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Regional differences in the ability of caffeine to affect haloperidol-induced striatal c-fos mRNA expression in the rat
Neuropharmacology 37 (1998) 331 – 337
Regional differences in the ability of caffeine to affect haloperidol-induced striatal c-fos mRNA expression in the rat Per Svenningsson *, Ricard Nerga˚rdh, Bertil B. Fredholm Section of Molecular Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden Accepted 11 February 1998
Abstract By using in situ hybridisation we examined the acute effects of caffeine on haloperidol-induced c-fos mRNA in rat striatum. A homogenous induction of striatal c-fos mRNA was found 30 min after injection of haloperidol (1 mg kg − 1). At this timepoint caffeine (40 mg kg − 1) did not affect c-fos mRNA in striatum but caused a significant increase of this gene in the somatosensory cortex. When caffeine was injected together with haloperidol c-fos mRNA was reduced in the medial part of the striatum, but enhanced in the caudal part. Similar region-specific effects of caffeine were observed on c-fos mRNA induced by the selective dopamine D2 antagonist raclopride (0.5 mg kg − 1). Both haloperidol and raclopride counteracted caffeine-induced c-fos mRNA expression in somatosensory cortex. By contrast no significant interactions between caffeine and the dopamine D1 antagonist SCH 23390 (0.5 mg kg − 1) on striatal c-fos mRNA expression were observed. The present data show that caffeine modulates c-fos mRNA induced by dopamine D2 receptor antagonism differentially in sensorimotor and limbic-related areas of striatum. It is suggested that this could depend upon a different action of caffeine on the cortical inputs to these two parts of the striatum. © 1998 Elsevier Science Ltd. All rights reserved. Keywords: Dopamine receptors; Neuroleptics; Adenosine receptors; Methylxanthines; Caudate-putamen; Cerebral cortex
1. Introduction Caffeine is the most widely consumed psychostimulant in the world (Daly, 1993; Fredholm, 1995). In stimulating doses caffeine exerts its action by antagonising adenosine receptors and adenosine A1 and A2A receptors are particularly important (Daly, 1993; Fredholm, 1995). These two adenosine receptor subtypes are abundantly expressed in the central nervous system. Adenosine A1 receptors show a wide-spread distribution, with moderate to high levels in striatum, hippocampus, cerebellar and cerebral cortex (Fastbom et al., 1987), where they play an important role in regulating neuronal firing and neurotransmitter release (Fredholm, 1995). Adenosine A2A receptors show a more restricted distribution and high levels are found only in striatum and tuberculum olfactorium (Parkinson and Fredholm, 1990). There are two major neuronal efferent pathways from striatum, that project to * Corresponding author. Tel.: + 46 8 7287940; fax: +46 8 341280; e-mail: [email protected]. 0028-3908/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0028-3908(98)00045-8
either globus pallidus or substantia nigra pars reticulata/nucleus entopeduncularis (Gerfen, 1992). Both these subpopulations consist of medium-sized spiny neurons and use GABA as a neurotransmitter. In addition to these efferent neurons there are subpopulations of intrinsic interneurons in the striatum. Interestingly, expression of the gene encoding adenosine A2A receptors can be detected only in those efferent neurons that project to globus pallidus and not in the other efferent neurons or in intrinsic interneurons (Schiffmann and Vanderhaeghen, 1993). The striatopallidal neurons also express dopamine D2 receptors (Fink et al., 1992; Schiffmann and Vanderhaeghen, 1993; Svenningsson et al., 1997a) and a functionally important negative interaction between the actions of dopamine and adenosine takes place in these neurons (Ferre´ et al., 1992). One way to determine the effects of various drug treatments is to study their regulation of so called immediate early genes (IEGs), like c-fos, NGFI-A and NGFI-B. The underlying rationale for such studies is that the expression of these genes correlates well with the metabolic activity in most neuronal structures
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(Sheng and Greenberg, 1990). Using this approach it has been shown that dopamine D2 antagonism, e.g. haloperidol treatment, leads to a selective up-regulation of IEG expression in striatopallidal neurons within 30 min (Robertson et al., 1992). Conversely, we have previously shown that stimulatory (i.e. low) doses of caffeine down-regulate the expression of some of these genes in the striatum (Svenningsson et al., 1995, 1997b). As in the case of haloperidol this effect of caffeine occurred predominantly in striatopallidal neurons and could be mimicked by treating animals with a selective A2A receptor antagonist (Svenningsson et al., 1997b). There are therefore several reasons to believe that caffeine could functionally interact with neuroleptic drugs in the striatum and that this interaction could manifest itself in changes in c-fos mRNA. It is believed that schizophrenic patients in psychiatric wards are high caffeine consumers and there is some evidence that schizophrenic patients treated with neuroleptics further increase their caffeine intake, for instance, when having neurotic symptoms (Hamera et al., 1995). The caffeine thus consumed has been reported to exaggerate the schizophrenic process (Mikkelsen, 1978) and even to increase several aspects of psychopathology in patients treated with a classical dopamine D2 receptor blocking agent (Lucas et al., 1990), suggesting that caffeine indeed counteracts effects induced by neuroleptic drugs. In the present study we therefore examined the effects of simultaneous administration of caffeine and haloperidol on c-fos mRNA expression. Since haloperidol not only binds to dopamine D2-like receptors but also to dopamine D1 receptors we also co-administered caffeine with relatively selective antagonists at these receptors. The somewhat surprising result was that the interaction between caffeine and haloperidol differed considerably between parts of the striatal complex.
2. Methods Sprague-Dawley rats (B & K, Stockholm, Sweden) weighing 200–230 g were used. The experiments were approved by the regional ethical board. All rats had free access to food and drinking water and were maintained on a 12:12 h light:dark cycle. Each rat received two intraperitoneal (i.p.) injections within 30 s of each other. The following drug combinations were used; saline + saline (n= 8), caffeine (Sigma, Stockholm, Sweden) (40 mg kg − 1) +saline (n = 12), haloperidol (Research Biochemicals International, Natick, MA) (1 mg kg − 1)+ saline (n =10), caffeine (40 mg kg − 1)+ haloperidol (1 mg kg − 1) (n =5), raclopride (Research Biochemicals International) (0.5 mg kg − 1) +saline (n = 5), caffeine (40 mg kg − 1) +raclopride (0.5 mg kg − 1) (n=5), SCH 23390 (Research Biochemicals In-
ternational) (0.5 mg kg − 1)+ saline (n= 3), caffeine (40 mg kg − 1)+ SCH 23390 (n= 3). The choice of doses was based on preliminary experiments and data from studies cited in the Introduction. All rats were sacrificed by decapitation 30 min after treatment. Their brains were rapidly dissected out and frozen at − 80°C. Coronal cryostat-sections (14 mm thick) were made, + 1.00 mm and − 0.92 mm from bregma and thaw-mounted on slides coated with polyL-lysine (50 mg ml − 1). The following probes were used; c-fos, complementary to rat c-fos mRNA encoding amino acids 137–152 of the c-Fos protein (Curran et al., 1987); adenosine A1 receptor, complementary to nucleotides 985–1032 of the rat adenosine A1 receptor (Mahan et al., 1991); and adenosine A2A receptor, complementary to nucleotides 916–959 of the dog adenosine A2A receptor (Schiffmann et al., 1990). All probes were radiolabelled using terminal deoxyribonucleotidyl transferase (Pharmacia LKB, Uppsala, Sweden) and a-35S-dATP (Du PontNEN, Stockholm, Sweden) to a specific activity of about 109 cpm mg − 1. Mounted sections were hybridised in a cocktail containing 50% formamide (Fluka, Buchs, Switzerland), 4× sodium saline chloride, 1×Denhardt’s solution, 1% sarcosyl, 0.02 M NaPO4 (pH 7.0), 10% dextran sulphate, 0.5 mg ml − 1 yeast tRNA (Sigma, Labkemi, Stockholm, Sweden), 0.06 M dithiothreitol, 0.1 mg ml − 1 sheared salmon sperm DNA and 107 cpm ml − 1 of probe. After hybridisation for 16 h at 42°C the sections were washed four times for 15 min in 1×SSC at 55°C. Thereafter they were dipped briefly in water, 70, 95 and 99.5% ethanol. The dry sections were apposed to Hyperfilm b-max film (Amersham, Solna, Sweden) for 1–2 weeks and thereafter dipped in NTB-3 emulsion (Kodak, Ja¨rfa¨lla, Sweden) and exposed for 2 months. After the emulsion had been developed the sections were lightly stained with cresyl-violet (0.5%). Receptor autoradiography with the radioligands [3H]DPCPX (Du Pont, New England Nuclear, Stockholm, Sweden), a selective adenosine A1 receptor antagonist and [3H]SCH 58261 (Amersham, Solna, Sweden), a selective adenosine A2A receptor antagonist, was performed as previously described (Svenningsson et al., 1997b). The autoradiographic films from the in situ hybridization experiments against c-fos mRNA were analysed by using the Microcomputer Imaging Device system (M4, Imaging Research, Ontario, Canada). The areas examined are shown in Fig. 1. The system was calibrated with a Kodak density wedge and the results are presented as optical density values. In order to correct for background expression, measurements were done also in corpus callosum and the obtained white matter values were subtracted from those in nucleus accumbens, striatum and cerebral cortex in each section. Thereafter optical density values from the differ-
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ent treatment groups were statistically evaluated by using one-way ANOVAs for each region. In order to determine whether there were significant differences between individual treatment groups, pairwise comparisons were made using Newman – Keuls test for post-hoc comparisons (GraphPAD PRISM 2.1, San Diego, CA, USA). In addition, two-way ANOVAs (treatment× region) were performed to evaluate regional differences in the effects of caffeine on c-fos mRNA expression in striatum and nucleus accumbens from animals treated with saline, haloperidol, raclopride and SCH 23390. In all cases P values less than 0.05 were considered significant.
3. Results The distribution of adenosine A1 receptor mRNA and protein, as determined with [3H]DPCPX-binding, agreed well with previous work (Mahan et al., 1991) and high levels of both mRNA and protein were found in the cerebral cortex, especially in the somatosensory part (Fig. 2A–B). The slight difference in the detailed distribution (more superficial labelling for mRNA than for protein) probably indicates that many of the receptors are located in nerve terminals rather than cell bodies. In agreement with previous work (Schiffmann et al., 1990; Svenningsson et al., 1997b), adenosine A2A receptors, as determined with [3H]SCH 58261 binding, as well as adenosine A2A receptor mRNA were highly and homogenously expressed throughout the entire striatum (Fig. 2C–D). Caffeine (40 mg kg − 1) did not raise c-fos mRNA expression above the low level seen in saline-treated rats in any of the examined parts of striatum or nucleus accumbens (Figs. 3 and 6A – D) as described earlier
Fig. 1. Schematic drawings, adapted from Paxinos and Watson (1986), showing with grey rectangles the areas chosen for quantitative analysis. Panel A is +1.00 mm from bregma, whereas panel B is −0.92 mm from bregma. SSC, somatosensory cortex; CC, cingulate cortex; DL, dorsolateral caudate-putamen; MED, medial caudateputamen; ACC, nucleus accumbens; CAU, caudal caudate-putamen.
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Fig. 2. Darkfield autoradiograms showing the distribution of adenosine A1 receptor mRNA (A) and binding of the selective adenosine A1 receptor antagonist [3H]DPCPX (B). Note the relatively high amounts of receptors and their corresponding mRNA in the somatosensory parts of the cortex. Panels C and D show the high and homogenous expression of adenosine A2A receptor mRNA (C) and binding of the selective adenosine A2A receptor antagonist, [3H]SCH 58261 (D), throughout the entire striatum.
(Nakajima et al., 1989; Johansson et al., 1993). However, caffeine caused a significant increase in the expression of c-fos mRNA in the somatosensory part of cerebral cortex, whereas it had no significant effect in the cingulate cortex (Figs. 5 and 6E–F).Haloperidol (1 mg kg − 1) caused a homogenous and rather uniform induction of c-fos mRNA throughout the striatal complex without affecting cortical c-fos mRNA levels (Figs. 3 and 6A–F). The induction of striatal c-fos mRNA occured in a sub-population of medium-sized neurons (Fig. 4). The pattern of striatal c-fos mRNA expression was markedly changed when caffeine was co-administered with haloperidol. In these animals there was a significantly lower c-fos mRNA expression in the dorsomedial part of striatum as compared to those treated with haloperidol alone, but in the caudal parts of striatum the level was significantly higher (Figs. 3 and 6B–D). In the nucleus accumbens there was a strong tendency to a decrease in c-fos mRNA in caffeine+ haloperidol treated animals as compared to those treated only with haloperidol (Fig. 6A). The selective dopamine D2 receptor antagonist raclopride (0.5 mg kg − 1) induced c-fos mRNA in the dorsolateral and caudal parts of caudate-putamen (Fig. 6A–D). No specific regional differences in the striatal complex were found in animals treated with raclopride alone as compared to those treated with both raclopride and caffeine. However, two-way ANOVAs (treatment× region) revealed statistically significant differences between regions in animals treated with raclopride alone as compared to those that also received caffeine. A similar region-dependent significant difference was also found in animals treated with haloperidol when compared to those that received both haloperidol and caffeine. This reflects a shift to a more heteroge-
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Fig. 3. Darkfield autoradiograms showing the effects of intraperitoneal injections of either caffeine (40 mg kg − 1) (A, B) or haloperidol (1 mg kg − 1) (C, D) on c-fos mRNA expression in the rostral (A, C) and caudal (B, D) striatum. Panels E and F are from animals treated with both caffeine (40 mg kg − 1) and haloperidol (1 mg kg − 1) and illustrates the interaction of these compounds on striatal c-fos mRNA expression.
nous labelling pattern of striatal c-fos mRNA expression when haloperidol or raclopride was co-administered with caffeine. Both haloperidol and raclopride inhibited caffeine-induced c-fos mRNA expression in the somatosensory cortex (Fig. 6E). The dopamine D1 receptor antagonist SCH 23 390 did not significantly affect c-fos mRNA in the regions studied (Fig. 6A–F). Moreover, there were no alterations in c-fos mRNA when it was combined with caffeine (40 mg kg − 1).
4. Discussion The present results confirm that the haloperidol-induced increase in c-fos mRNA is due to antagonism of dopamine D2-like receptors located on medium-sized neurons in the striatum. The more wide-spread effect of haloperidol compared to raclopride on striatal c-fos mRNA might be due to a higher effective dose. Caf-
Fig. 4. Brightfield photomicrograph from emulsion-dipped sections showing c-fos mRNA expression in a sub-population of mediumsized neurons following haloperidol (1 mg kg − 1) treatment (filled arrows). The open arrow indicates a medium-sized neuron without c-fos mRNA induction. Scale bar =10 mm.
feine could counteract c-fos mRNA expression due to dopamine D2 receptor blockade in the dorsomedial striatum, but at the same time, enhance it in the caudal part. In the dose used here, 40 mg kg − 1, caffeine appears to exert its effects secondary to blockade of the actions of endogenous adenosine on adenosine A1 and A2A receptors (Fredholm, 1995). Both dopamine D2 and adenosine A2A receptors are relatively evenly distributed in striatum (Boyson et al., 1986; Parkinson and Fredholm, 1990; present data) and there are no apparent discrepancies in their degree of co-localisation between different subregions of striatum (Svenningsson et al., 1997a). We have previously found that a selective adenosine A2A receptor antagonist mimics the effect of a low dose of caffeine (Svenningsson et al., 1995, 1997b) and causes a decrease in the constitutive expres-
Fig. 5. Darkfield autoradiograms showing the cortical levels of c-fos mRNA in a saline-treated control animal (A) and the increased expression of this gene in the somatosensory cortex in an animal treated with caffeine (40 mg kg − 1) (B).
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Fig. 6. Histograms showing c-fos mRNA expression in the nucleus accumbens (A), medial caudate-putamen (B), dorsolateral caudate-putamen (C), caudal caudate-putamen (D), somatosensory cortex (E) and cingulate cortex (F) following treatment with saline, haloperidol (1 mg kg − 1), raclopride (0.5 mg kg − 1) or SCH 23390 (0.5 mg kg − 1) together with saline (open bars) or caffeine (40 mg kg − 1) (solid bars). Data represent mean9 S.E.M. of the optical density values measured in the different regions. An ANOVA followed by Newman – Keuls test for pairwise comparisons was done for each region. a PB 0.05 versus saline + saline and b PB 0.05 haloperidol + saline versus caffeine + haloperidol. In addition, for the striatal complex, i.e. caudate-putamen and nucleus accumbens (A – D), a two-way ANOVA (treatment ×region) showed significant differences in the region parameter between haloperidol +saline versus caffeine+haloperidol and raclopride +saline versus caffeine+ raclopride.
sion of two other IEGs, NGFI-A and NGFI-B, throughout striatum (Svenningsson et al., 1997b). Therefore caffeine acting on A2A receptors co-localised with D2 receptors is likely to uniformly reduce the
increase in c-fos mRNA expression that is seen following D2 receptor blockade. Indeed, in a recent study (Boegman and Vincent, 1996), it was shown that administration of a selective adenosine A2A receptor an-
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tagonist reduces haloperidol-induced c-Fos immunoreactivity even in the dorsolateral striatum, where we found that caffeine, if anything, caused an increase. Therefore, caffeine probably acts on some other target than the adenosine A2A receptor on striatopallidal neurons to cause the enhancement of the haloperidol effects in caudal striatum. Furthermore actions at this potential target should result in different effects in various regions of striatum. The dopaminergic afference from mesencephalon shows subregion-specific features; the dorsolateral and caudal or sensorimotor part of the striatum receives afferents predominantly from substantia nigra pars compacta, whereas the more rostral and medial or mesolimbic-related parts are mainly innervated by the ventral tegmental area (Gerfen, 1992). Caffeine causes a small increase in dopamine turnover and dopamine release in the striatum and these effects are mediated via adenosine A1 and not A2A receptors (Ferre´ et al., 1992; Okada et al., 1997), but there is no evidence that neurons that originate in the substantia nigra are more affected than those that originate in the ventral tegmental area. Furthermore, caffeine (40 mg kg − 1) has been shown to increase c-fos mRNA expression much more readily after 6-OH dopamine lesions of the substantia nigra and particularly in the dorsolateral part of the striatum (Johansson et al., 1993). Therefore it is unlikely that differential activation of the dopaminergic input provides the explanation that is sought. There are also differences in the anatomical connections between cerebral cortex and striatum. The dorsolateral and caudal parts of striatum receive excitatory glutamatergic afference from the sensorimotor parts of cerebral cortex whereas the dorsomedial part of striatum and the nucleus accumbens are mainly innervated by the medial prefrontal and cingulate cortices (McGeorge and Faull, 1989). Interestingly, we have previously observed that caffeine, but not the A2A receptor antagonist SCH 58261, potently induced NGFI-A and NGFIB mRNAs in the somatosensory part of cerebral cortex, but less in the cingulate and prefrontal cortex (Svenningsson et al., 1995, 1997b). Furthermore, in the present study we found that caffeine increases c-fos mRNA in the somatosensory cortex but not in the cingulate cortex. The present study also highlights the fact that adenosine A1 receptors are highly expressed in the somatosensory part of the cerebral cortex and could be an important target for caffeine. Thus, it is possible that the spatial heterogeneity in the effects of caffeine on haloperidol-induced c-fos mRNA in the striatum involves differential changes in the afferent glutamatergic neurotransmission. Indeed, it has previously been shown that high doses (100 mg kg − 1) of caffeine induce c-fos mRNA at least partly via an activation of NMDA receptors (Svenningsson et al., 1996).
Taken together, these findings suggest that caffeine, in addition to counteracting striatal IEG expression by locally antagonising A2A receptors, also activates an excitatory afferent pathway that projects predominantly to the caudal and dorsolateral parts of the striatum. Under normal conditions the dopamine acting at D2 receptors locally in the striatum suppresses the effects of this cortical afference. Thus, when striatal dopamine D2 receptors are blocked (or the dopaminergic innervation is disrupted) the effect of the caffeine-mediated activation of neurons in the somatosensory cortex manifests itself as an enhanced c-fos mRNA signal in the innervated parts of the striatum. This facilitation of the glutamatergic input may be related to the inhibition of glutamate release mediated by dopamine D2 receptors (Maura et al., 1988). Such a postulated heterogenous increase in glutamatergic input combined with the action of caffeine on postsynaptic adenosine A2A receptors throughout the entire striatum could result in a marked heterogeneity in striatal activity, with gradients from the rostral to the caudal and the medial to the lateral parts. In conclusion, these data show that caffeine regulates haloperidol-induced c-fos mRNA in a spatially heterogenous manner. We believe that this is caused by a combination of local events at the striatopallidal neuron and subregion-specific changes in the cortical input to the striatum.
Acknowledgements These studies were supported by the Swedish Medical Research Council (proj. No. 2553), by the Wallenberg Foundation and by the Institute for Scientific Information on Caffeine.
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Regional differences in the ability of caffeine to affect haloperidol-induced striatal c-fos mRNA expression in the rat Per Svenningsson *, Ricard Nerga˚rdh, Bertil B. Fredholm Section of Molecular Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden Accepted 11 February 1998
Abstract By using in situ hybridisation we examined the acute effects of caffeine on haloperidol-induced c-fos mRNA in rat striatum. A homogenous induction of striatal c-fos mRNA was found 30 min after injection of haloperidol (1 mg kg − 1). At this timepoint caffeine (40 mg kg − 1) did not affect c-fos mRNA in striatum but caused a significant increase of this gene in the somatosensory cortex. When caffeine was injected together with haloperidol c-fos mRNA was reduced in the medial part of the striatum, but enhanced in the caudal part. Similar region-specific effects of caffeine were observed on c-fos mRNA induced by the selective dopamine D2 antagonist raclopride (0.5 mg kg − 1). Both haloperidol and raclopride counteracted caffeine-induced c-fos mRNA expression in somatosensory cortex. By contrast no significant interactions between caffeine and the dopamine D1 antagonist SCH 23390 (0.5 mg kg − 1) on striatal c-fos mRNA expression were observed. The present data show that caffeine modulates c-fos mRNA induced by dopamine D2 receptor antagonism differentially in sensorimotor and limbic-related areas of striatum. It is suggested that this could depend upon a different action of caffeine on the cortical inputs to these two parts of the striatum. © 1998 Elsevier Science Ltd. All rights reserved. Keywords: Dopamine receptors; Neuroleptics; Adenosine receptors; Methylxanthines; Caudate-putamen; Cerebral cortex
1. Introduction Caffeine is the most widely consumed psychostimulant in the world (Daly, 1993; Fredholm, 1995). In stimulating doses caffeine exerts its action by antagonising adenosine receptors and adenosine A1 and A2A receptors are particularly important (Daly, 1993; Fredholm, 1995). These two adenosine receptor subtypes are abundantly expressed in the central nervous system. Adenosine A1 receptors show a wide-spread distribution, with moderate to high levels in striatum, hippocampus, cerebellar and cerebral cortex (Fastbom et al., 1987), where they play an important role in regulating neuronal firing and neurotransmitter release (Fredholm, 1995). Adenosine A2A receptors show a more restricted distribution and high levels are found only in striatum and tuberculum olfactorium (Parkinson and Fredholm, 1990). There are two major neuronal efferent pathways from striatum, that project to * Corresponding author. Tel.: + 46 8 7287940; fax: +46 8 341280; e-mail: [email protected]. 0028-3908/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0028-3908(98)00045-8
either globus pallidus or substantia nigra pars reticulata/nucleus entopeduncularis (Gerfen, 1992). Both these subpopulations consist of medium-sized spiny neurons and use GABA as a neurotransmitter. In addition to these efferent neurons there are subpopulations of intrinsic interneurons in the striatum. Interestingly, expression of the gene encoding adenosine A2A receptors can be detected only in those efferent neurons that project to globus pallidus and not in the other efferent neurons or in intrinsic interneurons (Schiffmann and Vanderhaeghen, 1993). The striatopallidal neurons also express dopamine D2 receptors (Fink et al., 1992; Schiffmann and Vanderhaeghen, 1993; Svenningsson et al., 1997a) and a functionally important negative interaction between the actions of dopamine and adenosine takes place in these neurons (Ferre´ et al., 1992). One way to determine the effects of various drug treatments is to study their regulation of so called immediate early genes (IEGs), like c-fos, NGFI-A and NGFI-B. The underlying rationale for such studies is that the expression of these genes correlates well with the metabolic activity in most neuronal structures
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(Sheng and Greenberg, 1990). Using this approach it has been shown that dopamine D2 antagonism, e.g. haloperidol treatment, leads to a selective up-regulation of IEG expression in striatopallidal neurons within 30 min (Robertson et al., 1992). Conversely, we have previously shown that stimulatory (i.e. low) doses of caffeine down-regulate the expression of some of these genes in the striatum (Svenningsson et al., 1995, 1997b). As in the case of haloperidol this effect of caffeine occurred predominantly in striatopallidal neurons and could be mimicked by treating animals with a selective A2A receptor antagonist (Svenningsson et al., 1997b). There are therefore several reasons to believe that caffeine could functionally interact with neuroleptic drugs in the striatum and that this interaction could manifest itself in changes in c-fos mRNA. It is believed that schizophrenic patients in psychiatric wards are high caffeine consumers and there is some evidence that schizophrenic patients treated with neuroleptics further increase their caffeine intake, for instance, when having neurotic symptoms (Hamera et al., 1995). The caffeine thus consumed has been reported to exaggerate the schizophrenic process (Mikkelsen, 1978) and even to increase several aspects of psychopathology in patients treated with a classical dopamine D2 receptor blocking agent (Lucas et al., 1990), suggesting that caffeine indeed counteracts effects induced by neuroleptic drugs. In the present study we therefore examined the effects of simultaneous administration of caffeine and haloperidol on c-fos mRNA expression. Since haloperidol not only binds to dopamine D2-like receptors but also to dopamine D1 receptors we also co-administered caffeine with relatively selective antagonists at these receptors. The somewhat surprising result was that the interaction between caffeine and haloperidol differed considerably between parts of the striatal complex.
2. Methods Sprague-Dawley rats (B & K, Stockholm, Sweden) weighing 200–230 g were used. The experiments were approved by the regional ethical board. All rats had free access to food and drinking water and were maintained on a 12:12 h light:dark cycle. Each rat received two intraperitoneal (i.p.) injections within 30 s of each other. The following drug combinations were used; saline + saline (n= 8), caffeine (Sigma, Stockholm, Sweden) (40 mg kg − 1) +saline (n = 12), haloperidol (Research Biochemicals International, Natick, MA) (1 mg kg − 1)+ saline (n =10), caffeine (40 mg kg − 1)+ haloperidol (1 mg kg − 1) (n =5), raclopride (Research Biochemicals International) (0.5 mg kg − 1) +saline (n = 5), caffeine (40 mg kg − 1) +raclopride (0.5 mg kg − 1) (n=5), SCH 23390 (Research Biochemicals In-
ternational) (0.5 mg kg − 1)+ saline (n= 3), caffeine (40 mg kg − 1)+ SCH 23390 (n= 3). The choice of doses was based on preliminary experiments and data from studies cited in the Introduction. All rats were sacrificed by decapitation 30 min after treatment. Their brains were rapidly dissected out and frozen at − 80°C. Coronal cryostat-sections (14 mm thick) were made, + 1.00 mm and − 0.92 mm from bregma and thaw-mounted on slides coated with polyL-lysine (50 mg ml − 1). The following probes were used; c-fos, complementary to rat c-fos mRNA encoding amino acids 137–152 of the c-Fos protein (Curran et al., 1987); adenosine A1 receptor, complementary to nucleotides 985–1032 of the rat adenosine A1 receptor (Mahan et al., 1991); and adenosine A2A receptor, complementary to nucleotides 916–959 of the dog adenosine A2A receptor (Schiffmann et al., 1990). All probes were radiolabelled using terminal deoxyribonucleotidyl transferase (Pharmacia LKB, Uppsala, Sweden) and a-35S-dATP (Du PontNEN, Stockholm, Sweden) to a specific activity of about 109 cpm mg − 1. Mounted sections were hybridised in a cocktail containing 50% formamide (Fluka, Buchs, Switzerland), 4× sodium saline chloride, 1×Denhardt’s solution, 1% sarcosyl, 0.02 M NaPO4 (pH 7.0), 10% dextran sulphate, 0.5 mg ml − 1 yeast tRNA (Sigma, Labkemi, Stockholm, Sweden), 0.06 M dithiothreitol, 0.1 mg ml − 1 sheared salmon sperm DNA and 107 cpm ml − 1 of probe. After hybridisation for 16 h at 42°C the sections were washed four times for 15 min in 1×SSC at 55°C. Thereafter they were dipped briefly in water, 70, 95 and 99.5% ethanol. The dry sections were apposed to Hyperfilm b-max film (Amersham, Solna, Sweden) for 1–2 weeks and thereafter dipped in NTB-3 emulsion (Kodak, Ja¨rfa¨lla, Sweden) and exposed for 2 months. After the emulsion had been developed the sections were lightly stained with cresyl-violet (0.5%). Receptor autoradiography with the radioligands [3H]DPCPX (Du Pont, New England Nuclear, Stockholm, Sweden), a selective adenosine A1 receptor antagonist and [3H]SCH 58261 (Amersham, Solna, Sweden), a selective adenosine A2A receptor antagonist, was performed as previously described (Svenningsson et al., 1997b). The autoradiographic films from the in situ hybridization experiments against c-fos mRNA were analysed by using the Microcomputer Imaging Device system (M4, Imaging Research, Ontario, Canada). The areas examined are shown in Fig. 1. The system was calibrated with a Kodak density wedge and the results are presented as optical density values. In order to correct for background expression, measurements were done also in corpus callosum and the obtained white matter values were subtracted from those in nucleus accumbens, striatum and cerebral cortex in each section. Thereafter optical density values from the differ-
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ent treatment groups were statistically evaluated by using one-way ANOVAs for each region. In order to determine whether there were significant differences between individual treatment groups, pairwise comparisons were made using Newman – Keuls test for post-hoc comparisons (GraphPAD PRISM 2.1, San Diego, CA, USA). In addition, two-way ANOVAs (treatment× region) were performed to evaluate regional differences in the effects of caffeine on c-fos mRNA expression in striatum and nucleus accumbens from animals treated with saline, haloperidol, raclopride and SCH 23390. In all cases P values less than 0.05 were considered significant.
3. Results The distribution of adenosine A1 receptor mRNA and protein, as determined with [3H]DPCPX-binding, agreed well with previous work (Mahan et al., 1991) and high levels of both mRNA and protein were found in the cerebral cortex, especially in the somatosensory part (Fig. 2A–B). The slight difference in the detailed distribution (more superficial labelling for mRNA than for protein) probably indicates that many of the receptors are located in nerve terminals rather than cell bodies. In agreement with previous work (Schiffmann et al., 1990; Svenningsson et al., 1997b), adenosine A2A receptors, as determined with [3H]SCH 58261 binding, as well as adenosine A2A receptor mRNA were highly and homogenously expressed throughout the entire striatum (Fig. 2C–D). Caffeine (40 mg kg − 1) did not raise c-fos mRNA expression above the low level seen in saline-treated rats in any of the examined parts of striatum or nucleus accumbens (Figs. 3 and 6A – D) as described earlier
Fig. 1. Schematic drawings, adapted from Paxinos and Watson (1986), showing with grey rectangles the areas chosen for quantitative analysis. Panel A is +1.00 mm from bregma, whereas panel B is −0.92 mm from bregma. SSC, somatosensory cortex; CC, cingulate cortex; DL, dorsolateral caudate-putamen; MED, medial caudateputamen; ACC, nucleus accumbens; CAU, caudal caudate-putamen.
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Fig. 2. Darkfield autoradiograms showing the distribution of adenosine A1 receptor mRNA (A) and binding of the selective adenosine A1 receptor antagonist [3H]DPCPX (B). Note the relatively high amounts of receptors and their corresponding mRNA in the somatosensory parts of the cortex. Panels C and D show the high and homogenous expression of adenosine A2A receptor mRNA (C) and binding of the selective adenosine A2A receptor antagonist, [3H]SCH 58261 (D), throughout the entire striatum.
(Nakajima et al., 1989; Johansson et al., 1993). However, caffeine caused a significant increase in the expression of c-fos mRNA in the somatosensory part of cerebral cortex, whereas it had no significant effect in the cingulate cortex (Figs. 5 and 6E–F).Haloperidol (1 mg kg − 1) caused a homogenous and rather uniform induction of c-fos mRNA throughout the striatal complex without affecting cortical c-fos mRNA levels (Figs. 3 and 6A–F). The induction of striatal c-fos mRNA occured in a sub-population of medium-sized neurons (Fig. 4). The pattern of striatal c-fos mRNA expression was markedly changed when caffeine was co-administered with haloperidol. In these animals there was a significantly lower c-fos mRNA expression in the dorsomedial part of striatum as compared to those treated with haloperidol alone, but in the caudal parts of striatum the level was significantly higher (Figs. 3 and 6B–D). In the nucleus accumbens there was a strong tendency to a decrease in c-fos mRNA in caffeine+ haloperidol treated animals as compared to those treated only with haloperidol (Fig. 6A). The selective dopamine D2 receptor antagonist raclopride (0.5 mg kg − 1) induced c-fos mRNA in the dorsolateral and caudal parts of caudate-putamen (Fig. 6A–D). No specific regional differences in the striatal complex were found in animals treated with raclopride alone as compared to those treated with both raclopride and caffeine. However, two-way ANOVAs (treatment× region) revealed statistically significant differences between regions in animals treated with raclopride alone as compared to those that also received caffeine. A similar region-dependent significant difference was also found in animals treated with haloperidol when compared to those that received both haloperidol and caffeine. This reflects a shift to a more heteroge-
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Fig. 3. Darkfield autoradiograms showing the effects of intraperitoneal injections of either caffeine (40 mg kg − 1) (A, B) or haloperidol (1 mg kg − 1) (C, D) on c-fos mRNA expression in the rostral (A, C) and caudal (B, D) striatum. Panels E and F are from animals treated with both caffeine (40 mg kg − 1) and haloperidol (1 mg kg − 1) and illustrates the interaction of these compounds on striatal c-fos mRNA expression.
nous labelling pattern of striatal c-fos mRNA expression when haloperidol or raclopride was co-administered with caffeine. Both haloperidol and raclopride inhibited caffeine-induced c-fos mRNA expression in the somatosensory cortex (Fig. 6E). The dopamine D1 receptor antagonist SCH 23 390 did not significantly affect c-fos mRNA in the regions studied (Fig. 6A–F). Moreover, there were no alterations in c-fos mRNA when it was combined with caffeine (40 mg kg − 1).
4. Discussion The present results confirm that the haloperidol-induced increase in c-fos mRNA is due to antagonism of dopamine D2-like receptors located on medium-sized neurons in the striatum. The more wide-spread effect of haloperidol compared to raclopride on striatal c-fos mRNA might be due to a higher effective dose. Caf-
Fig. 4. Brightfield photomicrograph from emulsion-dipped sections showing c-fos mRNA expression in a sub-population of mediumsized neurons following haloperidol (1 mg kg − 1) treatment (filled arrows). The open arrow indicates a medium-sized neuron without c-fos mRNA induction. Scale bar =10 mm.
feine could counteract c-fos mRNA expression due to dopamine D2 receptor blockade in the dorsomedial striatum, but at the same time, enhance it in the caudal part. In the dose used here, 40 mg kg − 1, caffeine appears to exert its effects secondary to blockade of the actions of endogenous adenosine on adenosine A1 and A2A receptors (Fredholm, 1995). Both dopamine D2 and adenosine A2A receptors are relatively evenly distributed in striatum (Boyson et al., 1986; Parkinson and Fredholm, 1990; present data) and there are no apparent discrepancies in their degree of co-localisation between different subregions of striatum (Svenningsson et al., 1997a). We have previously found that a selective adenosine A2A receptor antagonist mimics the effect of a low dose of caffeine (Svenningsson et al., 1995, 1997b) and causes a decrease in the constitutive expres-
Fig. 5. Darkfield autoradiograms showing the cortical levels of c-fos mRNA in a saline-treated control animal (A) and the increased expression of this gene in the somatosensory cortex in an animal treated with caffeine (40 mg kg − 1) (B).
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Fig. 6. Histograms showing c-fos mRNA expression in the nucleus accumbens (A), medial caudate-putamen (B), dorsolateral caudate-putamen (C), caudal caudate-putamen (D), somatosensory cortex (E) and cingulate cortex (F) following treatment with saline, haloperidol (1 mg kg − 1), raclopride (0.5 mg kg − 1) or SCH 23390 (0.5 mg kg − 1) together with saline (open bars) or caffeine (40 mg kg − 1) (solid bars). Data represent mean9 S.E.M. of the optical density values measured in the different regions. An ANOVA followed by Newman – Keuls test for pairwise comparisons was done for each region. a PB 0.05 versus saline + saline and b PB 0.05 haloperidol + saline versus caffeine + haloperidol. In addition, for the striatal complex, i.e. caudate-putamen and nucleus accumbens (A – D), a two-way ANOVA (treatment ×region) showed significant differences in the region parameter between haloperidol +saline versus caffeine+haloperidol and raclopride +saline versus caffeine+ raclopride.
sion of two other IEGs, NGFI-A and NGFI-B, throughout striatum (Svenningsson et al., 1997b). Therefore caffeine acting on A2A receptors co-localised with D2 receptors is likely to uniformly reduce the
increase in c-fos mRNA expression that is seen following D2 receptor blockade. Indeed, in a recent study (Boegman and Vincent, 1996), it was shown that administration of a selective adenosine A2A receptor an-
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tagonist reduces haloperidol-induced c-Fos immunoreactivity even in the dorsolateral striatum, where we found that caffeine, if anything, caused an increase. Therefore, caffeine probably acts on some other target than the adenosine A2A receptor on striatopallidal neurons to cause the enhancement of the haloperidol effects in caudal striatum. Furthermore actions at this potential target should result in different effects in various regions of striatum. The dopaminergic afference from mesencephalon shows subregion-specific features; the dorsolateral and caudal or sensorimotor part of the striatum receives afferents predominantly from substantia nigra pars compacta, whereas the more rostral and medial or mesolimbic-related parts are mainly innervated by the ventral tegmental area (Gerfen, 1992). Caffeine causes a small increase in dopamine turnover and dopamine release in the striatum and these effects are mediated via adenosine A1 and not A2A receptors (Ferre´ et al., 1992; Okada et al., 1997), but there is no evidence that neurons that originate in the substantia nigra are more affected than those that originate in the ventral tegmental area. Furthermore, caffeine (40 mg kg − 1) has been shown to increase c-fos mRNA expression much more readily after 6-OH dopamine lesions of the substantia nigra and particularly in the dorsolateral part of the striatum (Johansson et al., 1993). Therefore it is unlikely that differential activation of the dopaminergic input provides the explanation that is sought. There are also differences in the anatomical connections between cerebral cortex and striatum. The dorsolateral and caudal parts of striatum receive excitatory glutamatergic afference from the sensorimotor parts of cerebral cortex whereas the dorsomedial part of striatum and the nucleus accumbens are mainly innervated by the medial prefrontal and cingulate cortices (McGeorge and Faull, 1989). Interestingly, we have previously observed that caffeine, but not the A2A receptor antagonist SCH 58261, potently induced NGFI-A and NGFIB mRNAs in the somatosensory part of cerebral cortex, but less in the cingulate and prefrontal cortex (Svenningsson et al., 1995, 1997b). Furthermore, in the present study we found that caffeine increases c-fos mRNA in the somatosensory cortex but not in the cingulate cortex. The present study also highlights the fact that adenosine A1 receptors are highly expressed in the somatosensory part of the cerebral cortex and could be an important target for caffeine. Thus, it is possible that the spatial heterogeneity in the effects of caffeine on haloperidol-induced c-fos mRNA in the striatum involves differential changes in the afferent glutamatergic neurotransmission. Indeed, it has previously been shown that high doses (100 mg kg − 1) of caffeine induce c-fos mRNA at least partly via an activation of NMDA receptors (Svenningsson et al., 1996).
Taken together, these findings suggest that caffeine, in addition to counteracting striatal IEG expression by locally antagonising A2A receptors, also activates an excitatory afferent pathway that projects predominantly to the caudal and dorsolateral parts of the striatum. Under normal conditions the dopamine acting at D2 receptors locally in the striatum suppresses the effects of this cortical afference. Thus, when striatal dopamine D2 receptors are blocked (or the dopaminergic innervation is disrupted) the effect of the caffeine-mediated activation of neurons in the somatosensory cortex manifests itself as an enhanced c-fos mRNA signal in the innervated parts of the striatum. This facilitation of the glutamatergic input may be related to the inhibition of glutamate release mediated by dopamine D2 receptors (Maura et al., 1988). Such a postulated heterogenous increase in glutamatergic input combined with the action of caffeine on postsynaptic adenosine A2A receptors throughout the entire striatum could result in a marked heterogeneity in striatal activity, with gradients from the rostral to the caudal and the medial to the lateral parts. In conclusion, these data show that caffeine regulates haloperidol-induced c-fos mRNA in a spatially heterogenous manner. We believe that this is caused by a combination of local events at the striatopallidal neuron and subregion-specific changes in the cortical input to the striatum.
Acknowledgements These studies were supported by the Swedish Medical Research Council (proj. No. 2553), by the Wallenberg Foundation and by the Institute for Scientific Information on Caffeine.
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