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Phasic activation by risk suggests that dopamine neurons represent the sum of exploration and exploitation value
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Selective inhibition by adenosine of mGluR IPSPs in dopamine neurons after cocaine treatment
No full textWith repeated exposure to psychostimulants such as cocaine and amphetamine, long lasting changes occur in the mesolimbic dopamine system that are thought to underlie continued drug-seeking and relapse. One consequence of repeated cocaine treatment is an increase in extracellular adenosine in the ventral tegmental area (VTA), which results in tonic inhibition of synaptic input to dopamine neurons. The synapse specificity of this increased adenosine tone was examined on glutamate- and GABA-mediated responses using the selective Al receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The slow, metabotropic glutamate receptor (mGluR)-mediated. inhibitory postsynaptic potential (IPSP) was enhanced by DPCPX only in slices from psychostimulant-treated animals. Under resting conditions, DPCPX was without effect on fast excitatory postsynaptic currents (EPSCs) in slices from saline- or cocaine-treated animals. However, in the presence of amphetamine, DPCPX did augment fast EPSCs in slices from cocaine-treated rats. Although DPCPX increased GABA, IPSPs, the magnitude of the increase was not altered by cocaine pretreatment, even in the presence of amphetamine. This suggests that the elevated adenosine tone induced by cocaine treatment acts preferentially on glutamate terminals. Furthermore, the inhibition of the mGluR IPSP by endogenous adenosine may result in more effective burst firing mediated by glutamate afferents in cocaine-treated rats, a phenomenon known to enhance dopamine release
Cholinergic inhibition of ventral midbrain dopamine neurons
No full textMuscarinic acetylcholine receptors are common throughout the CNS. The predominant subtypes in the brain are positively coupled to phosphoinositide hydrolysis and have been found to modulate multiple conductances. Muscarinic receptor activation is most often observed to be excitatory because of suppression of various potassium conductances. Here it is reported that three distinct effects of muscarinic receptor activation can be observed in isolation from one another, depending on the duration of receptor activation and the concentration of agonist. Brief activation of muscarinic receptors, as is likely to occur with normal synaptic transmission, hyperpolarized dopamine neurons of the ventral midbrain through a calcium-activated potassium conductance. With repeated or persistent activation of muscarinic receptors, the hyperpolarizing response was entirely desensitized in the absence of any change in resting membrane potential. With sustained activation by higher concentrations of agonist, dopamine neurons were depolarized. This demonstrates that muscarinic receptors can mediate very diverse, and even opposing, postsynaptic effects on neurons depending on the pattern of acetylcholine release
Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons
No full textRapid information transfer within the brain depends on chemical signalling between neurons that is mediated primarily by glutamate and GABA (gamma-aminobutyric acid), acting at ionotropic receptors to cause excitatory or inhibitory postsynaptic potentials (EPSPs or IPSPs), respectively. In addition, synaptically released glutamate acts on metabotropic receptors to excite neurons on a slower timescale through second-messenger cascades, including phosphoinositide hydrolysis'. We now report a unique IPSP mediated by the activation of metabotropic glutamate receptors. Tn ventral midbrain dopamine neurons, activation of metabotropic glutamate receptors (mGluR1) mobilized calcium from caffeine/ryanodine-sensitive stores and increased an apamin-sensitive potassium conductance. The underlying potassium conductance and dependence on calcium stores set this IPSP apart from the slow IPSPs described so far(2-4). The mGluR-induced hyperpolarization was dependent on brief exposure to agonist, because prolonged application of exogenous agonist desensitized the hyperpolarization and caused the more commonly reported depolarization(1,5,6). The rapid rise and brief duration of synaptically released glutamate in the extracellular space can therefore mediate a rapid excitation through activation of ionotropic receptors, followed by inhibition through the mGluR1 receptor. Thus the idea that glutamate is solely an excitatory neurotransmitter must be replaced with a more complex view of its dual function in synaptic transmission
Opioid desensitization: Interactions with G-protein-coupled receptors in the locus coeruleus
No full textIn rat locus coeruleus (LC) neurons, alpha(2) adrenoceptors, mu-opioid and somatostatin receptors all activate the same potassium conductance. Chronic treatment with morphine causes a loss of sensitivity that is specific to the mu-opioid response, with no change in the alpha(2) adrenoceptor-mediated response. Acute desensitization induced by opioid, somatostatin, and alpha(2)-adrenoceptor agonists was studied in brain slices of rat LC using intracellular recording, A supramaximal concentration of the opioid agonist Met(5)-enkephalin induced a profound homologous desensitization but little heterologous desensitization to an alpha(2)-adrenoceptor agonist (UK 14304) or somatostatin, All desensitized currents showed partial recovery. A supramaximal concentration of UK14304 caused a relatively small amount of desensitization. Although little interaction was observed among inhibitory G-protein-coupled receptors, activation of an excitatory receptor had marked effects on inhibitory responses. Muscarinic agonists, which produce an inward current in LC neurons, reduced the magnitude of agonist-induced outward currents and increased both the rate and amount of opioid desensitization. Muscarinic activation did not alter desensitization of alpha(2)-adrenoceptor responses. Acute desensitization shares several characteristics with the tolerance induced by chronic morphine treatment of animals
A-type potassium channels as a mechanism for predictive homeostasis of membrane excitability.
Full text linkNeurons exhibit a great diversity of homeostatic mechanisms, including a large number of K+ channel subtypes that maintain neuronal excitability. Consistent with principles of “efficient coding” (Barlow, 1961), it has been proposed that the diversity of K+ channels allows neurons to predict and counteract diverse temporal patterns of synaptic excitation, a phenomenon which could be called “predictive homeostasis” (Fiorillo, 2008). According to this theory, the particular K+ channels expressed by a neuron should have properties that are matched to the statistically common temporal patterns of synaptic excitation that the neuron experiences. As a result, the neuron’s output would correspond to “prediction error,” and the neuron’s information about its stimulus would tend to be maximized. If the theory is correct, then it should be possible to predict the properties of K+ channels given knowledge of common patterns of synaptic excitation. We focus here on A-type K+ channels, which are distinguished by their strong and rapid inactivation
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