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Alessandro Tozzi,
Antonio de Iure,
Valentina Marsili,
Rosaria Romano,
Michela Tantucci,
Massimiliano Di Filippo,
Cinzia Costa,
Francesco Napolitano,
Nicola Biagio Mercuri, Franco Borsini,
Carmen Giampà,
Francesca Romana Fusco,
Barbara Picconi,
Alessandro Usiello,
Paolo Calabresi
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ABSTRACT: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents.
Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors.
The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine.
PLoS ONE 01/2012; 7(6):e38312. · 4.09 Impact Factor
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Alessandro Tozzi,
Antonio de Iure,
Massimiliano Di Filippo,
Michela Tantucci,
Cinzia Costa, Franco Borsini,
Veronica Ghiglieri,
Carmen Giampà,
Francesca Romana Fusco,
Barbara Picconi,
Paolo Calabresi
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ABSTRACT: A(2A) adenosine receptor antagonists are currently under investigation as potential therapeutic agents for Parkinson's disease (PD). However, the molecular mechanisms underlying this therapeutic effect is still unclear. A functional antagonism exists between A(2A) adenosine and D(2) dopamine (DA) receptors that are coexpressed in striatal medium spiny neurons (MSNs) of the indirect pathway. Since this interaction could also occur in other neuronal subtypes, we have analyzed the pharmacological modulation of this relationship in murine MSNs of the direct and indirect pathways as well in striatal cholinergic interneurons. Under physiological conditions, endogenous cannabinoids (eCBs) play a major role in the inhibitory effect on striatal glutamatergic transmission exerted by the concomitant activation of D(2) DA receptors and blockade of A(2A) receptors in both D(2)- and D(1)-expressing striatal MSNs. In experimental models of PD, the inhibition of striatal glutamatergic activity exerted by D(2) receptor activation did not require the concomitant inhibition of A(2A) receptors, while it was still dependent on the activation of CB(1) receptors in both D(2)- and D(1)-expressing MSNs. Interestingly, the antagonism of M1 muscarinic receptors blocked the effects of D(2)/A(2A) receptor modulation on MSNs. Moreover, in cholinergic interneurons we found coexpression of D(2) and A(2A) receptors and a reduction of the firing frequency exerted by the same pharmacological agents that reduced excitatory transmission in MSNs. This evidence supports the hypothesis that striatal cholinergic interneurons, projecting to virtually all MSN subtypes, are involved in the D(2)/A(2A) and endocannabinoid-mediated effects observed on both subpopulations of MSNs in physiological conditions and in experimental PD.
Journal of Neuroscience 02/2011; 31(5):1850-62. · 7.11 Impact Factor
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Vincenzo Belcastro,
Alessandro Tozzi,
Michela Tantucci,
Cinzia Costa,
Massimiliano Di Filippo,
Alessia Autuori,
Barbara Picconi,
Sabrina Siliquini,
Elisa Luchetti, Franco Borsini,
Paolo Calabresi
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ABSTRACT: Adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the experimental pharmacological therapy for Parkinson's disease (PD). Moreover, it has been postulated that A2A adenosine receptor antagonists exert neuroprotective effects in experimental models of PD and progressive supranuclear palsy (PSP). Interestingly, in both these pathological conditions a deficit of mitochondrial complex I has been found. Thus, utilizing extracellular and intracellular recordings from corticostriatal brain slices, we have tested the possible neuroprotective action of two A2A receptor antagonists, ST1535 and ZM241385, on the irreversible electrophysiological effects induced by the acute application of rotenone, a pesticide acting as a selective inhibitor of mitochondrial complex I activity. Both these antagonists reduced the rotenone-induced loss of corticostriatal field potential amplitude as well as the membrane depolarization caused by this toxin on striatal spiny neurons. The use of A2A receptor antagonists might represent a promising neuroprotective strategy in basal ganglia disorders involving a deficit of mitochondrial complex I activity.
Experimental Neurology 06/2009; 217(1):231-4. · 4.70 Impact Factor
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ABSTRACT: Adenosine and dopamine (DA) strongly modulate the neuronal activity in the striatum by pre- and postsynaptic mechanisms. As several behavioral and molecular studies indicate a functional antagonism between A2A adenosine and D2 DA receptors, compounds that are able to block A2A receptors are of particular interest as antiparkinsonian agents. To study the interaction of A2A and D2 receptors in the striatum, we performed intracellular recordings with sharp microelectrodes and whole-cell patch clamp recordings from spiny neurons in rat corticostriatal slices. The amplitude of the evoked excitatory postsynaptic potentials (EPSPs), as well as the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), were affected neither by the A2A receptor antagonists ST1535 and ZM241385, nor by the D2 receptor agonist quinpirole when applied in isolation. However, co-application of quinpirole and ST1535 or ZM241385 significantly reduced the EPSPs amplitude. This inhibitory effect was associated with an increased paired-pulse facilitation suggesting a presynaptic mechanism of action. Accordingly, whole-cell recordings showed that the concomitant activation of D2 receptors and the antagonism of A2A receptors decreased the frequency of sEPSCs without affecting their amplitude. These results suggest that A2A and D2 receptors converge in the control of corticostriatal glutamatergic transmission by exerting an opposite function.
Neuropharmacology 12/2007; 53(6):783-9. · 4.81 Impact Factor
