- Email: [email protected]
Opioid-Induced Adaptations of cAMP Dynamics in the Nucleus Accumbens
TIPS 1687 No. of Pages 3
Trends in Pharmacological Sciences
Spotlight
Opioid-Induced Adaptations of cAMP Dynamics in the Nucleus Accumbens 1
Sarah Zych and Christopher P. Ford1,* To investigate how opioid exposure alters dopamine (DA) responses in medium spiny neurons (MSNs), Muntean et al. used a novel cAMP sensor to track cAMP dynamics and report a coordinated effort of adaptations in D1- and D2-MSNs to integrate DA inputs and shift signaling strengths in various states of opioid dependence. Opioid receptors are Gα i/o -coupled G-protein-coupled receptors (GPCRs) that, when activated, inhibit cellular excitability and synaptic transmission. Opioids modulate synaptic transmission broadly throughout the brain owing to the wide distribution of these receptors. Acute opioid receptor activity has been reported to: inhibit adenylyl cyclase (AC), thus decreasing cAMP; activate potassium conductance; inhibit calcium conductance; and reduce neurotransmitter release [1,2]. Conversely, chronic opioid exposure increases AC and cyclic AMP-dependent protein kinase activity in several brain regions [3].
D1 receptors to produce an increase in cAMP through activation of AC, and decreasing cAMP by activating D2 receptors to inhibit AC. It is well documented that opioid exposure alters signaling in numerous brain circuits. Studies examining D1-MSN and D2-MSN pathways have found that the rewarding effects of drugs of abuse (opioids) are mediated by D1-MSN activity, while aversion is mediated by D2-MSN activity [4]. One of the most robust adaptations to repeated opioid exposure is the upregulation of AC activity and enhanced responsiveness to drugstimulated cAMP accumulation, known as AC supersensitization [6,7]. The molecular mechanisms of AC supersensitization vary depending on the isoform of AC, because different isoforms have distinct regulatory properties and, thus, modulate cAMP with distinct spatiotemporal dynamics. Tracking the modulation of cAMP concentration provides a readout of the regulation exerted by opioid receptors or other GPCRs.
in vivo alters the processing of DA inputs in MSNs in the NAc [9]. Using acute brain slices from CAMPER mice to measure cAMP levels, the authors found that morphine exposure differentially adjusted the response strength of D1- and D2-MSNs to DA inputs depending upon the opioid exposure paradigm, which modeled either acute exposure, chronic exposure, or withdrawal from chronic exposure. A single injection of morphine, modeling acute morphine exposure, resulted in a significant increase in baseline cAMP levels in D1-MSNs, whereas no change occurred in D2-MSNs. This cAMP increase in D1-MSNs supports previous findings that upregulated cAMP pathways following acute opioid exposure are D1 receptor mediated [10]. To investigate cAMP dynamics following the activation of D1 or D2 receptors, the authors expressed channelrhodopsin, a light-activated ion channel, in DA neurons, allowing optical stimulation of DA neurons to evoke DA release. Following acute morphine exposure, both D1- and D2-MSNs displayed reduced cAMP responses to evoked DA release, but to differing degrees, with D2-MSNs exhibiting a greater reduction. To better understand how opioid-induced adaptations affect signal integration of DA inputs, the researchers then measured cAMP levels produced by a range of stimulated DA neuron-firing frequencies after acute morphine exposure. They found that the cAMP response to phasic DA release, which encodes reward signals in the NAc, was reduced in D1-MSNs, while the cAMP response to maximum stimulation frequencies was reduced in D2-MSNs. By equating cAMP responses to the magnitude of signaling strength in MSNs, the authors propose that acute morphine adjusts cAMP dynamics such that D1-MSNs maintain maximal signaling strength, while the signaling strength of D2-MSNs is suppressed.
How inputs generate distinct secondmessenger effects in a cell- and receptorspecific manner within intact brain circuits is poorly understood. To study how GPCRs generate distinct secondary messenger cascades, Muntean et al. previously developed a cAMP-encoded reporter (CAMPER) mouse encoding the cAMP sensor TEpacVV, which reports cAMP binding by measuring changes in Förster resonance energy transfer (FRET) with In the nucleus accumbens (NAc), conver- high sensitivity and in real time [8]. The augence of diverse neural inputs drives thors demonstrated the validity and utility of two main subtypes of GABAergic MSN: this sensor by resolving the spatiotemporal D1-MSN and D2-MSNs. D1- and D2-MSN profiles of cAMP signaling in MSNs prosubtypes differ in their receptor expression, duced by different receptor agonists (DA, the brain regions they innervate, and adenosine, acetylcholine, and morphine). their functional roles [4]. DA actions on This novel in vivo tool allows the study of D1-MSNs signal through Gαolf/s-coupled cAMP dynamics, which provide insight into GPCRs to exert excitatory downstream sig- how GPCRs integrate inputs to produce naling, whereas DA actions on D2-MSNs distinct profiles of intracellular signaling. Since repeated exposure to opioids is serve to inhibit neuronal excitability through Gαi/o-coupled D2 receptors [5]. DA modu- In their recent work, the authors applied known to cause long-term cellular and cirlates cAMP levels in MSNs by activating this tool to explore how morphine exposure cuit adaptations, the authors next examined Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
1
Trends in Pharmacological Sciences
the effects of chronic opioid exposure, including intermittent opioid exposure to model tolerance, and abstinence following repeated exposures to model withdrawal. They found that chronic morphine exposure reversed the basal changes seen in acute exposure D1-MSNs, such that basal cAMP levels were significantly reduced, yet the response amplitude to DA was unchanged. Conversely, basal cAMP levels in D2MSNs sharply increased with an accompanying increase in DA response compared with acute exposure D2-MSNs. This suggests that the relative signaling strength of D2 receptors is increased after chronic morphine. In the abstinence model, after a 24-h withdrawal from chronic exposure, D1- and D2-MSNs displayed similarly reduced and elevated basal cAMP levels, respectively, compared with the tolerance state. Together, both chronic exposure and abstinence appear to reduce the signaling strength of D1-MSN while preserving output from D2-MSNs. The finding that opioid exposure differentially alters the signaling of MSN subtypes raises the question of what molecular mechanisms underlie these changes in response properties. The authors investigated the role of presynaptic dopamine transporters (DATs) and postsynaptic phosphodiesterases (PDEs) in shaping MSN responses to DA inputs following morphine exposure. DAT inhibition by cocaine increased DA availability and resulted in increased cAMP response amplitude in D1-MSNs and decreased response in D2-MSNs. A comparison of the cAMP response to varied stimulation frequencies revealed that, in the naïve state, absent of opioid exposure, DATs selectively limited the sensitivity of D1-MSNs to phasic DA stimulation, whereas, following acute morphine exposure, the role of DATs shifted toward limiting the sensitivity of D2-MSNs to DA. In the naïve state, inhibition of postsynaptic PDEs, the enzymes that metabolize 2
cAMP, increased basal cAMP levels in both MSN subtypes, as expected, but only modulated DA-driven cAMP levels in D2-MSNs. Acute morphine exposure broadened the role of PDEs to limit peak cAMP responses in D1-MSNs; however, this may be due to limitations of cAMP production because acute morphine increases basal cAMP levels. PDEs were also found to tune D1 -sensitivity to DA during highfrequency stimulation, whereas, after morphine, PDEs no longer modulated response sensitivity in D1-MSNs. These results suggest that the role of DATs and PDEs in modulating DA-driven cAMP responses differs between D1- and D2MSNs in opioid exposure. It will be important to further probe the intracellular mechanisms underlying opioid-induced changes in signaling.
how selective neuronal populations integrate and process neurotransmitter inputs.
Given that opioid exposure is known to alter DA signaling [11,12], long-term opioid-induced DA changes likely cause neuroadaptations in local NAc circuitry between MSNs and interneurons. Moving forward, it will be important to study the effects of morphine on cAMP responses across other NAc neuron populations, including cholinergic interneurons, which provide extensive local innervation and are key modulators of NAc microcircuits. These interneurons modulate MSN activity both directly through muscarinic receptors and indirectly through nicotinic receptormediated DA release [13,14]. Given that cholinergic interneurons also have a documented role in behavioral responses to drugs of abuse [15], determining drugFinally, to better understand and visualize induced shifts in cAMP dynamics in cholinthese opioid-induced changes in MSN ergic interneurons will expand our undersignaling, the authors modeled the data standing of striatal circuit adaptations in using principal component analysis (PCA) addiction. to simplify their multidimensional data and identify key correlated variables of Since the initial observation that opioids cAMP parameters, including basal cAMP upregulate the cAMP pathway in the levels, response amplitudes, and signaling NAc, significant advances have been duration. PCA showed that D1-MSNs made in understanding the role of cAMP displayed enhanced signaling only after in drug addiction. Interestingly, equivalent acute morphine exposure and sup- cAMP adaptations in the NAc are induced pressed signaling during tolerance and by both chronic morphine and cocaine, abstinence, whereas D2-MSNs exhibited but not by nonabused psychoactive suppressed signaling after acute mor- drugs [3]. This suggests that, within the phine and enhanced signaling during toler- NAc, upregulation of cAMP mediates reance and abstinence. When the signaling ward tolerance and dependence. This scores of D1- and D2-MSNs were com- also points to a possible common mechabined, the result was a net increase in nism underlying the reinforcing behavior of D1-MSN signaling during acute morphine addiction. The findings from Muntean et al. exposure that reversed to a net increase [9] support a shift in reward valuation in adin D2-MSN signaling during the tolerance diction, mediated by changes in the signaland abstinence paradigms. This model ing strength of NAc D1- and D2-MSNs. It aligns with the current theory that is unknown whether similar populationD1-MSNs are associated with encoding specific adaptations occur due to other the acute reward induced by opioids, classes of drugs of abuse, such as stimuwhile D2-MSNs contribute to aversive lants and alcohol. It would be interesting phenotypes seen in tolerance and with- to apply this tool to determine whether drawal [4]. Thus, these findings support equivalent adaptations occur in NAc the concept of drug-induced shifts in MSNs in various types of addiction,
Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
Trends in Pharmacological Sciences
substance and behavioral, and whether shared mechanisms underlie addiction, tolerance, and dependence. Acknowledgements This work was supported by National Institutes of Health (NIH) Grants DA35821 (C.P.F.), NS95809
3.
4.
(C.P.F.), and F30-DA48543 (S.Z.).
5.
1
6.
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA *Correspondence: [email protected] (C.P. Ford).
7.
https://doi.org/10.1016/j.tips.2020.01.004 © 2020 Elsevier Ltd. All rights reserved.
References 1. Taussig, R. et al. (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261, 218–221 2. Torrecilla, M. et al. (2002) G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate
8.
9.
the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 22, 4328–4334 Terwilliger, R.Z. et al. (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res. 548, 100–110 Kravitz, A.V. et al. (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 Gerfen, C.R. and Surmeier, D.J. (2011) Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 Sharma, S.K. et al. (1975) Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc. Natl. Acad. Sci. U. S. A. 72, 3092–3096 Thomas, J.M. and Hoffman, B.B. (1996) Isoform-specific sensitization of adenylyl cyclase activity by prior activation of inhibitory receptors: role of beta gamma subunits in transducing enhanced activity of the type VI isoform. Mol. Pharmacol. 49, 907–914 Muntean, B.S. et al. (2018) Interrogating the spatiotemporal landscape of neuromodulatory GPCR signaling by realtime imaging of cAMP in intact neurons and circuits. Cell Rep. 22, 255–268 Muntean, B.S. et al. (2019) Allostatic changes in the cAMP system drive opioid-induced adaptation in striatal dopamine signaling. Cell Rep. 29, 946–960
10. Borgkvist, A. et al. (2007) Activation of the cAMP/PKA/ DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. Neuropsychopharmacology 32, 1995–2003 11. Mazei-Robison, M.S. et al. (2011) Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72, 977–990 12. Koo, J.W. et al. (2012) BDNF is a negative modulator of morphine action. Science 338, 124–128 13. Mamaligas, A.A. and Ford, C.P. (2016) Spontaneous synaptic activation of muscarinic receptors by striatal cholinergic neuron firing. Neuron 91, 574–586 14. Zhou, F.M. et al. (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat. Neurosci. 4, 1224–1229 15. Mark, G.P. et al. (2006) Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats. Brain Res. 1123, 51–59
Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
3
Trends in Pharmacological Sciences
Spotlight
Opioid-Induced Adaptations of cAMP Dynamics in the Nucleus Accumbens 1
Sarah Zych and Christopher P. Ford1,* To investigate how opioid exposure alters dopamine (DA) responses in medium spiny neurons (MSNs), Muntean et al. used a novel cAMP sensor to track cAMP dynamics and report a coordinated effort of adaptations in D1- and D2-MSNs to integrate DA inputs and shift signaling strengths in various states of opioid dependence. Opioid receptors are Gα i/o -coupled G-protein-coupled receptors (GPCRs) that, when activated, inhibit cellular excitability and synaptic transmission. Opioids modulate synaptic transmission broadly throughout the brain owing to the wide distribution of these receptors. Acute opioid receptor activity has been reported to: inhibit adenylyl cyclase (AC), thus decreasing cAMP; activate potassium conductance; inhibit calcium conductance; and reduce neurotransmitter release [1,2]. Conversely, chronic opioid exposure increases AC and cyclic AMP-dependent protein kinase activity in several brain regions [3].
D1 receptors to produce an increase in cAMP through activation of AC, and decreasing cAMP by activating D2 receptors to inhibit AC. It is well documented that opioid exposure alters signaling in numerous brain circuits. Studies examining D1-MSN and D2-MSN pathways have found that the rewarding effects of drugs of abuse (opioids) are mediated by D1-MSN activity, while aversion is mediated by D2-MSN activity [4]. One of the most robust adaptations to repeated opioid exposure is the upregulation of AC activity and enhanced responsiveness to drugstimulated cAMP accumulation, known as AC supersensitization [6,7]. The molecular mechanisms of AC supersensitization vary depending on the isoform of AC, because different isoforms have distinct regulatory properties and, thus, modulate cAMP with distinct spatiotemporal dynamics. Tracking the modulation of cAMP concentration provides a readout of the regulation exerted by opioid receptors or other GPCRs.
in vivo alters the processing of DA inputs in MSNs in the NAc [9]. Using acute brain slices from CAMPER mice to measure cAMP levels, the authors found that morphine exposure differentially adjusted the response strength of D1- and D2-MSNs to DA inputs depending upon the opioid exposure paradigm, which modeled either acute exposure, chronic exposure, or withdrawal from chronic exposure. A single injection of morphine, modeling acute morphine exposure, resulted in a significant increase in baseline cAMP levels in D1-MSNs, whereas no change occurred in D2-MSNs. This cAMP increase in D1-MSNs supports previous findings that upregulated cAMP pathways following acute opioid exposure are D1 receptor mediated [10]. To investigate cAMP dynamics following the activation of D1 or D2 receptors, the authors expressed channelrhodopsin, a light-activated ion channel, in DA neurons, allowing optical stimulation of DA neurons to evoke DA release. Following acute morphine exposure, both D1- and D2-MSNs displayed reduced cAMP responses to evoked DA release, but to differing degrees, with D2-MSNs exhibiting a greater reduction. To better understand how opioid-induced adaptations affect signal integration of DA inputs, the researchers then measured cAMP levels produced by a range of stimulated DA neuron-firing frequencies after acute morphine exposure. They found that the cAMP response to phasic DA release, which encodes reward signals in the NAc, was reduced in D1-MSNs, while the cAMP response to maximum stimulation frequencies was reduced in D2-MSNs. By equating cAMP responses to the magnitude of signaling strength in MSNs, the authors propose that acute morphine adjusts cAMP dynamics such that D1-MSNs maintain maximal signaling strength, while the signaling strength of D2-MSNs is suppressed.
How inputs generate distinct secondmessenger effects in a cell- and receptorspecific manner within intact brain circuits is poorly understood. To study how GPCRs generate distinct secondary messenger cascades, Muntean et al. previously developed a cAMP-encoded reporter (CAMPER) mouse encoding the cAMP sensor TEpacVV, which reports cAMP binding by measuring changes in Förster resonance energy transfer (FRET) with In the nucleus accumbens (NAc), conver- high sensitivity and in real time [8]. The augence of diverse neural inputs drives thors demonstrated the validity and utility of two main subtypes of GABAergic MSN: this sensor by resolving the spatiotemporal D1-MSN and D2-MSNs. D1- and D2-MSN profiles of cAMP signaling in MSNs prosubtypes differ in their receptor expression, duced by different receptor agonists (DA, the brain regions they innervate, and adenosine, acetylcholine, and morphine). their functional roles [4]. DA actions on This novel in vivo tool allows the study of D1-MSNs signal through Gαolf/s-coupled cAMP dynamics, which provide insight into GPCRs to exert excitatory downstream sig- how GPCRs integrate inputs to produce naling, whereas DA actions on D2-MSNs distinct profiles of intracellular signaling. Since repeated exposure to opioids is serve to inhibit neuronal excitability through Gαi/o-coupled D2 receptors [5]. DA modu- In their recent work, the authors applied known to cause long-term cellular and cirlates cAMP levels in MSNs by activating this tool to explore how morphine exposure cuit adaptations, the authors next examined Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
1
Trends in Pharmacological Sciences
the effects of chronic opioid exposure, including intermittent opioid exposure to model tolerance, and abstinence following repeated exposures to model withdrawal. They found that chronic morphine exposure reversed the basal changes seen in acute exposure D1-MSNs, such that basal cAMP levels were significantly reduced, yet the response amplitude to DA was unchanged. Conversely, basal cAMP levels in D2MSNs sharply increased with an accompanying increase in DA response compared with acute exposure D2-MSNs. This suggests that the relative signaling strength of D2 receptors is increased after chronic morphine. In the abstinence model, after a 24-h withdrawal from chronic exposure, D1- and D2-MSNs displayed similarly reduced and elevated basal cAMP levels, respectively, compared with the tolerance state. Together, both chronic exposure and abstinence appear to reduce the signaling strength of D1-MSN while preserving output from D2-MSNs. The finding that opioid exposure differentially alters the signaling of MSN subtypes raises the question of what molecular mechanisms underlie these changes in response properties. The authors investigated the role of presynaptic dopamine transporters (DATs) and postsynaptic phosphodiesterases (PDEs) in shaping MSN responses to DA inputs following morphine exposure. DAT inhibition by cocaine increased DA availability and resulted in increased cAMP response amplitude in D1-MSNs and decreased response in D2-MSNs. A comparison of the cAMP response to varied stimulation frequencies revealed that, in the naïve state, absent of opioid exposure, DATs selectively limited the sensitivity of D1-MSNs to phasic DA stimulation, whereas, following acute morphine exposure, the role of DATs shifted toward limiting the sensitivity of D2-MSNs to DA. In the naïve state, inhibition of postsynaptic PDEs, the enzymes that metabolize 2
cAMP, increased basal cAMP levels in both MSN subtypes, as expected, but only modulated DA-driven cAMP levels in D2-MSNs. Acute morphine exposure broadened the role of PDEs to limit peak cAMP responses in D1-MSNs; however, this may be due to limitations of cAMP production because acute morphine increases basal cAMP levels. PDEs were also found to tune D1 -sensitivity to DA during highfrequency stimulation, whereas, after morphine, PDEs no longer modulated response sensitivity in D1-MSNs. These results suggest that the role of DATs and PDEs in modulating DA-driven cAMP responses differs between D1- and D2MSNs in opioid exposure. It will be important to further probe the intracellular mechanisms underlying opioid-induced changes in signaling.
how selective neuronal populations integrate and process neurotransmitter inputs.
Given that opioid exposure is known to alter DA signaling [11,12], long-term opioid-induced DA changes likely cause neuroadaptations in local NAc circuitry between MSNs and interneurons. Moving forward, it will be important to study the effects of morphine on cAMP responses across other NAc neuron populations, including cholinergic interneurons, which provide extensive local innervation and are key modulators of NAc microcircuits. These interneurons modulate MSN activity both directly through muscarinic receptors and indirectly through nicotinic receptormediated DA release [13,14]. Given that cholinergic interneurons also have a documented role in behavioral responses to drugs of abuse [15], determining drugFinally, to better understand and visualize induced shifts in cAMP dynamics in cholinthese opioid-induced changes in MSN ergic interneurons will expand our undersignaling, the authors modeled the data standing of striatal circuit adaptations in using principal component analysis (PCA) addiction. to simplify their multidimensional data and identify key correlated variables of Since the initial observation that opioids cAMP parameters, including basal cAMP upregulate the cAMP pathway in the levels, response amplitudes, and signaling NAc, significant advances have been duration. PCA showed that D1-MSNs made in understanding the role of cAMP displayed enhanced signaling only after in drug addiction. Interestingly, equivalent acute morphine exposure and sup- cAMP adaptations in the NAc are induced pressed signaling during tolerance and by both chronic morphine and cocaine, abstinence, whereas D2-MSNs exhibited but not by nonabused psychoactive suppressed signaling after acute mor- drugs [3]. This suggests that, within the phine and enhanced signaling during toler- NAc, upregulation of cAMP mediates reance and abstinence. When the signaling ward tolerance and dependence. This scores of D1- and D2-MSNs were com- also points to a possible common mechabined, the result was a net increase in nism underlying the reinforcing behavior of D1-MSN signaling during acute morphine addiction. The findings from Muntean et al. exposure that reversed to a net increase [9] support a shift in reward valuation in adin D2-MSN signaling during the tolerance diction, mediated by changes in the signaland abstinence paradigms. This model ing strength of NAc D1- and D2-MSNs. It aligns with the current theory that is unknown whether similar populationD1-MSNs are associated with encoding specific adaptations occur due to other the acute reward induced by opioids, classes of drugs of abuse, such as stimuwhile D2-MSNs contribute to aversive lants and alcohol. It would be interesting phenotypes seen in tolerance and with- to apply this tool to determine whether drawal [4]. Thus, these findings support equivalent adaptations occur in NAc the concept of drug-induced shifts in MSNs in various types of addiction,
Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
Trends in Pharmacological Sciences
substance and behavioral, and whether shared mechanisms underlie addiction, tolerance, and dependence. Acknowledgements This work was supported by National Institutes of Health (NIH) Grants DA35821 (C.P.F.), NS95809
3.
4.
(C.P.F.), and F30-DA48543 (S.Z.).
5.
1
6.
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA *Correspondence: [email protected] (C.P. Ford).
7.
https://doi.org/10.1016/j.tips.2020.01.004 © 2020 Elsevier Ltd. All rights reserved.
References 1. Taussig, R. et al. (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261, 218–221 2. Torrecilla, M. et al. (2002) G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate
8.
9.
the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 22, 4328–4334 Terwilliger, R.Z. et al. (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res. 548, 100–110 Kravitz, A.V. et al. (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 Gerfen, C.R. and Surmeier, D.J. (2011) Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 Sharma, S.K. et al. (1975) Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc. Natl. Acad. Sci. U. S. A. 72, 3092–3096 Thomas, J.M. and Hoffman, B.B. (1996) Isoform-specific sensitization of adenylyl cyclase activity by prior activation of inhibitory receptors: role of beta gamma subunits in transducing enhanced activity of the type VI isoform. Mol. Pharmacol. 49, 907–914 Muntean, B.S. et al. (2018) Interrogating the spatiotemporal landscape of neuromodulatory GPCR signaling by realtime imaging of cAMP in intact neurons and circuits. Cell Rep. 22, 255–268 Muntean, B.S. et al. (2019) Allostatic changes in the cAMP system drive opioid-induced adaptation in striatal dopamine signaling. Cell Rep. 29, 946–960
10. Borgkvist, A. et al. (2007) Activation of the cAMP/PKA/ DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. Neuropsychopharmacology 32, 1995–2003 11. Mazei-Robison, M.S. et al. (2011) Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72, 977–990 12. Koo, J.W. et al. (2012) BDNF is a negative modulator of morphine action. Science 338, 124–128 13. Mamaligas, A.A. and Ford, C.P. (2016) Spontaneous synaptic activation of muscarinic receptors by striatal cholinergic neuron firing. Neuron 91, 574–586 14. Zhou, F.M. et al. (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat. Neurosci. 4, 1224–1229 15. Mark, G.P. et al. (2006) Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats. Brain Res. 1123, 51–59
Trends in Pharmacological Sciences, Month 2020, Vol. xx, No. xx
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