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Antonello Bonci

Publications and source records attributed to Antonello Bonci.

At least 19 recordsLinked to original sources
PubMed2006

Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors.

Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D1/D5 receptor agonist. The effect of cocaine was blocked by a DA D1/D5 receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2B and their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D5-like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors.

Animals↗
PubMed2006

Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens.

The core and shell of the nucleus accumbens have critical, differential roles in drug-dependent behaviors. Here we show that operant cocaine self-administration inhibits long-term depression (LTD) in both structures after 1 d of abstinence. However, after 21 d of abstinence, LTD was abolished exclusively in the nucleus accumbens core of cocaine self-administering rats, suggesting that voluntary cocaine self-administration induced long-lasting neuroadaptations in the core that could underlie drug-seeking behavior and relapse.

Animals↗
PubMed2006

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.

Analysis of Variance↗
PubMed2005

The dopamine D2 receptor: new surprises from an old friend.

Drugs acting at dopamine D2 receptors (D2R) are commonly used to alleviate symptoms produced by diseases such as Parkinson's disease, schizophrenia, and depression. A limitation to the use of these drugs is that they sometimes afflict patients with severe side effects. This review discusses recent evidence for several proteins that represent novel mediators of the downstream consequences of D2R activation, since selective targeting of particular D2R-mediated signaling pathways could lead to the development of improved treatments for these devastating diseases.

Animals↗
PubMed2005

Dopamine responsiveness is regulated by targeted sorting of D2 receptors.

Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

Animals↗
PubMed2005

Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras.

The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B- to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity.

Adaptor Protein Complex 2↗
PubMed2005

Atypical protein kinase C is a novel mediator of dopamine-enhanced firing in nucleus accumbens neurons.

Current concepts suggest that nucleus accumbens (NAcb) dopamine mediates several motivated and addictive behaviors. Although the role of protein kinase A (PKA) and dopamine and cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa in NAcb dopamine receptor throughput has been studied extensively, the contribution of protein kinase C (PKC) to NAcb firing is poorly understood. Here we show that dopamine-mediated enhancement of spike firing in NAcb shell medium spiny neurons was prevented by the PKC inhibitor bisindolylmaleimide but not by the phospholipase C inhibitor 1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione, suggesting a role for a diacylglycerol-independent atypical PKC (aPKC) isoform. In this regard, modulation of firing by dopamine was prevented by intracellular perfusion of a pseudosubstrate peptide inhibitor for aPKCs. We also provide evidence, using an in vitro kinase assay, that dopamine receptor activation increased aPKC activity in striatal membranes. Finally, direct activation of PKA with forskolin enhanced firing even during inhibition of aPKCs, suggesting that aPKCs acted upstream of PKA activation. Thus, aPKCs appear to mediate dopaminergic enhancement of spike firing in the NAcb shell, and may therefore play a critical role in NAcb- and dopamine-dependent goal-directed behaviors.

Action Potentials↗
PubMed2005

Synaptic plasticity and drug addiction.

Recent studies have suggested that the development of addictive behaviours shares common features with traditional learning models. Synaptic plasticity, a possible substrate for learning, has been demonstrated in neural reward circuits and might contribute to the learning of addictive behaviours. Changes in the strength of synaptic connections have been investigated in dopaminergic cells of the ventral tegmental area in response to several addictive drugs. Rapid and persistent forms of synaptic plasticity (specifically, long-lasting synaptic potentiation) have been demonstrated to accompany some of the behavioural effects of addictive drugs. We hypothesize that drug-induced synaptic plasticity might play a role in reward-related learning and addiction by modifying the fine tuning of dopaminergic cell firing.

Brain↗
PubMed2005

Ion channels and intracellular signaling proteins as potential targets for novel therapeutics for addictive and depressive disorders.

Modern neuroscience is placing increased emphasis on understanding how the activity of ion channels and intracellular molecules in the central nervous system affect behavior. An improved understanding of the brain and the biological bases of conditions such as addictive and depressive disorders is important because it should ultimately enable the design of innovative treatments for these conditions. The development of rational therapies that are based on knowledge of what is different about the addicted or depressed brain would be an important advance. Here, we describe how multidisciplinary studies that combine numerous approaches (behavioral analysis, physiology, molecular biology, and genetic engineering) have begun to provide important advances that have helped to establish causal relationships between the pathophysiology of these conditions and behavior. This type of work has identified classes of molecules on the outside of cells (receptors and ion channels) that receive signals from other cells and initiate cellular events that have short-term effects on the neurons. It has also identified other classes of molecules that are inside of cells (signal transduction molecules) that can have immediate effects on cell function (e.g., ion channel phosphorylation), as well longer term effects (alterations in protein expression) that affect the ways in which neurons function within circuits. Innovative treatments that block, negate, or even reverse the extracellular or intracellular neuroadaptations resulting from exposure to drugs of abuse or stress might be more effective than current therapies because they directly target the molecular processes that cause maladaptive behaviors.

Animals↗
PubMed2004

Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.

The ventral tegmental area (VTA) plays a critical role in motivation and reinforcement. Kappa and mu opioid receptor (KOP-R and MOP-R) agonists microinjected into the VTA produce powerful and largely opposing motivational actions. Glutamate transmission within the VTA contributes to these motivational effects. Therefore information about opioid control of glutamate release onto VTA neurons is important. To address this issue, we performed whole cell patch-clamp recordings in VTA slices and measured excitatory postsynaptic currents (EPSCs). There are several classes of neuron in the VTA: principal, secondary, and tertiary. The KOP-R agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593; 1 microM) produced a small reduction in EPSC amplitude in principal neurons (14%) and a significantly larger inhibition in secondary (47%) and tertiary (33%) neurons. The MOP-R agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO; 3 microM) inhibited glutamate release in principal (42%), secondary (45%), and tertiary neurons (35%). Unlike principal and tertiary neurons, in secondary neurons, the magnitude of the U69593 EPSC inhibition was positively correlated with that produced by DAMGO. Finally, DAMGO did not occlude the U69593 effect in principal neurons, suggesting that some glutamatergic terminals are independently controlled by KOP and MOP receptor activation. These findings show that MOP-R and KOP-R agonists regulate excitatory input onto each VTA cell type.

Analgesics, Opioid↗
PubMed2004

Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats.

The initiation of the psychostimulant sensitization process depends on the mesolimbic system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens. Although such initiation is primarily dependent on glutamatergic activity in VTA neurons, the exact role VTA excitatory synapses play in this process is poorly understood. Here, we examine the effects of repeated in vivo injections of cocaine on the magnitude and duration of the increase in strength at VTA excitatory synapses reported previously to be elicited by a single in vivo exposure to cocaine (Ungless et al., 2001; Saal et al., 2003). We also compare the synaptic modifications induced by cocaine with its effects on locomotor activity. Surprisingly, repeated cocaine exposure potentiated the ratio of AMPA receptor-mediated to NMDA receptor-mediated EPSCs to a similar extent and duration as a single in vivo cocaine exposure. In naive animals, the magnitude of the cocaine-induced locomotor activity after a single injection of cocaine correlated with the magnitude of the accompanying synaptic enhancement. This correlation was lost on the seventh day of repeated cocaine administration, as well as when a challenge injection was given 10 d after the cessation of repeated cocaine administration. These results suggest that the cocaine-induced synaptic plasticity at VTA excitatory synapses is transient, and its duration depends on the last exposure to cocaine. Furthermore, chronic cocaine exposure disrupts the normal, presumably adaptive relationship between synaptic enhancement in the VTA and behavior.

Animals↗
PubMed2004

The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference.

Adenosine is an important mediator of ethanol intoxication. In vitro, ethanol stimulates adenosine signaling by inhibiting the type 1 equilibrative nucleoside transporter (ENT1), whereas chronic ethanol exposure downregulates ENT1. It is not known, however, whether ENT1 is important for ethanol intoxication or consumption in vivo. Here we report that ENT1-null mice show reduced hypnotic and ataxic responses to ethanol and greater consumption of alcohol as compared with their wild-type littermates. These features are associated with a decrease in adenosine tone, as measured indirectly as a reduction in A(1) receptor-mediated inhibition of glutamate excitatory postsynaptic currents (EPSCs) in the nucleus accumbens, leading to increased phosphorylation of CRE-binding protein (CREB) in the striatum. Treatment with an A(1) receptor agonist decreases EPSC amplitude and reduces ethanol consumption in ENT1-null mice. Our results indicate that ENT1 has a physiological role in ethanol-mediated behaviors and suggest that decreased A(1) adenosine receptor function promotes alcohol consumption.

Adenosine↗
PubMed2004

Recent advances in cyclic-adenosine monophosphate/protein kinase A signaling in ethanol-induced synaptic and behavioral alterations.

This article represents the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, California, organized and co-chaired by L. Judson Chandler and Richard A. Morrisett. The presentations were (1) PKA regulates chronic ethanol-induced synaptic targeting of NMDA receptors, by L. Judson Chandler; (2) Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure, by Antonello Bonci; (3) The DARPP-32 cascade and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens, by Richard A. Morrisett; (4) and The cAMP/PKA signal transduction pathway modulates ethanol consumption and sedative effects of ethanol, by Gary S. Wand.

Animals↗
PubMed2003

A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans.

The activities of many neuronal proteins are modulated by ethanol, but the fundamental mechanisms underlying behavioral effects of ethanol remain unclear. To identify mechanisms responsible for intoxication, we screened for Caenorhabditis elegans mutants with altered behavioral responses to ethanol. We found that slo-1 mutants, which were previously recognized as having slightly uncoordinated movement, are highly resistant to ethanol in two behavioral assays. Numerous loss-of-function slo-1 alleles emerged from our screens, indicating that slo-1 has a central role in ethanol responses. slo-1 encodes the BK potassium channel. Electrophysiological analysis shows that ethanol activates the channel in vivo, which would inhibit neuronal activity. Moreover, behaviors of slo-1 gain-of-function mutants resemble those of ethanol-intoxicated animals. These results demonstrate that selective activation of BK channels is responsible for acute intoxicating effects of ethanol in C. elegans. BK channel activation may explain a variety of behavioral responses to ethanol in invertebrate and vertebrate systems.

Amino Acid Sequence↗
PubMed2003

Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons.

Dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement of goal-directed behaviors. Furthermore, excitation of these neurons has been implicated in the addictive process initiated by drugs such as morphine that act at the micro-opioid receptor (MOR). In contrast, kappa-opioid receptor (KOR) activation in the VTA produces behavioral actions opposite to those elicited by MOR activation. The mechanism underlying this functional opposition, however, is poorly understood. VTA neurons have been categorized previously as principal, secondary, or tertiary on the basis of electrophysiological and pharmacological characteristics. In the present study using whole-cell patch-clamp recordings, we demonstrate that a selective KOR agonist (U69593, 1 microm) directly inhibits a subset of principal and tertiary but not secondary neurons in the VTA. This KOR-mediated inhibition occurs via the activation of a G-protein-coupled inwardly rectifying potassium channel and is blocked by the selective KOR antagonist nor-Binaltorphimine (100 nm). Significantly, regardless of cell class, KOR-mediated inhibition was found only in tyrosine hydroxylase-immunoreactive and thus dopaminergic neurons. In addition, we found a subset of principal neurons that exhibited both disinhibition by a selective MOR agonist ([d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) (3 microm) and direct inhibition by KOR agonists. These results provide a cellular mechanism for the opposing behavioral effects of KOR and MOR agonists and shed light on how KORs might regulate the motivational effects of both natural rewards and addictive drugs.

Analgesics↗
PubMed2003

Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons.

Stress increases addictive behaviors and is a common cause of relapse. Corticotropin-releasing factor (CRF) plays a key role in the modulation of drug taking by stress. However, the mechanism by which CRF modulates neuronal activity in circuits involved in drug addiction is poorly understood. Here we show that CRF induces a potentiation of NMDAR (N-methyl-D-aspartate receptor)-mediated synaptic transmission in dopamine neurons of the ventral tegmental area (VTA). This effect involves CRF receptor 2 (CRF-R2) and activation of the phospholipase C (PLC)-protein kinase C (PKC) pathway. We also find that this potentiation requires CRF binding protein (CRF-BP). Accordingly, CRF-like peptides, which do not bind the CRF-BP with high affinity, do not potentiate NMDARs. These results provide evidence of the first specific roles for CRF-R2 and CRF-BP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for both drugs of abuse and stress.

Animals↗
PubMed2003

Cooperative activation of dopamine D1 and D2 receptors increases spike firing of nucleus accumbens neurons via G-protein betagamma subunits.

Dopamine in the nucleus accumbens modulates both motivational and addictive behaviors. Dopamine D1 and D2 receptors are generally considered to exert opposite effects at the cellular level, but many behavioral studies find an apparent cooperative effect of D1 and D2 receptors in the nucleus accumbens. Here, we show that a dopamine-induced enhancement of spike firing in nucleus accumbens neurons in brain slices required both D1 and D2 receptors. One intracellular mechanism that might underlie cooperativity of D1 and D2 receptors is activation of specific subtypes of adenylyl cyclases by G-protein betagamma subunits (Gbetagamma) released from the Gi/o-linked D2 receptor in combination with Galpha(s)-like subunits from the D1 receptor. In this regard, dopaminergic enhancement of spike firing was prevented by inhibitors of protein kinase A or Gbetagamma. Furthermore, intracellular perfusion with Gbetagamma enabled D1 receptor activation but not D2 receptor activation to enhance spike firing. Finally, our data suggest that these pathways may increase spike firing by inhibition of a slow A-type potassium current. These results provide evidence for a novel cellular mechanism through which cooperative action of D1 and D2 receptors in the nucleus accumbens could mediate dopamine-dependent behaviors.

Action Potentials↗