Biomedical subjects

Anton Terasmaa

Publications and source records attributed to Anton Terasmaa.

8 recordsLinked to original sources

PubMed2006

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain.

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.

Analysis of Variance↗

PubMed2005

Subchronic haloperidol increases CB(1) receptor binding and G protein coupling in discrete regions of the basal ganglia.

The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D(2) receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB(1) receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of (3)H-raclopride and quinpirole-induced guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) in the striatum when compared to that measured in control animals. This increased D(2) receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB(1) receptor binding and CP55,940-stimulated [(35)S]GTPgammaS in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus pallidus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB(1) receptor-stimulated [(35)S]GTPgammaS bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB(1) receptor or [(35)S]GTPgammaS binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB(1) receptor supersensitivity after haloperidol treatment.

Analgesics↗

PubMed2005

Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function.

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A -D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.

Animals↗

PubMed2004

Kinetic and functional properties of [3H]ZM241385, a high affinity antagonist for adenosine A2A receptors.

We have characterized the binding of [2-(3)H]-4-(2-[7-Amino-2-(2-furyl)-[1,2,4]-triazolo-[2,3-a]-[1,3,5]-triazin-5-ylamino]ethyl)phenol ([(3)H]ZM241385) to adenosine A(2A) receptors in membranes of rat striatum and transfected CHO cells. Saturation experiments showed that [(3)H]ZM241385 binds to a single class of binding sites with high affinity (K(d) = 0.23 nM and 0.14 nM in CHO cell and striatal membranes, respectively). The membranes of CHO cells required pretreatment with adenosine deaminase (ADA) to achieve high-affinity binding, while ADA had no influence on the ligand binding properties in striatal membranes. The binding of [(3)H]ZM241385 was fast and reversible, achieving equilibrium within 20 minutes at all radioligand concentrations. The kinetic analysis of the [(3)H]ZM241385 interaction with A(2A) receptors indicated that the reaction had at least two subsequent steps. The first step corresponds to a fast equilibrium, which also determines the antagonist potency to competitively inhibit CGS21680-induced accumulation of cAMP (first equilibrium constant K(A) = 6.6 nM). The second step corresponds to a slow process of conformational isomerization (equilibrium constant K(i) = 0.03). The combination of the two steps gives the dissociation constant K(d) = 0.20 nM based on the kinetic data, which is in good agreement with the directly measured value. The data obtained shed light on the mechanism of the [(3)H]ZM241385 interaction with adenosine A(2A) receptors from different sources in vitro. The isomerization step of the A(2A) antagonist radioligand binding has to be taken into account for the interpretation of the binding parameters obtained from the various competition assays and explain the discrepancy between antagonist affinity in saturation experiments versus its potency in functional assays.

Adenosine↗

PubMed2003

Hyperactivity to novelty induced by social isolation is not correlated with changes in D2 receptor function and binding in striatum.

RATIONALE: Prolonged social isolation has been reported to induce different behavioral disturbances, among the most consistent of which are the increased locomotor response to novelty and the effects of psychostimulants. While these behavioral changes have been partly related to a dysregulation of dopaminergic activity in striatum (dorsal and ventral), the involvement of changes in the function of dopamine receptors is still a matter of controversy. OBJECTIVES: To investigate the effects of prolonged social isolation on the function of D2 receptors at both the behavioral and biochemical levels. METHODS: Sprague-Dawley rats were randomly placed at 21 days of age in groups or isolation for 2 months. Horizontal and vertical locomotor activities induced by novelty and also by systemic injections of the D2 agonist quinpirole (0.15, 0.50 and 1.5 mg/kg i.p.) and their modulation by the A2A agonist CGS 21680 (0.1 mg/kg i.p.) were studied. The effects of social isolation on the avoidance learning assessed by the passive avoidance test were also studied. Binding experiments were performed to study the number and affinity of D2 receptors by means of saturation and competition experiments with the D2 antagonist [(3)H]-raclopride and the interaction between D2 receptors and the G-protein by means of [(35)S]-GTPgammas binding in dorsal/ventral striatal membranes of both grouped and isolated rats. RESULTS: Rats reared in isolation were hyperactive to a novel environment and showed shorter retention latencies in the passive avoidance test. Isolation rearing did not modify the increase in motor activity produced by quinpirole nor the counteraction of these effects by the simultaneous stimulation of A2A receptors. Likewise, the number, affinity and functional efficacy of D2 receptors were not changed by social isolation. CONCLUSIONS: These results suggest that the hyperactivity to novelty and psychostimulants as well as other behavioral changes induced by social isolation do not parallel changes in the in vivo function or binding of D2 receptors in dorsal/ventral striatum.

Animals↗

PubMed2003

Effect of denervation of the locus coeruleus projections by DSP-4 treatment on [3H]-raclopride binding to dopamine D(2) receptors and D(2) receptor-G protein interaction in the rat striatum.

Changes in the control of dopaminergic neurotransmission by noradrenergic locus coeruleus (LC) projections has been implicated in such disorders as depression, drug addiction, and Parkinson's disease. In the present study, the effect of DSP-4, a neurotoxin highly selective for LC projections, on D(2) receptor abundance as assessed by [3H]-raclopride binding in the striatum was studied in rats after administration in doses of 10 and 50 mg/kg either 3 days or 1 month before decapitation. Three days after DSP-4 the levels of noradrenaline in the frontal cortex were dose-dependently reduced; after 1 month, noradrenaline levels were lowered only by the higher dose. DOPAC levels were dose-dependently reduced in the frontal cortex and striatum 3 days but not 1 month after DSP-4 treatment. Cortical 5-HIAA levels were reduced 3 days but not 1 month after DSP-4. The apparent number of D(2) receptor binding sites in the striatum was higher 1 month after either dose of DSP-4. DSP-4 treatment had no effect on [3H]-raclopride binding affinity, the ability of dopamine (DA) to compete with [3H]-raclopride binding and to activate [35S]GTPgammaS binding or on the binding affinities of GDP and [35S]GTPgammaS for corresponding G proteins 1 month after administration of the neurotoxin. These data suggest that after administration of DSP-4, short-term reduction in DA and 5-HT metabolism occurs. Subsequently, an upregulation of D(2) receptor binding sites develops in the striatum even after a minor denervation of the LC projections. Thus, alterations in the LC projection systems elicit lasting adaptive changes in DA-ergic neurotransmission that can serve as a substrate for psychiatric disorders.

Animals↗

PubMed2003

Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.

The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 21680 by caffeine, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade.

Adenosine↗

PubMed2002

Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors.

Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A(2A) receptors (A(2A)R) and dopamine D(2) receptors (D(2)R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D(2)R and in cultured striatal cells. A(2A)R/D(2)R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D(2)R-transfected SH-SY5Y cells and from mouse fibroblast Ltk(-) cells stably transfected with human D(2)R (long form) and transiently cotransfected with the A(2A)R double-tagged with hemagglutinin. Long term exposure to A(2A)R and D(2)R agonists in D(2)R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A(2A)R and D(2)R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D(2)R are involved.

Animals↗