Dorsolateral Caudate-putamen Research Articles

Contrasting effects of dopamine antagonists and frequency reduction on Fos expression induced by lateral hypothalamic stimulation

To help further identify the reward-relevant regions activated by electrical stimulation of the lateral hypothalamus, Fos expression was quantified in 23 brain regions in naı̈ve, awake rats following non-contingent stimulation with a frequency that supports self-stimulation (100 Hz), a frequency that supports only minimal responding (50 Hz) and a frequency that does not support self-stimulation (25 Hz). Fos expression was also examined in stimulated and unstimulated rats pretreated with SCH 23390 (a dopamine D1 antagonist) or spiperone (a D2-like antagonist), at doses known to greatly inhibit responding for self-stimulation. Lowering the stimulation frequency from 100 to 50 Hz reduced Fos labelling in all areas, except for a few cells immediately surrounding the electrode tip. No differences were observed between unstimulated rats and those receiving 25 Hz stimulation. This suggests that a critical threshold of stimulation is required before other reward-relevant regions in the midbrain and forebrain are recruited with higher frequency stimulation. Pretreatment with SCH 23390 (0.1 mg/kg) inhibited stimulation-induced Fos expression in some key dopamine terminal areas, such as the nucleus accumbens (core and shell) and medial caudate-putamen, but not in directly driven neurons near the stimulation site. In contrast, spiperone (0.1 mg/kg) did not affect the pattern of stimulation-induced Fos expression, but induced immunolabelling in the dorsolateral caudate-putamen, an area associated with the extrapyramidal side-effects of antipsychotic drugs. These results reveal the utility of Fos immunohistochemistry to show how different treatments that alter the rewarding impact of electrical brain stimulation achieve their effects at the neural level.

Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus

Acute bouts of exercise have been shown to produce transient increases in regional cerebral glucose utilization, oxygen uptake, and cerebral blood flow in motor cortex, striatum, and hippocampus. The purpose of this study was to determine whether or not chronic exercise will cause long-term metabolic plasticity in brain structures activated during physical activity. The activity of cytochrome oxidase (COX), is coupled to the production of ATP, and reflects long-term plasticity in metabolic capacity. The present study examined whether or not 6 months of voluntary exercise would increase COX activity in the striatum, sensorimotor cortex, and three hippocampal subfields. Five-month-old, female Long–Evans hooded rats were randomly assigned to a control or exercise condition. Exercising rats had running wheels attached to their home cages. After the training period, fresh brains were rapidly frozen and sectioned with a cryostat. COX activity was measured using COX histochemical methods and optical densitometry. Rats in the exercise condition had significantly higher optical density in the hindlimb and forelimb motor cortices (18%, P<0.01) and dorsolateral caudate putamen (17%, P<0.01), but not in the ventrolateral caudate putamen or any subfield of the hippocampus. Although exercise is believed to increase neuronal activity in the hippocampus, motor cortex and striatum, only limb representations in the motor cortex and striatum increase bioenergetic capacity after regular exercise.

Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: regional fiber vulnerability in the striatum and the olfactory tubercle

Oxidant stress has been implicated in the pathogenesis of Parkinson's disease. To test the oxidant stress hypothesis of dopaminergic degeneration, age-related changes in the mesostriatal dopamine neuron system were compared between zitter mutant rats which have abnormal metabolism of oxygen species in the brain and Sprague–Dawley rat as a control using the neurochemistry and immunohistochemistry. Dopamine content in the caudate–putamen, nucleus accumbens and olfactory tubercle of zitter rats decreased significantly with age, and was lower than that found in corresponding age-matched controls. In the zitter rats, the reduction of dopamine was more prominent in the caudate–putamen than in the nucleus accumbens and olfactory tubercle. A characteristic decline of tyrosine hydroxylase-immunoreactive fibers in the caudate–putamen of the zitter rat was also observed. In the dorsolateral caudate–putamen, reduction of tyrosine hydroxylase-immunoreactive fibers was observed in the matrix-like area, whereas in the ventromedial caudate–putamen the reduction occurred in the patch-like areas. Degeneration of tyrosine hydroxylase-immunoreactive fibers which was characterized by swollen varicosities and clustered fibers was observed in the caudate–putamen and nucleus accumbens and preceded loss of normal tyrosine hydroxylase-immunoreactive fibers in the caudate–putamen. Thus, the depletion of dopamine in the terminal areas is related to axonal degeneration. However, there was no degenerative tyrosine hydroxylase-immunoreactive fibers in the olfactory tubercle at any examined age, but reductions of tyrosine hydroxylase-immunoreactive fibers and dopamine contents were noted in the olfactory tubercle after four months-of-age. Since the zitter rats have an abnormal oxygen metabolism, the degeneration of tyrosine hydroxylase-immunoreactive fibers could result from an accumulation of superoxide species. The present results provide support for the oxidant stress hypothesis of dopaminergic neuronal degeneration and further indicate the region-specific vulnerability of the nigrostriatal dopamine system.

Chronic administration of morphine alters immediate-early gene expression in the forebrain of post-dependent rats

Previous studies from this laboratory have demonstrated that acute, systemic administration of morphine results in an induction of the immediate-early gene (IEG) proteins, c-Fos and Jun-B, in the dorsomedial portion of the rat caudate–putamen (CPu). These studies have also shown that morphine can induce c-Fos in the central medial nucleus of the thalamus (CM). To determine whether this response is altered in post-dependent rats, twice-daily injections of an ascending dose of morphine were administered for 5 days, followed by a withdrawal period of 7 or 14 days. A challenge injection of morphine (10 mg/kg) was administered on the last day of withdrawal. As compared to an acute dose of morphine in a naive animal, the induction of c-Fos was increased in the dorsolateral CPu following challenge injection at 7 days, but not at 14 days. Induction of c-Fos in the CM following the challenge injection was blunted following 7 day, but not at 14 days, of withdrawal. An increase in the IEG protein, Jun-B, was also seen following 7 but not 14 days of withdrawal in both the dorsomedial and dorsolateral CPu. These findings demonstrate that a chronic treatment of morphine can result in altered patterns of IEG expression upon challenge with acute morphine, in a time-dependent manner, within the rat CPu and CM.

Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D 2 function

The present study investigated, in rats, whether blockade of cannabinoid CB 1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB 1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate–putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate–putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D 1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate–putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D 2-like agonist, quinpirole (0.25 mg/kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate–putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate–putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.

Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus

There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine A 1 and dopamine D 1 and between adenosine A 2A and dopamine D 2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine D 1 receptor antagonist [ 125I]SCH-23982, the dopamine D 2–3 receptor antagonist [ 3H]raclopride, the adenosine A 1 receptor antagonist [ 3H]DPCPX and the adenosine A 2A receptor antagonist [ 3H]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (V H), a possible animal model of schizophrenia. Both dopamine D 2–3 and adenosine A 2A receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A 1 receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D 1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and V H-lesioned rats.

Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate–putamen in rats sensitized to morphine

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate–putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompained by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate–putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate–putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.

Desensitization and enhancement of neurotensin/neuromedin N mRNA responses in subsets of rat caudate-putamen neurons following multiple administrations of haloperidol

Striatal neurons that respond to blockade of dopamine receptors with altered expression of neurotensin/neuromedin N mRNA were examined. Injections of haloperidol were given to rats at four or 24 h and both four and 24 h prior to sacrifice. Pair-matched controls were injected with equivalent volumes of vehicle at either 4 or 24 h prior to sacrifice. Sections of striatum were processed non-isotopically with a cRNA neurotensin/neuromedin N probe. Massive numbers of neurons exhibited hybridization in the lateral and dorsolateral caudate-putamen at 4 h. At 24 h, hybridized neurons were few in lateral and dorsolateral parts of the caudate-putamen, but more numerous in the dorsomedial and ventrolateral caudate-putamen than in controls. A second injection of haloperidol 4 h prior to sacrifice enhanced the dorsomedial/ventrolateral response, but failed to elicit substantial numbers of lateral and dorsolateral hybrids, as were observed at 4 h after one injection. Resistance of neurotensin expression to a second injection of haloperidol was selective for the lateral and dorsolateral parts of the caudate-putamen and may reflect residual blockade by haloperidol or altered DA receptors or second messengers. Sections subjected to immunohistochemical processing for neurotensin peptide and in situ hybridization with the neurotensin/neuromedin N mRNA probe exhibited numerous neurons in the dorsomedial and ventrolateral quadrants of the caudate-putamen that were double-labeled with immunoperoxidase and hybridization signals. This suggests that peptide synthesis, as opposed to decreased release of peptide, has a role in the accumulation of neurotensin immunoreactivity by dorsomedial and ventrolateral striatal neurons.

Genetics, Haloperidol, and the Fos Response in the Basal Ganglia: A Comparison of the C57BL/6J and DBA/2J Inbred Mouse Strains

The haloperidol-induced increase of Fos-like immunoreactive (Fos-li) neurons in the basal ganglia was compared in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The D2 strain is 10-fold more sensitive than the B6 strain to haloperidol-induced catalepsy, a putative animal model of the extrapyramidal symptoms (EPS) seen after the administration of typical neuroleptics. In contrast, the strains are equally sensitive to the haloperidol facilitation of prepulse inhibition of the acoustic startle response, a measure of drug efficacy on the mesolimbic dopamine system. The haloperidol effects on Fos-li neurons were examined over the range of 0.1 to 6.0 mg/kg; the ED50s for haloperidol-induced catalepsy are 0.4 and 3.8 mg/kg in the D2 and B6 strains, respectively. In neither the core or shell of the nucleus accumbens nor the caudate-putamen (including the dorsolateral aspect) did the D2 strain show a greater Fos response compared to the B6 strain. In fact, in the dorsolateral caudate-putamen, the B6 strain showed a modest but significantly greater Fos response. However, at the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra zona reticulata (SNr), the D2 strain consistently showed a greater Fos response. These data suggest that the EP and SNr may be important to understanding the difference in haloperidol-induced catalepsy between the D2 and B6 strains.

Expression of Fos protein in the limbic regions of the rat following haloperidol decanoate

To identify sites of antipsychotic drug action, the effects of acute and chronic haloperidol treatment on Fos protein expression in rat brain regions were examined by immunohistochemical methods. Male Wistar rats were injected with haloperidol decanoate (40 mg/kg, i.m.) or vehicle. Fourteen days after injection, each rat was given an acute subcutaneous injection of haloperidol (0.25 mg/kg) or vehicle, and was transcardially perfused 2 h after the second injection. A single dose of haloperidol to chronic vehicle-treated rats produced significant increases in Fos-positive neurons in 18 of 21 brain regions examined including the several cortical areas, caudate–putamen, nucleus accumbens, lateral septum, thalamic nuclei, amygdala, hippocampus CA1, mesencephalic dopaminergic nuclei, and periaqueductal grey. The rats treated with acute vehicle after chronic haloperidol showed persistent Fos increases in confined brain regions comprising the lateral and central amygdala, lateral septum, and entorhinal cortex. Additional haloperidol injection to the chronic haloperidol-treated rats induced significant increases in Fos immunoreactivity in more widespread limbic–thalamo–cortical areas, whereas no significant increase was seen in the dorsolateral caudate–putamen. The persisting effects of haloperidol in the limbic and related structures, especially the amygdala, lateral septum, and entorhinal area may be of significance to the efficacy of long-term haloperidol treatment.

Divergent corticostriatal projections from a single cortical column in the somatosensory cortex of rats

We injected biotinylated dextran amine (BDA) into single vibrissal `barrels' of primary somatosensory (SI) cortex and reconstructed the topography of labelled varicosities in the dorsolateral caudate–putamen. Plots of labelled varicosities revealed densely-packed clusters of corticostriatal arborizations along the dorsolateral edge of the caudate–putamen and sparsely-packed arborizations more medially. The medial and lateral clusters of labelled terminals were separated by regions of unlabelled neuropil and lead us to conclude that a single cortical column sends divergent projections to multiple regions of the caudate–putamen.

Expression of messenger RNAs encoding ionotropic glutamate receptors in rat brain: regulation by haloperidol

In situ hybridization was used to study the regional distribution of messenger RNAs encoding ionotropic glutamate receptor subtypes in the rat brain's dopaminergic cell body regions and their forebrain projection areas. Short oligonucleotide probes specific for the messenger RNAs encoding the flip or flop splice forms of the GluR1 and GluR2 AMPA ( α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptor subunits, or for the messenger RNAs encoding the N-methyl- d-aspartate R1 subunit, were used. Significant differences were seen in the relative messenger RNA levels, and the distribution of the flip and flop splice forms, of GluR1 and GluR2. In the dopaminergic cell groups of the substantia nigra pars compacta and the ventral tegmental area, the flip form of both GluR1 and GluR2 dominated over the flop form. Similarly, in the core division of the nucleus accumbens, GluR1 and GluR2 flip forms dominated over the flop forms. In contrast, in the accumbens shell, the GluR1 and GluR2 flop forms dominated over the flip forms. As a comparison to the AMPA receptor subunits, N-methyl- d-aspartate R1 messenger RNA was relatively evenly distributed in all the regions analysed. The results demonstrate a heterogeneous distribution of the flip and flop splice forms of GluR1 and GluR2 in the brain's dopaminergic pathways, which could contribute to physiological differences in regulation of the pathways by glutamatergic neurotransmission. We also studied regulation of glutamate receptor subunit expression in these regions by antipsychotic drugs, based on previous reports of altered levels of subunit immunoreactivity after drug treatment. Chronic administration of the typical antipsychotic drug, haloperidol, caused a small but significant induction of GluR2 flip messenger RNA in the dorsolateral caudate–putamen. This effect was not seen after chronic administration of the atypical antipsychotic drug, clozapine. Significant drug regulation of the other glutamate receptor subunits studied was not observed.

The new heparins

The motivational properties of the non-peptide δ-opioid receptor agonists BW373U86 and SNC 80 were investigated using the place-conditioning paradigm. BW373U86 (0.5–1.0 mg/kg s.c.) and SNC 80 (1.25–5.0 mg/kg s.c.) elicited significant preference for the drug-paired compartment, in a dose-related fashion. Naltrindole (5.0 mg/kg s.c.) pretreatment, while failing to modify preference when given alone, completely prevented place-preference induced by BW373U86 (1.0 mg/kg s.c.) and SNC 80 (1.25 mg/kg s.c.). The dopamine D1 receptor antagonist SCH23390, given at doses that do not affect place-preference (0.012 mg/kg s.c.), completely prevented the place-preference induced by BW373U86 and SNC 80. At the doses effective in eliciting place-preference, BW373U86 and SNC 80 failed to modify extracellular dopamine in the medial nucleus accumbens, while in the dorso-lateral caudate-putamen BW373U86 (1.0 and 2.5 mg/kg s.c.) reduced extracellular dopamine, and this effect was prevented by naltrindole (5.0 mg/kg s.c.). SNC 80, only at the dose of 5 mg/kg s.c., significantly reduced extracellular DA in the dorso-lateral caudate-putamen. The results indicate that stimulation of δ-opioid receptors has incentive properties that might be related to an indirect amplification of post-synaptic dopamine transmission.

Concurrent elevation of the levels of expression of striatal preproenkephalin and preprodynorphin mRNA in the rat brain by chronic treatment with caffeine

Caffeine is a widely consumed substance that elicits psychomotor stimulant effects and also displays addictive properties. In order to assess the effect of caffeine on striatal neuropeptide mRNA expression, male rats were injected (i.p.) with caffeine at 20, 40 or 80 mg/kg of body weight twice daily for 9 consecutive days. Preproenkephalin (PPE), preprotachykinin A (PPT-A) and preprodynorphin (PPD) mRNA levels were determined in coronal sections of brain tissue by in situ hybridization histochemistry. PPE mRNA levels were increased by chronic caffeine in all subdivisions of the striatum at 80 mg/kg (dorsolateral caudate-putamen (dlCPu), +139%; dorsomedial CPu (dmCPu), +42%; ventrolateral CPu (vlCPu), +102%; ventromedial CPu (vmCPu), +20%; and anterior CPu (aCPu), +75% relative to vehicle-injected controls that were normalized to 0% change). Similarly, PPD mRNA expression was increased in all aspects of the striatum at 80 mg/kg (dlCPu, dmCPu, vlCPu, vmCPu and aCPu, +98%, +25%, +104%, +9% and +85%, respectively). In contrast to PPE mRNA, PPD mRNA was increased +117% above control in the nucleus accumbens (NAc) at 20 mg/kg of caffeine. PPT-A mRNA expression was not significantly affected by caffeine treatment in the CPu or NAc. The data demonstrate that repeated exposure to caffeine selectively increases opioid neuropeptide mRNA expression in the striatum and the NAc of the rat brain by a dopamine-independent mechanism.

Effect of chronic antipsychotic drug treatment on preprosomatostatin and preprotachykinin A mRNA levels in the medial prefrontal cortex, the nucleus accumbens and the caudate putamen of the rat.

In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.

Decreased levels of preprotachykinin-A and tachykinin NK 1 receptor mRNA in specific regions of the rat striatum after electroconvulsive stimuli

The effects of electroconvulsive stimuli on the expression of mRNAs coding for preprotachykinin-A and the substance P-sensitive tachykinin NK 1 receptor were examined in subregions of the rat striatum. In the electroconvulsive stimuli-treated animals, a 43% decrease in preprotachykinin-A mRNA was detected in the dorso-lateral caudate-putamen as compared to sham electroconvulsive stimuli treated animals. A 75% decrease in numerical density of tachykinin NK 1 receptor mRNA positive neurons was found in the caudal part of the nucleus accumbens core. These findings provide new evidence for selective effects of electroconvulsive stimuli on specific populations of neurons in the rat striatum.

Ultrastructural immunocytochemical localization of the dopamine D 2 receptor within GABAergic neurons of the rat striatum

Classical antipsychotics, which block dopamine (DA) D 2 receptors, show intrastriatal variation in their effectiveness in modulating GABAergic function. To determine the cellular basis for such differences, we examined the electron microscopic immunocytochemical labeling of D 2 receptors and GABA in the dorsolateral caudate-putamen (CPn) and the nucleus accumbens (Acb) shell. In both regions, peroxidase reaction product and gold-silver deposits representing D 2 receptor immunoreactivity (D 2-IR) and GABA immunoreactivity (GABA-IR), respectively, were detected in dendrites and perikarya having characteristics of either spiny projection neurons or aspiny interneurons. Some perikarya in both regions were dually labeled with D 2-IR and GABA-IR. Numerous axon terminals in each region also contained one or both markers. However, there were notable regional differences in the immunolabeling patterns. In the CPn, D 2-IR was more commonly seen in dendrites/spines than in axon terminals, and proportionally more dendrites were dually labeled than in the Acb. In the Acb shell, D 2-IR was detected with similar frequency in terminals and dendrites/spines, but more terminals co-localized D 2-IR and GABA-IR in this region compared with the CPn. These results provide the first ultrastructural evidence for direct D 2-mediated effects of DA on striatal GABAergic neurons. They further suggest that modulation of GABAergic neurons by DA acting at D 2 receptors may be relatively more postsynaptic in the CPn, but more presynaptic in the Acb shell.

Reduced eticlopride-induced fos expression in caudate–putamen and globus pallidus after unilateral frontal cortex injury: relation to neglect

Unilateral ablation of medial agranular cortex in rats results in neglect of contralateral stimuli and reductions in amphetamine-induced expression of the immediate early gene, c-fos, in both caudate–putamen and globus pallidus. Both unilateral neglect and the reductions in dopamine agonist induction of subcortical Fos immunoreactivity dissipate over a matter of weeks. Dopamine agonism induces Fos predominantly in striatonigral cells and in globus pallidus via striatopallidal disinhibition, whereas Fos is induced in striatopallidal cells by administration of antagonists of the D2 dopamine receptor subfamily. To examine more directly effects of cortical injury on striatopallidal function, induction of striatal Fos by the D2 antagonist eticlopride (0.1mg/kg, s.c.) was examined in rats with medial agranular cortex ablation. In the same animals, eticlopride-induced Fos in globus pallidus was also examined. Five days after unilateral cortex injury, in rats showing neglect, the numbers of Fos immunoreactive nuclei induced by eticlopride were reduced by 50% in caudate–putamen and 25% in globus pallidus of the ipsilateral hemisphere. These lesion effects were restricted to dorsolateral caudate–putamen and dorsal pallidum. Three or more weeks after cortical injury, in rats recovered from neglect, eticlopride-induced Fos was normalized in caudate–putamen, but still decreased by 20% in globus pallidus.Along with previous findings, these results suggest that behavioral recovery from neglect produced by cortical injury may be at least partially mediated by normalizations of function of both striatopallidal and striatonigral neurons. In addition, the present findings suggest that normalization of function of pallidal cells activated by eticlopride is not necessary for behavioral recovery from frontal cortex ablation. Lingering reductions in excitatory cortico-subthalamo-pallidal input may be responsible for the longer-lasting dysfunctions of these pallidal cells.

Effect of MK 801 on priming of D 1-dependent contralateral turning and its relationship to c- fos expression in the rat caudate-putamen

In rats with a unilateral 6-hydroxydopamine lesion of the ascending dopamine neurons, we investigated the relationship between the expression of Fos-like immunoreactivity in the caudate-putamen and contralateral turning behavior in response to dopamine agonists during the induction and expression of sensitization (priming) to D 1-dependent turning behavior. Priming was induced by apomorphine (0.1 mg/kg s.c.) or by SKF 38393 (10 mg/kg s.c.) 14 days after 6-hydroxydopamine lesions and was expressed by challenge with SKF 38393 (3 mg/kg s.c.). In the induction phase of priming, administration of MK 801 (0.1 mg/kg s.c.) potentiated contralateral turning but differentially influenced stimulation of Fos expression in the caudate-putamen by apomorphine and by SKF 38393. Thus, MK 801 reduced in the expression phase of priming the stimulation of Fos expression by apomorphine in the dorsolateral caudate-putamen, but did not affect that by SKF 38393. MK 801, while preventing priming of SKF 38393-induced turning by apomorphine, failed to affect priming by SKF 38393. MK 801, given with apomorphine in the induction phase, reduced the stimulation of Fos expression in the dorsolateral caudate-putamen by SKF 38393. No such inhibitory effect of MK 801 on SKF 38393-stimulated Fos expression was observed in rats primed with SKF 38393. These results are consistent with the possibility that MK 801 disrupts sensitization of D 1 transduction by reducing the activation of c- fos by the DA agonist during the induction phase of priming.

DOPAMINE-DEPENDENT BEHAVIOURAL STIMULATION BY NON-PEPTIDE DELTA OPIOIDS, BW373U86 AND SNC80

The motivational properties of the non-peptide delta-opioid receptor agonists BW373U86 and SNC 80 were investigated using the place-conditioning paradigm. BW373U86 (0.5-1.0 mg/kg s.c.) and SNC 80 (1.25-5.0 mg/kg s.c.) elicited significant preference for the drug-paired compartment, in a dose-related fashion. Naltrindole (5.0 mg/kg s.c.) pretreatment, while failing to modify preference when given alone, completely prevented place-preference induced by BW373U86 (1.0 mg/kg s.c.) and SNC 80 (1.25 mg/kg s.c.). The dopamine D1 receptor antagonist SCH23390, given at doses that do not affect place-preference (0.012 mg/kg s.c.), completely prevented the place-preference induced by BW373U86 and SNC 80. At the doses effective in eliciting place-preference, BW373U86 and SNC 80 failed to modify extracellular dopamine in the medial nucleus accumbens, while in the dorso-lateral caudate-putamen BW373U86 (1.0 and 2.5 mg/kg s.c.) reduced extracellular dopamine, and this effect was prevented by naltrindole (5.0 mg/kg s.c.). SNC 80, only at the dose of 5 mg/kg s.c., significantly reduced extracellular DA in the dorso-lateral caudate-putamen. The results indicate that stimulation of delta-opioid receptors has incentive properties that might be related to an indirect amplification of post-synaptic dopamine transmission.