Biomedical subjects

J S Fink

Publications and source records attributed to J S Fink.

At least 19 recordsLinked to original sources

PubMed2001

The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice.

The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D(2)R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D(2)R interaction. However, whether the D(2)R is required for the A(2A)R to exert its neural function is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D(2) KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D(2)R, although the stimulation was significantly attenuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D(2)R deficiency. Consistent with the D(2) KO phenotype, A(2A)R inactivation partially reversed both acute D(2)R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are partially independent of D(2)Rs. Moreover, endogenous adenosine acting at striatal A(2A)Rs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D(2)R neurotransmission.

Adenosine↗

PubMed2000

A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

Chromosome Mapping↗

PubMed2000

Transplantation of embryonic porcine mesencephalic tissue in patients with PD.

OBJECTIVE: To assess the safety and the effect on standardized clinical rating measures of transplanted embryonic porcine ventral mesencephalic (VM) tissue in advanced PD. METHODS: Twelve patients with idiopathic PD underwent unilateral implantation of embryonic porcine VM tissue; six received cyclosporine immunosuppression and six received tissue treated with a monoclonal antibody directed against major histocompatibility complex class I. Patients were followed for 12 months and assessed by clinical examination, MRI, and 18F-levodopa PET. Porcine endogenous retrovirus testing was conducted by PCR-based method on peripheral blood mononuclear cells. RESULTS: Cell implantation occurred without serious adverse events in all patients. Cultures were negative for bacterial and unknown viral contamination. No porcine endogenous retrovirus DNA sequences were found. MRI demonstrated cannula tracts within the putamen and caudate, with minimal or no edema and no mass effect at the transplant sites. In the medication-off state, total Unified Parkinson's Disease Rating Scale scores improved 19% (p = 0.01). Three patients improved over 30%. There were two patients with improved gait. 18F-levodopa PET failed to show changes on the transplanted side. CONCLUSIONS: Unilateral transplantation of porcine embryonic VM cells into PD patients was well tolerated with no evidence of transmission of porcine endogenous retrovirus. Changes in standardized clinical PD rating measures were variable, similar to the results of the first trials of unilateral human embryonic allografts that transplanted small amounts of tissue.

Aged↗

PubMed2000

Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A(2A) adenosine receptors.

A(2A) adenosine receptors are highly expressed in the striatum where they modulate dopaminergic activity. The role of A(2A) receptors in psychostimulant action is less well understood because of the lack of A(2A)-selective compounds with access to the central nervous system. To investigate the A(2A) adenosinergic regulation of psychostimulant responses, we examined the consequences of genetic deletion of A(2A) receptors on psychostimulant-induced behavioral responses. The extent of dopaminergic innervation and expression of dopamine receptors in the striatum were indistinguishable between A(2A) receptor knockout and wild-type mice. However, locomotor responses to amphetamine and cocaine were attenuated in A(2A) knockout mice. In contrast, D(1)-like receptor agonists SKF81297 and SKF38393 produced identical locomotor stimulation and grooming, respectively, in wild-type and A(2A) knockout mice. Similarly, the D(2)-like agonist quinpirole produced motor-depression and stereotypy that were indistinguishable between A(2A) knockout and wild-type mice. Furthermore, attenuated amphetamine- (but not SKF81297-) induced locomotion was observed in pure 129-Steel as well as hybrid 129-SteelxC57BL/6 mice, confirming A(2A) receptor deficiency (and not genetic background) as the cause of the blunted psychostimulant responses in A(2A) knockout mice. These results demonstrate that A(2A) receptor deficiency selectively attenuates psychostimulant-induced behavioral responses and support an important role for the A(2A) receptor in modulating psychostimulant effects.

Animals↗

PubMed2000

Study of A(2A) adenosine receptor gene deficient mice reveals that adenosine analogue CGS 21680 possesses no A(2A) receptor-unrelated lymphotoxicity.

Cell surface A(2A) adenosine receptor (A(2A)R) mediated signalling affects a variety of important processes and adenosine analogues possess promising pharmacological properties. Demonstrating the receptor specificity of potentially lymphotoxic adenosine-based drugs facilitates their development for clinical applications. To distinguish between the receptor-dependent and -independent lymphotoxicity and apoptotic activity of adenosine and its analogues we used lymphocytes from A(2A)R-deficient mice. Comparison of A(2A)R-expressing (+/+) and A(2A)R-deficient (-/-) cells in cyclic AMP accumulation assays confirmed that the A(2A)R agonist CGS 21680 is indeed selective for A(2A) receptors in T-lymphocytes. Incubation of A(2A)R-expressing thymocytes with extracellular adenosine or CGS 21680 in vitro results in the death of about 7-15% of thymocytes. In contrast, no death was induced in parallel assays in cells from A(2A)R-deficient mice, providing genetic evidence that CGS 21680 does not display adenosine receptor-independent intracellular cytotoxicity. The A(2A) receptor-specific lymphotoxicity of CGS 21680 is also demonstrated in a long-term (6-day) in vitro model of thymocyte positive selection where addition of A(2A)R antagonist ZM 241,385 did block the effects of CGS 21680, allowing the survival of T cells. The use of cells from adenosine receptor-deficient animals is proposed as a part of the screening process for potential adenosine-based drugs for their receptor-independent cytotoxicity and lymphotoxicity.

Adenosine↗

PubMed1999

A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice.

Extracellular adenosine critically modulates ischemic brain injury, at least in part through activation of the A(1) adenosine receptor. However, the role played by the A(2A) receptor has been obscured by intrinsic limitations of A(2A) adenosinergic agents. To overcome these pharmacological limitations, we explored the consequences of deleting the A(2A) adenosine receptor on brain damage after transient focal ischemia. Cerebral morphology, as well as vascular and physiological measures (before, during, and after ischemia) did not differ between A(2A) receptor knock-out and wild-type littermates. The volume of cerebral infarction, as well as the associated neurological deficit induced by transient filament occlusion of the middle cerebral artery, were significantly attenuated in A(2A) receptor knock-out mice. This neuroprotective phenotype of A(2A) receptor-deficient mice was observed in different genetic backgrounds, confirming A(2A) receptor disruption as its cause. Together with complimentary pharmacological studies, these data suggest that A(2A) receptors play a prominent role in the development of ischemic injury within brain and demonstrate the potential for anatomical and functional neuroprotection against stroke by A(2A) receptor antagonists.

Aging↗

PubMed1998

Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways.

We have used the response of the superior cervical ganglia (SCG) to axotomy to investigate interactions between neuropoietic cytokines and neurotrophins. Postganglionic sympathetic axotomy leads to a prolonged leukemia inhibitory factor (LIF)-dependent activation of signal transducers and activators of transcription (STAT) factors. To study regulation of LIF-dependent activation of STAT proteins and to mimic the loss of target-derived NGF resulting from postganglionic axotomy in vivo, SCG were explanted into media lacking NGF and activation of STAT proteins was assessed by electrophoretic mobility shift assay. Like postganglionic axotomy in vivo. STAT proteins were activated for up to 8 days after explantation of SCG in vitro. SCG cultured in the presence of NGF showed decreased STAT binding when compared to ganglia cultured in NGF-free media. This inhibition of STAT activation by NGF was only present in ganglia cultured for more than 5 days and was mimicked by brain-derived neurotrophic factor (BDNF). The serine kinase inhibitor H7 augmented the increase of STAT binding produced by explantation, suggesting the presence of a labile repressor of STAT activation in the SCG. These data indicated that the neuropoietic cytokine-signaling pathway interacts with neurotrophin and H7-sensitive-signaling pathways to regulate activation of STAT proteins in sympathetic neurons. Moreover, these data suggest that one of the mechanisms leading to prolonged activation of STAT proteins after postganglionic axotomy in vivo is loss of target-derived neurotrophins.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1998

NFAT interactions with the vasoactive intestinal peptide cytokine response element.

The vasoactive intestinal peptide cytokine response element (VIP CyRE) is responsible for mediating the transcriptional induction of the VIP gene to the neuropoietic cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). In investigating the sequence and function of the CyRE, we found a region of DNA with homology to the distal NFAT site in the IL-2 promoter. In this paper we characterize this sequence and show that the VIP NFAT site recognizes T cell NFAT with similar affinity to the previously characterized IL-2 NFAT site. However, despite its location in the middle of the CyRE, we find no CNTF/LIF induced binding to it. Instead we show that in NBFL neuroblastoma cells, the calcium ionophore A23187 induces a protein to bind to the VIP NFAT site. This A23187-mediated induction of nuclear protein binding to an NFAT oligonucleotide is dependent on extracellular calcium but not dependent on de novo protein synthesis. Thus, this protein has the characteristics of an NFAT-like protein and is recognized by an NFAT3-specific antiserum suggesting that it is indeed an NFAT protein. The location of the NFAT site in the VIP CyRE suggests that this may be one mechanism through which different signaling pathways engage in cross talk to alter VIP gene transcription.

Animals↗

PubMed1998

Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2.

The src homology 2 (SH2) domain-containing protein-tyrosine phosphatase SHP-2 has been implicated as an important positive regulator of several mitogenic signaling pathways. SHP-2 has more recently been shown to be tyrosine phosphorylated and recruited to the gp130 component of the ciliary neurotrophic factor (CNTF) receptor complex upon stimulation with CNTF. CNTF does not, however, have a proliferative effect on responsive cells, but rather enhances the survival and differentiation of sympathetic, motor, and sensory neurons. In this study, expression of an interfering mutant of SHP-2 in the neuroblastoma cell line NBFL increased CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene, and in cultures of sympathetic neurons, it resulted in an up-regulation of endogenous VIP and substance P (SP) gene expression. Members of the CNTF family of cytokines transmit their signal by activating signaling pathways involving both STAT and Fos-Jun transcription factors. In CNTF-stimulated NBFL cells that constitutively express the SHP-2 interfering mutant, there was increased and prolonged formation of STAT/DNA complexes, but decreased AP-1 binding activity, that mirrored a down-regulation of c-fos expression both at the mRNA and protein level. Taken together, these data indicate that SHP-2 has dual and opposing roles in a signaling cascade triggered by the same ligand, as illustrated by its ability to differentially regulate the levels of activity of both STAT and AP-1 transcription factors.

Animals↗

PubMed1997

A sweat gland-derived differentiation activity acts through known cytokine signaling pathways.

The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development. Similar changes are induced in cultured sympathetic neurons by sweat gland cells or by one of the following cytokines: leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), or cardiotrophin-1 (CT-1). None of these is the sweat gland-derived differentiation activity. LIF, CNTF, and CT-1 act through the known receptors LIF receptor beta (LIFRbeta) and gp130 and well defined signaling pathways including receptor phosphorylation and STAT3 activation. Therefore, to determine whether the gland-derived differentiation activity was a member of the LIF/CNTF cytokine family, we tested whether it acted via these same receptors and signal cascades. Blockade of LIFRbeta inhibited the sweat gland differentiation activity in neuron/gland co-cultures, and extracts of gland-containing footpads stimulated tyrosine phosphorylation of LIFRbeta and gp130. An inhibitor (CGX) of molecules that bind the CNTFRalpha, which is required for CNTF signaling, did not affect the gland-derived differentiation activity. Soluble footpad extracts induced the same changes in NBFL neuroblastoma cells as LIF and CNTF, including increased vasoactive intestinal peptide mRNA, STAT3 dimerization, and DNA binding, and stimulation of transcription from the vasoactive intestinal peptide cytokine-responsive element. Thus, the sweat gland-derived differentiation activity uses the same signaling pathway as the neuropoietic cytokines, and is likely to be a family member.

Animals↗

PubMed1997

Protein kinase C regulates adenosine A2a receptor mRNA expression in SH-SY5Y cells.

Protein kinase C regulates mRNAs encoding several G protein-linked receptors but its role in adenosine A2a receptor expression is not known. We tested the hypothesis that protein kinase C activated by tetradecanoyl phorbol acetate (TPA) regulates adenosine A2a receptor mRNA levels. SH-SY5Y human neuroblastoma cells express adenosine receptors which positively couple to adenylyl cyclase with a pharmacologic profile expected of the A2a subtype. Northern blotting demonstrated an adenosine A2a receptor mRNA species of similar molecular size in SH-SY5Y cells and in human brain. TPA increased adenosine A2a receptor mRNA in a dose- and time-dependent fashion. Transcription or translation inhibition prevented increases in adenosine A2a receptor mRNA. Bisindolylmaleimide blocked TPA effects. Adenosine A2a receptor mRNA stability was unchanged by TPA. This study identifies a human neuroblastoma cell line expressing functional adenosine A2a receptors. Protein kinase C activation appears to enhance transcription of the adenosine A2a receptor gene.

Adenosine↗

PubMed1997

Integration of Jak-Stat and AP-1 signaling pathways at the vasoactive intestinal peptide cytokine response element regulates ciliary neurotrophic factor-dependent transcription.

Ciliary neurotrophic factor (CNTF)-dependent induction of expression of the neuropeptide vasoactive intestinal peptide (VIP) gene is mediated by a 180-base pair cytokine response element (CyRE) in the VIP promoter. To elucidate the molecular mechanisms mediating the transcriptional activation by CNTF, intracellular signaling to the CyRE has been studied in a neuroblastoma cell line. It has been shown previously that CNTF induces Stat proteins to bind to a site within the CyRE. CNTF also induces a second protein to bind to a C/EBP-like site within the CyRE. In this report, we show that this inducible CyRE binding protein is composed of the AP-1 proteins c-Fos, JunB, and JunD. These proteins bind to a non-canonical AP-1 site located near the previously characterized C/EBP site. The serine/threonine kinase inhibitor H7 prevents CNTF-dependent induction of AP-1 binding and CyRE-mediated transcription, suggesting that an H7-sensitive kinase is important to mediating CNTF effects on VIP transcription. The integration at the VIP CyRE of the Jak-Stat and AP-1 signaling pathways with other pre-existing proteins provides a cellular mechanism for cell- and cytokine-specific signaling.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1997

Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization.

Expression in striatum of c-Fos, a 35 kDa Fos-related antigen (FRA) and the phosphorylated form of cyclic AMP response element binding protein (phosphoCREB) was assessed using Western blots in rats that developed behavioral sensitization following repeated amphetamine administration. Treatment with d-amphetamine (5 mg/kg) for 5 consecutive days produced behavioral sensitization. Similar to previous observations using chronic cocaine administration, amphetamine sensitized animals had decreased c-Fos and increased FRA proteins in striatum. Supershift analysis with antisera to c-Fos and FRA proteins demonstrated that 4-Fos and the 35 kDa FRA are components of the striatal AP-1 binding complex from sensitized rats. Thus, amphetamine sensitization is accompanied by alterations in the composition of the AP-1 DNA binding complex. An increased amount of phosphoCREB protein was also present in the striatum of amphetamine sensitized rats. These results suggest that alterations in Fos, FRA and CREB transcription factors are common neuronal responses to chronic psychostimulant administration and may contribute to regulation of genes important to the neuroplastic changes underlying psychostimulant sensitization.

Activating Transcription Factor 2↗

PubMed1997

Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats.

Chronic treatment with dopaminergic agonists is associated with response fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D1 and D2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-depleted rodents this phenomenon has been referred to as "priming" or reverse tolerance. The neurochemical changes that underlie "priming" of dopaminergic agonist responses are poorly understood. Some aspects of priming of D1 agonist-mediated rotation in the 6-hydroxydopamine-lesioned rat have been characterized, but priming of D2-agonist-dependent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunoreactivity were used to investigate changes in the striatal outflow systems in response to treatment with the D2 agonist quinpirole in 6-hydroxydopamine-lesioned rats that had been primed with apomorphine. Administration of apomorphine (0.5 mg/kg; three injections at three to six day intervals) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to produce robust contralateral rotation and to induce the expression of Fos in striatal neurons belonging to the striato-nigro-entopeduncular ("direct") pathway. The increase in contralateral rotation and ipsilateral striatal Fos expression following administration of quinpirole to apomorphine-primed rats was mediated by a D2-like receptor and did not appear to be due to a change in sensitivity of D2 receptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the striatopallidal ("indirect") pathway. Western blot analysis confirmed that treatment with quinpirole induced the expression of c-Fos protein with no change in the expression of 35-37,000 mol. wt Fos-related antigens in apomorphine-primed rats treated with water or quinpirole. Induction of Fos expression in the striatum generally results from blockade of D2 receptors and the striato-nigro-entopeduncular pathway preferentially expresses D1 receptors. Thus, the quinpirole-dependent induction of striatal Fos in apomorphine-primed 6-hydroxydopamine-lesioned rats represents a qualitative alteration in striatal outflow. These studies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats with apomorphine increases the activity of the "direct" and "indirect" striatal outflow pathways in response to D2 receptor stimulation. These changes have the net result of enhancing thalamocortical activity and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, particularly in the striato-nigro-entopeduncular pathway, may contribute to alterations in D2-dependent motor responses observed after chronic dopaminergic stimulation in the dopamine-depleted striatum.

Animals↗

PubMed1997

Transplantation in Parkinson's disease.

The modification of nervous system function by cell replacement and the introduction of heterologous genes are being developed as possible therapeutic approaches in degenerative diseases of the nervous system. The use of cellular transplantation in the nervous system of patients with neurodegenerative diseases will be reviewed with an emphasis on Parkinson's disease.

Adrenal Medulla↗

PubMed1996

Synergistic interaction between an adenosine antagonist and a D1 dopamine agonist on rotational behavior and striatal c-Fos induction in 6-hydroxydopamine-lesioned rats.

The interaction between adenosine and D1 dopamine systems in regulating motor behavior and striatal c-Fos expression was examined in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. These results were compared to the synergistic interaction between D1 and D2 dopamine systems in 6-OHDA rats. Coadministration of the adenosine antagonist 3,7-dimethyl-1-propargylxanthine (DMPX: 10 mg/kg) and the D1 dopamine agonist SKF38393 (0.5 mg/kg) to 6-OHDA-lesioned rats produced significant contralateral rotation and c-Fos expression in the ipsilateral striatum compared to 6-OHDA rats treated with either drug alone. However, the regional pattern of striatal c-Fos activation following treatment of 6-OHDA rats with SKF38393 and DMPX was different from the dorsolateral pattern of striatal c-Fos induction observed after coadministration of D1 and D2 dopamine agonists (SKF38393: 0.5 mg/kg + quinpirole: 0.05 mg/kg). These data are consistent with a functional interaction between D1 dopamine and adenosine systems in the striatum, but suggest that activation of different subsets of striatal neurons underlie the behavioral synergy observed following combined adenosine antagonist-D1 dopamine agonist and combined D1 dopamine agonist-D2 dopamine agonist treatment.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1996

STAT proteins are activated by ciliary neurotrophic factor in cells of central nervous system origin.

Neuropoietic cytokines, including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), have survival effects on cells of the peripheral and central nervous systems (PNS and CNS). CNTF and LIF also produce differentiation in some cells of the PNS. We have shown previously that CNTF activates the signal transducers and activators of transcription (STAT) family of transcription factors, and that this signaling pathway may be one of several employed by CNTF to regulate the expression of the vasoactive intestinal peptide (VIP) gene in cells of the PNS (Symes et al.: Proc Natl Acad Sci USA 90:572-576, 1993; Symes et al.: Mol Endocrinol 8:1750-1763, 1994). To investigate the mechanisms of action of CNTF in the CNS, we have analyzed the activation of STAT proteins in a septal-derived cell line, SN48, and in primary CNS cultures. CNTF treatment of SN48 cells produces a sustained activation of Stat3. CNTF treatment of SN48 cells also activated transcription mediated by the VIP cytokine responsive element (CyRE) which contains a STAT binding site. Mutation of the STAT site in the CyRE attenuated transcriptional activation by CNTF, indicating the importance of STAT proteins to CNTF-dependent transcriptional activation of SN48 cells. In cultures of embryonic rat septum and other brain areas, in addition to Stat3, CNTF also activates Stat1. As in cells of the PNS and non-neuronal cells, the Janus kinase (Jak)-STAT pathway is activated in CNS cells by cytokines. The SN48 cell line may be valuable in further characterization of regulation of the Jak-STAT pathway by neuropoietic cytokines.

Animals↗

PubMed1996

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 A2a 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 N6-cyclohexyladenosine (CHA) or the adenosine A2a 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 A2a 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.

Adenosine↗