Dynorphin opioid inhibition of cocaine-induced,D1 dopamine receptor-mediated immediatem-early gene expression in the striatum

Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that (1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5–250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); (2) systemic administration of the kappa opioid receptor agonist spiradoline (0.5–10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; (3) intrastriatal infusion of spiradoline (1–50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and (4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum. © 1995 Wiley-Liss, Inc.     

Effects of MK-801 on D1 dopamine receptor-mediated immediate early gene expression in the dopamine-depleted striatum

Previous work indicates that intrastriatal administration of MK-801 does not completely block D1 agonist-induced gene expression in dopamine-depleted rats. The present study examined the effects of systemic MK-801 on such gene expression. A low dose of MK-801 did not affect induction of c-fos or zif268. A high dose completely blocked induction of c-fos, but only slightly suppressed zif268. The data suggest that NMDA receptor activity may not always be necessary for D1-induced gene expression.     

C-type natriuretic peptide (CNP) regulates cocaine-induced dopamine increase and immediate early gene expression in rat brain

The neuropeptide C-type natriuretic peptide (CNP) is the primary biologically active natriuretic peptide in brain. Using in situ hybridization, the present report demonstrates that CNP regulates egr-1, c-fos and junB immediate early gene expression in rat brain. In the frontal cortex, CNP induced immediate early gene expression whereas it inhibited dose-dependently the cocaine-induced early gene expression in the dopaminergic projection fields nucleus accumbens and caudate-putamen. CNP may produce its effect directly on dopaminergic neurons because we found that its receptor, guanylyl cyclase GC-B, was expressed in the mesencephalon where dopaminergic neurons originate, as well as in their projection fields. The inhibition by CNP of the early gene expression elicited by cocaine in the caudate-putamen is correlated with a CNP-evoked decrease in cocaine-induced rise in extracellular dopamine, measured by in vivo microdialysis experiments. The significance of the inhibition of cocaine-induced dopamine release and early gene induction by the endogenous peptide CNP is demonstrated by data indicating that CNP reduced the cocaine-induced spontaneous locomotor activation. By inhibiting dopaminergic neuronal activity, CNP represents a potential negative regulator of related behavioural effects of cocaine.     

D1 dopamine receptor-mediated induction of zif268 and c-fos in the dopamine-depleted striatum: Differential regulation and independence from NMDA receptors

Excitatory amino acid afferents from cerebral cortex and dopamine afferents from the substantia nigra synapse on common projection neurons in the striatum. Activation of D1 dopamine receptors increases immediate early gene expression in the striatum and conductance through the N-methyl-d-aspartate (NMDA) receptor. To examine the contribution of NMDA receptor activation to dopamine receptor-mediated responses, we determined the effects of intrastriatal administration of NMDA antagonists on immediate early gene expression in the striatum and rotational behavior induced by stimulation of the D1 receptor in rats with unilateral dopamine depletions. Systemic administration of SKF 38393 increased c-fos and zif268 mRNAs in the striatum and induced contralateral rotation. Intrastriatal infusion of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid caused a dose-dependent attenuation of SKF 38393-induced rotation and partially decreased c-fos mRNA expression. However, D1-mediated increases in zif268 mRNA were not affected, except by the highest concentration of antagonist used (10 mM). Another competitive antagonist, 2-amino-5-phosphonovaleric acid, had similar effects. Like the competitive antagonists, intrastriatal infusion of the non-competitive NMDA antagonist MK-801 partially decreased c-fos, but not zif268, mRNA in the area around the microdialysis probe. However, unlike competitive antagonists, local infusion of 1 mM MK-801 potentiated D1-mediated increases in c-fos and zif268 mRNAs in lateral striatum. These data suggest that 1) some D1 dopamine receptor-mediated effects on striatal function are independent of ongoing NMDA receptor activation, whereas other effects are at least partially mediated by NMDA receptor activity in the striatum, and 2) competitive and non-competitive antagonists of the NMDA receptor differently affect D1-mediated immediate early gene expression in the striatum. © 1996 Wiley-Liss, Inc.     

Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: Relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction

Dynorphin, an endogenous kappa opioid receptor ligand, acts in the striatum to regulate the response of striatonigral neurons to D1 dopamine receptor stimulation. We investigated the relative contributions of both presynaptic kappa receptors on dopamine terminals and postsynaptic kappa receptors on striatal neurons by analyzing opioid regulation of D1 effects in the absence of presynaptic kappa receptors, after 6-hydroxydopamine depletion of striatal dopamine. D1-receptor-mediated immediate-early gene induction was measured by using in situ hybridization histochemistry. First, repeated treatment with the D1-receptor agonist SKF-38393 (2 mg/kg/day, 3–14 days) was used to increase dynorphin levels in rats with dopamine depletions. In the nucleus accumbens, increased dynorphin expression was accompanied by reduced induction of the immediate-early genes c-fos and zif 268 by SKF-38393. In contrast, in dorsal/lateral aspects of the dopamine-depleted striatum, this D1 response was sustained despite a large increase in dynorphin expression. These results are consistent with a requirement of dopamine terminals (presynaptic kappa receptors) for the inhibitory action of dynorphin in the dorsal/lateral striatum, but not in the ventral striatum. Second, the kappa receptor agonist spiradoline (1–10 mg/kg) reduced c-fos and zif 268 induction by SKF-38393 (2.5 mg/kg) preferentially in ventral parts of the dopamine-depleted striatum, which contain higher levels of kappa receptor mRNA and binding. These results also indicate that postsynaptic kappa receptors contribute to the inhibition of the D1 response at least in the ventral striatum. Together, these results indicate that dynorphin in the striatum functions to regulate dopamine input to striatonigral neurons, acting at both pre- and postsynaptic sites, and that the relative contributions of these mechanisms differ between dorsal and ventral striatal regions. © 1996 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, in the public domain in the United States of America.

     

Novel temporal configurations of stimuli produce discrete changes in immediate-early gene expression in the rat hippocampus

Changes in limbic brain activity in response to novel configurations of visual stimuli were assessed by quantifying two immediate-early genes, c-fos and zif268. Rats were first trained to use distal, visual cues to support radial-arm maze performance. Two separate sets of visual cues were used, one in the morning (Set A) and the other in the afternoon (Set B). On the final day the experimental group was tested with a novel configuration created by combining four of the eight visual cues from Set A with four of the eight visual cues from Set B. Although each individual cue was in a familiar location, the combination of cues was novel. Comparisons with a control group revealed discrete decreases in Fos centred in the hippocampus and retrosplenial cortex. The hippocampal c-fos findings produced a dissociation with the perirhinal cortex, where no change was observed. Other regions seemingly unaffected by the novel stimulus configuration included the postrhinal, entorhinal and parietal cortices. Zif268 levels in the experimental group increased in the anterior ventral thalamic nucleus. Although previous studies have shown how the rat hippocampus is involved in responding to the spatial rearrangement of visual stimuli, the present study examined temporal rearrangement. The selective immediate-early gene changes in the hippocampus and two closely related sites (retrosplenial cortex and anterior ventral thalamic nucleus) when processing the new stimulus configuration support the notion that the hippocampus is important for learning the 'relational' or 'structural' features of arrays of elements, be they spatial or temporal.     

Stimulus-dependent expression of immediate-early genes in rat somatosensory cortex

Using in situ hybridization histochemistry, we investigated the effects of whisker stimulation in freely moving rats on the expression of the immediate-early genes zif 268 and c-fos in the barrel cortex. Whiskers equipped with metal filaments were stimulated for 5–15 minutes with a pulsating magnetic field. Such whisker stimulation resulted in increased zif 268 and c-fos expression that was largely restricted to radial columns across the barrels representing the stimulated whiskers. In these columns, gene expression was elevated, to a variable degree, across the entire cortical thickness, with a distinct maximum in layer IV. The magnitude of gene expression in a barrel was proportional to the intensity of stimulation. Cellular analysis confirmed that whisker stimulation induced c-fos expression mostly in stellate cells of layer IV and in some pyramidal cells in other layers. However, even after the strongest stimulation, only subsets of neurons were labeled in all layers, suggesting that subpopulations of neurons with a differential genomic response to sensory input exist. These results indicate that the expression of these immediate-early genes is regulated by normal neuronal activity under physiological conditions, and suggest that such gene regulation is an integral part of neuronal function. J. Comp. Neurol. 380:145–153, 1997. © 1997 Wiley-Liss, Inc.

1 This article is a US government work and, as such, is in the public domain in the United States of America.

     

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24–48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments. Synapse 29:14–28, 1998. © 1998 Wiley-Liss, Inc.     

Sex and strategy use matters for pattern separation,adult neurogenesis,and immediate early gene expression in the hippocampus

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation, and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis, and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague‐Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the eight‐arm radial arm maze. Twenty‐seven days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore, male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly, neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity. © 2015 Wiley Periodicals, Inc.     

Role of dopamine D2 receptors in the striatal immediate early gene response to amphetamine in reserpinized rats

The indirect dopamine agonist amphetamine has been shown to induce a patchy pattern of immediate early gene (IEG) expression in the rostral striatum of both pharmacologically intact and reserpinized rats. The available data suggest that stimulation of D(2) dopamine receptors may play a role in the patterning of amphetamine-induced IEG expression, but direct evidence is lacking. In the current study of reserpinized animals, we found that pretreatment with the selective D(2) dopamine antagonist raclopride did not block the induction of the IEGs Fos and Arc by amphetamine, but greatly reduced the "patchiness" of the induced expression. Raclopride did not induce Fos or Arc expression by itself under the conditions studied here. These findings suggest that although stimulation of D(2) receptors is not necessary for amphetamine to induce IEG expression in reserpinized animals, these receptors do play a critical role in the spatial patterning of the resulting response.     

Acute and chronic caffeine administration differentially alters striatal gene expression in wild-type and adenosine A(2A) receptor-deficient mice

In order to assess for the respective involvement of adenosine A(1) and A(2A) receptors (A(2A)-R) in the consequences of short- and long-term caffeine exposure on gene expression, the effects of acute caffeine administration on striatal, cortical, and hippocampal expression of immediate early genes (IEG), zif-268 and arc, and the effects of long-term caffeine or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) exposure (once daily for 15 days) on striatal gene expression of substance P, enkephalin, and glutamic acid decarboxylase isoforms, GAD65 and GAD67, were evaluated in wild-type and A(2A)-R-deficient (A(2A)-R(-/-)) mice. In situ hybridization histochemistry was performed using oligonucleotides followed by quantitative image analysis. Our results demonstrated that a biphasic response of IEG expression to acute caffeine observed in the wild-type striatum was resumed in a monophasic response in the mutant striatum. In the cerebral cortex and hippocampus, the effect of caffeine was weak in wild-type, whereas in mutant mice it induced a 2-3-fold increase in the IEG expression to restore a level similar to the wild-type basal expression. Chronic caffeine and DPCPX-mediated regulation in neuropeptide and GADs striatal gene expression typically showed the mimicking of alterations resulting from the A(2A)-R genetic deficiency in 25 mg/kg caffeine-treated wild-type mice as well as the dose-dependent normalization of substance P and enkephalin expression in A(2A)-R(-/-) mice. These results indicate that, depending on the dose, the blockade of A(2A)-R or A(1) receptors by caffeine is preferentially revealed leading to highly differential alterations in striatal gene expression and they also suggested the central role of these two receptors on the control of dopaminergic functions.     

Group III metabotropic glutamate receptors and D1-like and D2-like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity

Evidence for functional interactions between metabotropic glutamate (mGlu) receptors and dopamine (DA) neurotransmission is now clearly established. In the present study, we investigated interactions between group III mGlu receptors and D1- and D2-like receptors in the nucleus accumbens (NAcc). Administration, into the NAcc, of the selective group III mGlu receptor agonist, AP4, resulted in an increase in locomotor activity, which was blocked by pretreatment with the group III mGlu receptor antagonist, MPPG. In addition, pretreatment with AP4 further blocked the increase in motor activity induced by the D1-like receptor agonist, SKF 38393, but potentiated the locomotor responses induced by either the D2-like receptor agonist, quinpirole, or coinfusion of SKF 38393 and quinpirole. MPPG reversed the effects of AP4 on the motor responses induced by D1-like and/or D2-like receptor activation. These results confirm that glutamate transmission may control DA-dependent locomotor function through mGlu receptors and further indicate that group III mGlu receptors oppose the behavioural response produced by D1-like receptor activation and favour those produced by D2-like receptor activation.     

Autoradiographic localization of dopamine D1 and D2 receptors in the brain of several mammalian species

Summary Dopamine D 1 and D 2 receptor distributions were studied in the brain of the mouse, rat, guinea pig, cat and monkey by means of in vitro quantitative autoradiography using [³H]SCH 23390 and [³H]CV 205–502 to label D 1 and D 2 subtypes respectively.The distribution of both subtypes of receptors was similar within the basal ganglia of all species investigated. The highest densities for both subtypes were found in the nucleus caudatus, putamen, nucleus accumbens, olfactory tubercle and substantia nigra.Outside of the basal ganglia, differences in the distribution of both receptors were found among the species examined in regions such as cerebellum, cortex, hippocampus, superior colliculus and olfactory bulb.In all species D 1 receptor densities were higher than those of D 2. The absolute amount of both subtypes, however, varied among species.These results indicate that dopamine receptor distribution is well preserved in the basal ganglia during evolution, although differences among species exist in their distribution outside the basal ganglia and their absolute amount.Abbreviations used in figures A corpus amygdalae - Acc nucleus accumbens - CA 1 CA 1 subfield of the hippocampus - CA 2 CA 2 subfield of the hippocampus - CgC cingular cortex - Cls claustrum - Cd nucleus caudatus - CPu caudate-putamen - DA dopamine - DG dentate gyrus of the hippocampus - EP nucleus entopeduncularis - GP globus pallidus - GPl globus pallidus, pars lateralis - GPm globus pallidus, pars medialis - gr granular layer of the cerebellum - IP nucleus interpeduncularis - LS lateral septum - mol molecular layer of the cerebellum - OT olfactory tubercle - Pk Purkinje cell layer of the cerebellum - Pu putamen - SC superior colliculus - snc substantia nigra, pars compacta - snr substantia nigra, pars reticulata - VTA area ventralis tegmentalis     

Enhanced expression of dopamine D1 and glutamate NMDA receptors in dopamine D4 receptor knockout mice

Expression of dopamine ([DA] D₁ and D₂) and glutamate ([Glu]), (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D₄ receptor knockout mice and their wild-type controls. Selective radioligand binding to D₄ receptors was virtually absent in D₄ receptor knockout mouse brain in contrast to significant specific D₄ binding in forebrain tissue of wild-type controls. Labeling of D₁ receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D₄-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA₁ (21%) and CA₃ (25%) regions of D₄ knockouts vs wild-type controls. No changes in D₂, AMPA or KA receptors were found. The findings suggest that D₁, D₄, and NMDA receptors might interact functionally and that developmental absence of D₄ receptors might trigger compensatory mechanisms that enhance expression of D₁ receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.     

Age-dependent decline of dopamine D1 receptors in human brain: A PET study

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [¹¹C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22–74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [¹¹C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly. Synapse 30:56–61, 1998. Published 1998 Wiley-Liss, Inc.     

The anabolic-androgenic steroid nandrolone decanoate affects the density of dopamine receptors in the male rat brain

In recent years a male group of anabolic-androgenic steroid misusers has been identified to share socio-demographic and personality related background factors with misusers of psychotropic substances, as well as being involved in habits of multiple drug use. The present study aimed to assess whether anabolic-androgenic steroids (AAS) would affect the density of the dopamine receptors in areas implicated in reward and behaviour in the male rat brain. The effects of 2 weeks of treatment with i.m. injections of nandrolone decanoate (15 mg/kg/day) on the expression of the D(1)-like and D(2)-like receptors were evaluated by autoradiography. Specific binding of D(1)-like receptors was significantly down regulated in the caudate putamen, the nucleus accumbens core and shell. D(2)-like receptor densities were down regulated in the nucleus accumbens shell, but up regulated in the caudate putamen, the nucleus accumbens core and the ventral tegmental area. These results are compatible with nandrolone induced neuroadaptive alterations in dopamine circuits associated with motor functions and behavioural paradigms known to be affected following AAS misuse.     

Tonic modulation of inhibition by dopamine D4 receptors in the rat hippocampus

Dopaminergic pathways have been recognized to play a critical role in cognition and emotion. Dopamine D2 and D4 receptors are the target for most common antipsychotics and their activation, particularly those in the medial temporal lobe structures, has been associated with their beneficial actions. The entorhinal cortex, which is the cortical area most consistently and severely affected in schizophrenia constitutes the main input to the hippocampus. Since the D4 receptor is highly concentrated in the hippocampus, and the effects of the selective activation of D4 receptors on the input/output function of the hippocampal formation are poorly understood, we sought to investigate the role of these receptors in the synaptic transmission and paired-pulse inhibition from the perforant path to area CA1 and the dentate gyrus. The D4 receptor antagonist, clozapine, translated paired-pulse inhibition into paired-pulse potentiation in both perforant path targets. By contrast, the D2/D3 antagonist quinpirole had no effect. The blockade of the D2/3 receptors with sulpiride, and of D1/5 receptors with SCH-23390, has no effect on paired-pulse inhibition, suggesting that these receptors are not involved in feedforward inhibition in these hippocampal areas. Interestingly, the perfusion of the D4 selective antagonist, L-745,870 (Patel et al., 1997: J Pharmacol Exp Ther 283:636-647) during the blockade of D2/3 and D1/5 receptors produces a reversible decrease in paired-pulse inhibition in CA1, but not in the DG. Our results show that endogenous DA tonically modulates feedforward inhibition in area CA1 and the dentate gyrus through the activation of D4 receptors located in the interneuronal population of these hippocampal regions. Since activation of the D4 receptor inhibits GABA release and GABAergic synaptic transmission, we suggest that the perforant path stimulates interneurons that have the D4 receptor and that, in turn, contact other interneurons that synapse onto pyramidal cells. (c) 2004 Wiley-Liss, Inc.