Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum

We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A₂ receptors (with the selective adenosine A₂ agonist CGS 21680) increases the dissociation constants of high- (K_h) and low-affinity (K_l) dopamine D₂ binding sites (labelled with the selective dopamine D₂ antagonist [³H]raclopride) without changing the proportion of high affinity binding sites (R_h). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both K_h and K_l values, stimulation of adenosine A₂ receptors is associated with an increase in R_h. These result suggest that, in the adult rat, adenosine A₂ stimulation may inhibit the behavioural effects induced by dopamine D₂ stimulation both by decreasing the affinity and the transduction of dopamine D₂ receptors. We have also studied the intramembrane A₂-D₂ receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D₂ receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (B_max values) of dopamine D₂ receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from native animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D₂ receptors in the contralateral neostriatum. In addition to the hightened sensitivity to dopamine agonists, it is known that the dopamine denervated striatum is more sensitive to adenosine antagonists like methylxanthines. If the adenosine A₂-dopamine D₂ interaction is the main mechanism of action mediating the central effects of methylxanthines, the dopamine denervation might also potentiate this interaction, i.e., dopamine D₂ receptors could be not only more sensitive to dopamine but also to adenosine A₂ receptor activation. Our results support this hypothesis, since membrane preparations from the denervated neostriatum are more sensitive to the effect of CGS 21680 on dopamine D₂ receptors. Thus a low dose of CGS 21680 (3 nM), which is not effective in membrane preparations from the neostriatum of naive animals, is still effective in membranes from the denervated neostriatum. These results underline the potential antiparkinsonian activity of adenosine A₂ antagonists.     

l-Dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of D-1 and D-2 receptors

Administration of l-dopa to unilaterally 6-hydroxydopamine-lesioned rats, activates the early gene c-fos in the lesioned caudate-putamen. D-1 receptor blockade by SCH 23390, preventedl-dopa-induced Fos-like immunoreactivity in the whole caudate-putamen, while D-2 receptor blockade by raclopride reduced Fos-like immunoreactivity only in the dorso-lateral portion. The results suggest thatl-dopa induces c-fos primarily through an activation of D-1 receptors, while D-2 receptor stimulation plays a facilitatory influence on D-1 mediated c-fos expression.     

Effects of D2 dopamine receptor antagonists on fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate

Recent studies have reported that acute administration of dopamine D₂ receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D₂ antagonists in primate species. Since all clinically effective antipsychotic drugs share D₂ receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D₂ receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extrapyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D₂ receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested. © 1996 Wiley-Liss, Inc.     

Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease

Adenosine A_2A receptors are a new target for drug development in Parkinson’s disease. Some experimental and clinical data suggest that A_2A receptor antagonists can provide symptomatic improvement by potentiating the effects of -DOPA as well as a decrease in secondary effects such as -DOPA-induced dyskinesia. -DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of -DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A_2A receptor agonist CGS 21680 and the A_2A receptor antagonist MSX-3 on -DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. -DOPA-induced behavioral sensitization was determined as an increase in -DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting -DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of -DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that -DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A_2A and D₂ receptor stimulation, since it was counteracted by MSX-3 and by the D₂ receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson’s disease.     

Effects of selective adenosine A1 and A2a agonists on amphetamine-induced locomotion and c-Fos in striatum and nucleus accumbens

Low to moderate doses of amphetamine produce locomotion which is dependent on release of dopamine in the anteromedial striatum and nucleus accumbens. The effects of selective adenosine A₁ and A_2a receptor agonists on locomotion and c-Fos induction following a moderate dose of amphetamine was assessed in rats. Pretreatment with the adenosine A₁ receptor agonist N-6-cyclohexyladenosine (CHA) or the adenosine A_2a receptor agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5′-N-ethylcarboxamidoadenosine (APEC) inhibited locomotion following an injection of amphetamine (1.5 mg/kg). This dose of amphetamine induced Fos-like immunoreactivity in an antero-dorsomedial distribution in the caudate-putamen and uniformly in the core and shell of the nucleus accumbens. Pretreatment with the adenosine A_2a receptor agonist APEC, but not the adenosine A₁ receptor agonist CHA, attenuated c-Fos induction in caudate-putamen and nucleus accumbens by amphetamine. These findings indicate that amphetamine-induced behavior is subject to modulation by adenosine receptors through mechanisms which are both related to and independent of c-Fos induction.     

7-OH-DPAT Differentially Reverses Clozapine- and Haloperidol-induced Increases in Fos-like Immunoreactivity in the Rodent Forebrain

The pattern of neurons which display haloperidol-induced Fos-like immunoreactivity closely matches the distribution of striatal D2 dopamine receptors, whereas clozapine-induced Fos-like immunoreactivity occurs primarily in regions that contain high levels of the D3 dopamine receptor. These neuroanatomical correlations suggest that haloperidol and clozapine may elevate Fos-like immunoreactivity by blocking D2 and D3 receptors respectively. In order to test this hypothesis, the abilities of prior administration of the D3 receptor-preferring agonist 7–hydroxy- N, N '-di- n -propyl-2-aminotetraline (7–OH-DPAT) to competitively reverse haloperidol- and clozapine-induced increases in Fos-like immunoreactivity were compared. Administration of 7–OH-DPAT (0.05 mg/kg, s.c.) 30 min before clozapine (20 mg/kg, s.c.) produced a 60% reduction in the number of neurons that displayed clozapine-induced Fos-like immunoreactivity in the major island of Calleja, nucleus accumbens and medial aspect of the striatum, while prior administration of 0.5 mg/kg (s.c.) of 7-OH-DPAT completely reversed these increases in Fos-like immunoreactivity. In contrast, the increases in Fos-like immunoreactivity in the major island of Calleja, nucleus accumbens and striatum (medial and dorsal aspects) induced by haloperidol (0.1 mg/kg, s.c.) were only reduced by the high dose of 7-OH-DPAT (0.5 mg/kg, s.c.). Hence, clozapine-induced increases in Fos-like immunoreactivity were more readily reversed by 7-OH-DPAT than elevations in Fos-like immunoreactivity produced by haloperidol. These results suggest that D3 receptor blockade plays a larger role in mediating clozapine- than haloperidol-induced increases in Fos-like immunoreactivity.     

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

Blockade of dopamine D₂ receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus α-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus α-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D₂ receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D₂ receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.     

Central adenosine A2A receptors: an overview

Recent advances in molecular biology, biochemistry, cell biology and behavioral pharmacology together with the development of more selective ligands to the various adenosine receptors have increased our understanding of the functioning of central adenosine A_2A receptors. The A_2A receptor is one of four adenosine receptors found in the brain. Its expression is highest in striatum, nucleus accumbens and olfactory tubercles, although it also occurs in neurons and microglia in most other brain regions. The receptor has seven transmembrane domains and couples via Gs to adenyl cyclase stimulation. Antagonistic interactions between A_2A receptors and dopamine D₂ receptors have been described, as stimulation of the A_2A receptor leads to a reduction in the affinity of D₂ receptors for D₂ receptor agonists. The A_2A receptor is thought to play a role in a number of physiological responses and pathological conditions. Indeed, A_2A receptor antagonists may be useful for the treatment of acute and chronic neurodegenerative disorders such as cerebral ischemia or Parkinson's disease. A_2A receptor agonists may treat certain types of seizures or sleep disorders. This review discusses the characteristics, distribution, pharmacochemical properties and regulation of central A_2A receptors, as well as A_2A receptor-mediated behavioural responses and their potential role in various neuropsychiatric disorders.     

SCH 23390-induced behavioral supersensitivity is not related to striatal c-fos levels

Stereotyped behavior and striatal c-fos levels induced by chronic treatment with the D₁ dopamine antagonist SCH 23390 have been investigated in rats which received subsequent subacute dopamine agonist treatment. SCH 23390 treatment (0.5 mg/kg/day) for 21 days increased both apomorphine-induced orofacial stereotypies and striatal c-fos levels. Treatment with the D₁ dopamine agonist SKF 38393 (10 mg/kg/day) and the combination of SKF 38393 with the D₂ dopamine agonist quinpirole (1 mg/kg/day), for 5 consecutive days, attenuated apomorphine-induced stereotypies without changing c-fos levels in rats previously treated with SCH 23390. These findings suggest that SCH 23390-induced behavioral supersensitivity and the increased striatal c-fos levels are concomitant but unrelated phenomena.     

D1 dopamine receptors mediate neuroleptic-induced Fos expression in the islands of Calleja

Systemic injections of the selective, full, D₁ agonists A-77636 and SKF-82958 induced pronounced Fos-like immunoreactivity in the islands of Calleja in the olfactory tubercle of intact rats. Fos expression in this region could also be induced by injections of the D₂-like dopamine antagonist raclopride (0.5 mg/kg). Pretreatment with the selective D₁ dopamine antagonist SCH-23390 (0.2 mg/kg) completely abolished this response, but was without significant effect on raclopride-induced Fos expression in the dorsolateral region of the striatum. SCH-23390 was also able to prevent the atypical neuroleptic clozapine (30 mg/kg) from inducing Fos expression in the islands of Calleja. These findings demonstrate that stimulation of D₁ dopamine receptors plays an essential role in neuroleptic induction of Fos-like immunoreactivity in the islands of Calleja, but not in the dorsal striatum, and thus suggest that different mechanisms underlie neuroleptic stimulation of immediate early gene expression in these two structures. Synapse 28:154–159, 1998. © 1998 Wiley-Liss, Inc.     

Expression of Fos protein in rat brain following administration of a nicotinic acetylcholine receptor agonist epibatidine

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D₁ and D₂ receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 μg/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D₁ receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5.0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 μg/kg). Pretreatment with sulpiride, a dopamine D₂ receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D₁ receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D₂ receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.     

The effect of serotonin1A receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens

Serotonin (5-HT)_1A receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT_1A receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT_1A receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT_2A/D₂ receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0.03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01–1.0 mg/kg), potent D₂ receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1–0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT_2A receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT_1A receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT_2A receptors. The significance of these results for EPS and antipsychotic action is discussed.     

Blunted brain metabolic response to ketamine in mice lacking D1A dopamine receptors

The interaction of glutamatergic and dopamine neurotransmission is thought to have relevance to both the pathophysiology and pharmacotherapy of schizophrenia. For example, subanesthetic doses of the N-methyl- -aspartate receptor (NMDA-R) antagonist ketamine induce schizophrenia-like behavioral effects in humans and both behavioral and brain metabolic activation in rodents. Blockade of NMDA-R results in dopamine release, and antipsychotic drugs that block dopamine neurotransmission decrease NMDA-R antagonist-induced behavioral activation. The involvement of dopamine receptors in brain metabolic activation induced by ketamine is, however, unknown. The present study used D_1A knockout mice to determine the role of dopamine D_1A receptors in the effects of subanesthetic doses of ketamine on both behavioral responses and on alterations in regional [¹⁴C]2-deoxyglucose (2-DG) uptake. There was less ketamine-induced behavioral activation in D_1A knockout mice than in wild-type mice. In wild-type mice, ketamine (30 mg/kg) induced dramatic increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, basolateral amygdala, and caudal parts of the substantia nigra pars reticulata. D_1A knockout mice exhibited blunted metabolic activation in response to ketamine in a neuroanatomically specific manner. The selective D₁ antagonist, SCH23390 (0.3 mg/kg), inhibited both ketamine-induced brain metabolic activation and behavioral responses in the wild-type mice, with a similar neuroanatomical specificity observed in the D_1A knockout mice. Thus, the neuroanatomically selective role that D_1A receptors play in ketamine-induced behavior and regional brain metabolic activation in mice provides a useful model for further studies of how the D_1A receptor function may be altered in schizophrenia.     

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.

     

Enabling role of adenosine A1 receptors in adenosine A2A receptor-mediated striatal expression of c-fos

When striatal neurons are strongly activated they produce adenosine, which activates nearby adenosine A1 receptors (A1Rs) and adenosine A2A receptors (A2ARs). Although the effects of A1R or A2AR activation on neural activity in the striatum have been examined separately, the effects of coactivating both receptors has not been investigated. Using c-Fos immunohistochemistry as an indicator of neural activity, we examined the effects of coactivation of A1Rs and A2ARs on neural activity and their mechanism of interaction in the caudate-putamen, nucleus accumbens (NAc) and prefrontal cortex in rats. Administration of a motor-depressant dose of the A2AR agonist CGS 21680 (0.5 mg/kg i.p.) did not significantly induce c-fos expression in any of these brain regions. Administration of a motor-depressant dose of the A1R agonist CPA (0.3 mg/kg, i.p.) produced a small but significant induction of c-fos expression only in the shell of the NAc. Coadministration of CGS 21680 and CPA produced a synergistic induction of c-fos expression in the caudate-putamen, cingulate cortex, and especially the NAc. In the shell of the NAc administration of CPA significantly decreased extracellular dopamine levels measured by in vivo microdialysis and blocked CGS 21680-induced increases in dopamine levels. Because it has been previously shown that activation of dopamine D2 receptors (D2Rs) by endogenous dopamine blocks A2AR-mediated c-fos expression, it is hypothesized that the enabling role of A1Rs in A2AR-mediated striatal c-fos expression is related to the A1R-mediated inhibition of dopamine release.     

Interactive effects of stimulation of D1 and D2 dopamine receptors on fos-like immunoreactivity in the normosensitive rat striatum

Systemic administration of the selective, full, D₁ dopamine agonist A-77636 [(1R,3S)3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranhydrochloride] (0.36–2.9 mg/kg) led to a dose-dependent induction of Fos-like immunoreactivity (FLI) in the striatum. Quantitative analysis of the sections indicated that immunoreactive cells were more numerous in the medial than the lateral striatum and, within these regions, appeared to be randomly distributed. The staining produced by A-77636 could be abolished by pretreatment with the selective D₁ antagonist SCH-23390. The selective D₂ dopamine agonist quinpirole (3 mg/kg) had no effect on striatal FLI when given by itself, but markedly potentiated the weak striatal staining produced by low doses of A-77636. When combined with the highest dose of A-77636, which produced substantial staining by itself, quinpirole produced an increase in the number of immunoreactive cells seen in the lateral striatum but actually decreased the number present in the medial striatum. Statistical analysis of the distribution of immunoreactive cells demonstrated that, in both regions, quinpirole converted the relatively homogeneous staining seen after A-77636 alone into a markedly patchy pattern. These findings indicate that stimulation of D₂ receptors produces both stimulatory and inhibitory effects on the D₁-mediated expression of Fos in the striatum and that the interaction between D₁ and D₂ receptor stimulation must, therefore, be more complex than the simple synergism suggested by previous studies.     

Opposing actions of adenosine A2a and dopamine D2 receptor activation on GABA release in the basal ganglia: Evidence for an A2a/D2 receptor interaction in globus pallidus

There is increasing evidence that adenosine (ADO) and dopamine (DA) interact directly in the basal ganglia via actions at ADO A_2a and DA D₂ receptors, respectively. The purpose of this study was to determine 1) the extent to which these receptors modulate endogenous GABA release in discrete regions of the rat basal ganglia and 2) whether GABA release is modulated by a direct and opposing interaction between ADO A_2a and DA D₂ receptors. Tissue slices of striatum (STR) containing globus pallidus (GP; STR/GP) and micropunches of STR, GP, and substantia nigra pars reticulata (SNr) were studied. Radioligand binding demonstrated that ADO A₁, ADO A_2a, and DA D₂ receptors were present in each of the tissue preparations with the exception of SNr, in which ADO A_2a receptors were not detected. Stimulation of ADO A_2a receptors with CGS 21680 (1–10 nM) increased electrically stimulated GABA release in STR/GP slices and GP micropunches. Consistent with the lack of A_2a receptors in SNr, CGS 21680 had no effect on GABA release from this region. In contrast, stimulation of DA D₂ receptors with N-0437 (1–100 nM) inhibited evoked GABA release from STR/GP slices and both GP and SNr micropunches. The D₂-mediated inhibition of GABA release in GP was abolished in the presence of CGS 21680 (10 nM). These experiments demonstrate that stimulation of ADO A_2a and DA D₂ receptors has opposing effects on endogenous GABA release in STR and GP. These opposing actions may explain the antagonistic interactions between ADO and DA that have been observed in behavioral studies and support the hypothesis that the striatopallidal efferent system is an important anatomical substrate for the A_2a/D₂ receptor interaction. © 1996 Wiley-Liss, Inc.     

Morphine, 5-HT2 and 5-HT3 receptor antagonists reduce c-fos expression in the trigeminal nuclear complex following noxious chemical stimulation of the rat nasal mucosa

Noxious chemical stimulation of the rat nasal mucosa induces the expression of the immediate early gene c-fos in trigeminal brainstem neurons. In the present study, we applied the irritant mustard oil (1%) into the left nostril of urethane anesthetized rats. Immunohistochemical methods were used to evaluate the expression of Fos protein in the trigeminal subnuclei interpolaris and caudalis and to test the effects of putative analgesics that might depress synaptic transmission in neurons related to nociception. For this purpose, morphine (3 mg/kg and 10 mg/kg), the 5-HT₂ antagonist ketanserin (0.5 mg/kg and 5 mg/kg) and the 5-HT₃ antagonist ICS 205–930 (0.1 mg/kg and 1 mg/kg) were administered intravenously prior to noxious stimulation. Pretreatment with any of the three compounds reduced Fos-like immunoreactivity. The effect of morphine was reversible with naloxone. The reduction of the expression of Fos-like immunoreactivity by exogenous morphine speaks in favour of an opiodergic link in the modulation of orofacial pain in the trigeminal nuclei. The effects of the 5-HT receptor antagonists are most likely mediated via 5-HT₂ and 5-HT₃ receptors located on primary afferent fibres.     

Repeated intravenous cocaine administration: Locomotor activity and dopamine D2/D3 receptors

The dopamine D₃ receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D₂ and D₃ receptor density in the rat striatum and nucleus accumbens. Male Sprague-Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60-minute test sessions. Repeated cocaine treatment resulted in a significant dose-dependent increase in striatal D₃ receptors which was predicted by daily 60-minute central locomotor activity. Conversely, D₃ receptors in the nucleus accumbens exhibited a significant dose-dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose-dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D₂ receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D₃ receptor involvement in the expression of cocaine-induced behavioral sensitization. Thus, the D₃ receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D₃) and reinforcing aspects (nucleus accumbens D₃) of repeated cocaine administration. © 1996 Wiley-Liss, Inc.     

Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens

We reported previously that environmental novelty enhances the acute psychomotor activating effects of amphetamine, its ability to induce behavioral sensitization, and its ability to induce c-fos mRNA in the striatum and other structures, relative to when amphetamine is given in the home cage. The purpose of the present experiment was 2-fold: to determine (1) whether environmental novelty has a similar effect on the ability of cocaine to induce c-fos mRNA, and (2) whether this effect is seen in neurologically-intact rats (in previous experiments we studied the intact hemisphere of rats with a unilateral 6-OHDA lesion). In the dorsal portion of the caudate putamen, core and shell of the nucleus accumbens, and in several cortical regions, both amphetamine (1.5 mg/kg) and cocaine (15 mg/kg) induced higher levels of c-fos mRNA expression when administered in a novel environment, relative to when they were administered in the home cage. The ability of environmental context to modulate psychostimulant drug-induced immediate early gene expression may be related to its ability to modulate forms of drug experience-dependent plasticity, such as behavioral sensitization.