic immunocytochemistry to determine the functional sites for endogenous and exogenous D(4) receptor activation in this region. Of 1,090 D(4) receptor-labeled profiles observed in the AcbSh of rat brain, 65% were axons and axon terminals, while 22% were dendrites and dendritic spines. Within axons and terminals, D(4) receptor immunoreactivity was localized to segments of the plasma membrane and membranes of nearby vesicles. The axon terminals were morphologically heterogenous, varying in size and content of either all small synaptic vesicles (ssv), or ssv and large dense-core vesicles. The labeled terminals occasionally formed asymmetric excitatory-type axospinous synapses, but the majority were without recognizable synaptic specializations. In a separate series of tissue sections that were processed for dual-labeling of the D(4) receptor and the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), 56% of all observed associations were appositions between differentially labeled axonal profiles, and 17% were terminals that contained immunoreactivity for both antigens. Dendritic spines containing D(4) receptor-labeling also received convergent input from TH-immunoreactive terminals and unlabeled terminals forming asymmetric synapses. These results provide the first ultrastructural evidence for a major presynaptic, and a more minor postsynaptic, involvement of D(4) receptors in dopaminergic modulation of excitatory transmission in the AcbSh.

Animals↗
PubMed2000

Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area.

Serotonin (5-hydroxytryptamine, 5-HT) 2A receptor antagonists are clinically effective antipsychotics that may differentially target mesocortical and mesolimbic dopaminergic neurons having partially segregated distribution in the parabrachial (PB) and paranigral (PN) ventral tegmental area (VTA). We examined the ultrastructural immunocytochemical localization of the 5-HT2A receptor in these subdivisions of rat VTA, to determine (1) the functional sites for receptor activation, and (2) cellular associations between the receptor and dopaminergic neurons identified by their content of tyrosine hydroxylase (TH). The mean area density of neuronal profiles containing 5-HT2A receptor labeling was not significantly different in the PB and PN VTA. In each region approximately 44% of the 5-HT2A labeled profiles were dendrites while the remainder were mainly axons. Dendritic 5-HT2A-immunoreactivity was often localized to membranous cytoplasmic organelles resembling smooth endoplasmic reticulum, and to more rarely to segments of the plasma membrane beneath contacts from unlabeled axon terminals. 5-HT2A labeling was also seen within the cytoplasm of a few axon initial segments and many small unmyelinated axons. Approximately 40% of the 5-HT2A-labeled dendritic profiles contained TH in either PB or PN VTA. Our results suggest that 5-HT2A receptors in VTA are largely cytoplasmic and play an equally important role in modulating dopaminergic neurons in PB and PN VTA. These results also implicate 5-HT2A receptors in the postsynaptic activation of non-dopaminergic neurons and possibly the presynaptic release from terminals of axons originating in, or passing through, these regions.

Animals↗
PubMed2000

N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area: subcellular distribution and colocalization with 5-hydroxytryptamine(2A) receptors.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype have been implicated in behavioral sensitization to psychostimulants and in psychotic behaviors involving excitation of ventral tegmental area (VTA) dopaminergic neurons. Antagonists of serotonin (5-hydroxytryptamine, 5-HT) receptors of the 5-HT(2A) subtype are potent antipsychotics that attenuate these NMDA-evoked responses. We examined the electron microscopic immunocytochemical localization of antisera against the NMDA R1 subunit (NMDAR1) and 5-HT(2A) receptors to determine potential sites for their dual activation in the rat paranigral and parabrachial VTA subdivisions that are distinguished, in part, by their respective striatolimbic and cortical projections. In both regions, NMDAR1 immunoreactivity was localized mainly to the cytoplasm of somata and dendrites, and was only occasionally seen near or within excitatory-type asymmetric synapses. Many of the NMDAR1-labeled somata and dendrites also expressed 5-HT(2A) receptors, having a similar, but largely non-overlapping, neuronal distribution. The mean area density of NMDAR1 and dually labeled dendritic profiles was significantly greater in the paranigral than in the parabrachial VTA. NMDAR1 was also present in small axons showing a similar regional difference in area density. No regional difference in area density was seen in dendrites or small axons containing only 5-HT(2A) receptors. Our results indicate that NMDA and 5-HT(2A) receptors in the VTA are transiently expressed on synaptic plasma membranes of single neurons showing widespread cytoplasmic distributions of each of the receptors. They also suggest a major role for NMDA receptors in modulating the output of paranigral neurons and the release of transmitters from axons passing through this region.

Animals↗
PubMed2000

Dendritic and axonal targeting of the vesicular acetylcholine transporter to membranous cytoplasmic organelles in laterodorsal and pedunculopontine tegmental nuclei.

Autoregulation of cholinergic neurons in the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei has been implicated in many functions, most importantly in drug reinforcement and in the pathophysiology of schizophrenia. This autoregulation is attributed to the release of acetylcholine, but neither the storage or release sites are known. To determine these sites, we used electron microscopy for the immunocytochemical localization of antipeptide antiserum raised against the vesicular acetylcholine transporter (VAchT) that is responsible for the uptake of acetylcholine into storage vesicles. The cellular and subcellular distribution of VAchT was remarkably similar in the two regions by by using each of two methods, immunogold and immunoperoxidase. In both PPT and LDT nuclei, VAchT labeling was seen mainly on membranous organelles including the trans-Golgi network in many somata. VAchT-immunoreactive tubulovesicles resembling saccules of smooth endoplasmic reticulum were often seen near the plasma membrane in dendrites. The VAchT-containing dendrites comprised almost 50% of the labeled profiles (1027/2129) in PPT and LDT nuclei. The remaining VAchT-immunoreactive profiles were primarily small unmyelinated axons and axon terminals. In axon terminals, VAchT was densely localized to membranes of small synaptic vesicles. The VAchT-immunoreactive axon terminals formed either symmetric or asymmetric synapses. The postsynaptic targets of these axon terminals included dendrites that were with (36/110) or without (74/110) VAchT immunoreactivity. Our results suggest that dendrites, as well as axon terminals, have the potential for storage and release of acetylcholine in the LDT and PPT nuclei. The released acetylcholine is likely to play a major role in autoregulation of mesopontine cholinergic neurons.

Acetylcholine↗
PubMed2000

Presence of NMDA-type glutamate receptors in cingulate corticostriatal terminals and their postsynaptic targets.

The glutamatergic projection from the anterior cingulate cortex to the medial caudate-putamen nucleus (CPN) has been implicated in motor and cognitive functions, many of which are potently modulated by activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDARs). To determine the functional sites for NMDAR activation within this circuitry, we combined anterograde transport of biotinylated dextran amine (BDA) from deep layers of the rat anterior cingulate cortex with immunogold labeling of NMDAR subunit, NMDAR1, in the dorsomedial CPN. BDA-containing axons were seen in patch-like clusters in a neuropil that showed more uniform immunogold-silver labeling for NMDAR1. Electron microscopy of these regions showed that BDA-labeling was present exclusively in axons and terminals, 23% (98 of 421) of which also contained NMDAR1-immunoreactivity (IR). BDA-labeled terminals often apposed NMDAR1-immunoreactive neuronal and glial profiles. These terminals also formed asymmetric excitatory-type synapses with dendritic spines. Of 155 anterogradely labeled axon terminals forming asymmetric synapses, 34% were with NMDAR1-labeled, and 66% with unlabeled dendritic spines. These results provide ultrastructural evidence for the involvement of NMDARs in presynaptic regulation of glutamate transmission, and in postsynaptic modulation of the excitability of spiny neurons in patch-like compartments of the dorsomedial CPN. These dual NMDAR-mediated actions are likely to play a major role in the acquisition of new behaviors and reward-related processes that have been associated with cortical input to the striatal patch compartments.

Animals↗
PubMed2000

Anatomical substrates for baroreflex sympathoinhibition in the rat.

The fundamental neuronal substrates of the arterial baroreceptor reflex have been elucidated by combining anatomical, neurophysiological, and pharmacological approaches. A serial pathway between neurons located in the nuclei of the solitary tract (NTS), the caudal ventrolateral medulla (CVL), and the rostral ventrolateral medulla (RVL) plays a critical role in inhibition of sympathetic outflow following stimulation of baroreceptor afferents. In this paper, we summarize our studies using tract-tracing and electron microscopic immunocytochemistry to define the potential functional sites for synaptic transmission within this circuitry. The results are discussed as they relate to the literature showing: (1) baroreceptor afferents excite second-order neurons in NTS through the release of glutamate; (2) these NTS neurons in turn send excitatory projections to neurons in the CVL; (3) GABAergic CVL neurons directly inhibit RVL sympathoexcitatory neurons; and (4) activation of this NTS-->CVL-->RVL pathway leads to disfacilitation of sympathetic preganglionic neurons by promoting withdrawal of their tonic excitatory drive, which largely arises from neurons in the RVL. Baroreceptor control may also be regulated over direct reticulospinal pathways exemplified by a newly recognized sympathoinhibitory region of the medulla, the gigantocellular depressor area. This important autonomic reflex may also be influenced by parallel, multiple, and redundant networks.

Animals↗
PubMed2000

Dual ultrastructural localization of mu-opiate receptors and substance p in the dorsal horn.

Opiates active at the mu-opiate receptor (MOR) produce antinociception, in part, through actions involving substance P (SP), a peptide present in both unmyelinated primary afferents and interneurons within the dorsal horn. We examined potential functional sites for interactions between SP and MOR by using dual electron microscopic immunocytochemical localization of antisera against SP and a sequence-specific antipeptide antibody against MOR in rat cervical spinal dorsal horn. The distribution was compared with that of the functionally analogous dorsal horn of the trigeminal nucleus caudalis. Many of the SP-immunoreactive terminals in the dorsal horn contacted dendrites that contain MOR (53% in trigeminal; 70% in cervical spinal cord). Conversely, within the cervical spinal dorsal horn 79% of the MOR-labeled dendrites that received any afferent input were contacted by at least one SP-containing axon or terminal. Although SP-immunoreactive dendrites were rare, many of these (48%) contained MOR, suggesting that the activity of SP-containing spinal interneurons may be regulated by MOR ligands. A few SP-labeled terminals also contained MOR (12% in trigeminal; 6% in cervical spinal cord). These data support the idea that MOR ligands produce antinociception primarily through modulation of postsynaptic second-order nociceptive neurons in the dorsal horns of spinal cord and spinal trigeminal nuclei, some of which contain SP. They also suggest, however, that in each region, MOR agonists can act presynaptically to control the release of SP and/or glutamate from afferent terminals. The post- and presynaptic MOR sites are likely to account for the potency of MOR agonists as analgesics.

Animals↗
PubMed1999

Subcellular distribution of 5-hydroxytryptamine2A and N-methyl-D-aspartate receptors within single neurons in rat motor and limbic striatum.

The dorsolateral caudate-putamen nucleus (CPN) and the nucleus accumbens (NAc) shell, respectively, are involved in many motor and limbic functions that are affected by activation of the 5-hydroxytryptamine2A receptor (5HT2AR) and the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR). We examined the functional sites for 5HT2AR activation and potential interactions involving the NMDAR subunit NR1 (NMDAR1) within these striatal regions. For this examination, sequence-specific antipeptide antisera against these receptors were localized by electron microscopic dual-labeling immunocytochemistry in the rat brain. In the dorsolateral CPN and the NAc shell, the 5HT2AR-labeled profiles were mainly dendrites, but somata and axons were also immunoreactive. The neuronal somata contained round unindented nuclei that are typical of spiny striatal neurons, although few dendritic spines were 5HT2AR immunolabeled. In all neuronal profiles, the 5HT2AR labeling was primarily associated with cytoplasmic organelles and more rarely was localized to synaptic or nonsynaptic plasma membranes. Colocalization of 5HT2AR and NMDAR1 was seen primarily in somata and dendrites. Significantly greter numbers of 5HT2AR- or 5HT2AR- and NMDAR1-containing dendrites were seen in the dorsolateral CPN than in the NAc shell. As compared with 5HT2AR, NMDAR1 labeling was more often observed in dendritic spines, and these were also more numerous in the CPN. These results indicate that 5HT2A and NMDA receptors are coexpressed but differentially targeted in single spiny striatal neurons and are likely to play a major role in control of motor functions involving the dorsolateral CPN.

Animals↗
PubMed1999

Enhancement of N-methyl-D-aspartate (NMDA) immunoreactivity in residual dendritic spines in the caudate-putamen nucleus after chronic haloperidol administration.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype in the caudate-putamen nucleus (CPN) have been implicated in the adverse motor effects produced by chronic administration of the typical antipsychotic drug haloperidol. To determine the functionally relevant sites, we examined the electron microscopic immunocytochemical localization of the R1 receptor subunit (NMDAR1) in the dorsolateral CPN of rats receiving 4 months of biweekly depot intramuscular injections of either haloperidol or vehicle. In all animals, NMDAR1 immunoreactivity was seen mainly in dendritic spines, but was also present in a few somata and dendrites of spiny neurons, axon terminals, and glia. In comparison with controls, the dissector stereological analysis showed a significant reduction in the numerical density of total NMDAR1-labeled and unlabeled dendritic spines in the dorsolateral CPN after haloperidol administration. When labeled spines were identified separately based exclusively on the presence of immunoreactivity within a single plane of section, there was, however, a significant increase in the numerical density of NMDAR1-containing spines in haloperidol vs. control animals. This increase was not seen using a classic dissector, suggesting that the enhancement was mainly attributed to more frequent detection of spines having higher levels of NMDA immunoreactivity. Our results are the first to identify dendritic spines in the dorsolateral CPN as preferential sites for the regulated expression of NMDA receptors following chronic administration of haloperidol.

Animals↗