The Brain on Drugs: From Reward to Addiction
2015; Cell Press; Volume: 162; Issue: 4 Linguagem: Inglês
10.1016/j.cell.2015.07.046
ISSN1097-4172
AutoresNora D. Volkow, Marisela Morales,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoAdvances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain’s reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction. Advances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain’s reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction. The nature of addiction is frequently debated as either a personal “lifestyle choice” or a “biological vulnerability.” Current evidence shows that most drugs of abuse exert their initial reinforcing effects by activating reward circuits in the brain and that, while initial drug experimentation is largely a voluntary behavior, continued drug use impairs brain function by interfering with the capacity to exert self-control over drug-taking behaviors and rendering the brain more sensitive to stress and negative moods. Indeed, individuals with genetic vulnerabilities, exposed to chronic stress, or suffering from comorbid psychiatric conditions, as well as those who abused drugs during early adolescence, are at greater risk of transitioning into the automatic and compulsive behaviors that characterize addiction. Drugs modulate the expression of genes involved in neuroplasticity through epigenetic and possibly RNA modifications, ultimately perturbing intracellular signaling cascades and the neuronal circuits whose dysfunction have been implicated in the long-lasting changes associated with addiction. Here, we highlight some of the most significant and recent findings in drug reward and addiction, describing the circuit, behavioral, and synaptic mechanisms underlying this process. Space limitations do not allow us to review the intracellular signaling cascades and epigenetic modifications associated with addiction; thus, we refer readers to recent reviews on these topics (Heller et al., 2014Heller E.A. Cates H.M. Peña C.J. Sun H. Shao N. Feng J. Golden S.A. Herman J.P. Walsh J.J. Mazei-Robison M. et al.Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.Nat. Neurosci. 2014; 17: 1720-1727Crossref PubMed Scopus (0) Google Scholar, Nestler, 2012Nestler E.J. Transcriptional mechanisms of drug addiction.Clin. Psychopharmacol. Neurosci. 2012; 10: 136-143Crossref PubMed Scopus (13) Google Scholar, Pascoli et al., 2014aPascoli V. Cahill E. Bellivier F. Caboche J. Vanhoutte P. Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation.Biol. Psychiatry. 2014; 76: 917-926Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Dopamine (DA) neurons located in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) play a key role in the processing of reward-related stimuli, including those associated with drugs of abuse (Wise, 2008Wise R.A. Dopamine and reward: the anhedonia hypothesis 30 years on.Neurotox. Res. 2008; 14: 169-183Crossref PubMed Scopus (178) Google Scholar). Drugs of abuse, through their different pharmacological effects, increase the release of DA in the shell subregion of the NAc (Di Chiara, 2002Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction.Behav. Brain Res. 2002; 137: 75-114Crossref PubMed Scopus (521) Google Scholar), mimicking the phasic DA neuronal firing that leads to very fast DA increases (Owesson-White et al., 2009Owesson-White C.A. Ariansen J. Stuber G.D. Cleaveland N.A. Cheer J.F. Wightman R.M. Carelli R.M. Neural encoding of cocaine-seeking behavior is coincident with phasic dopamine release in the accumbens core and shell.Eur. J. Neurosci. 2009; 30: 1117-1127Crossref PubMed Scopus (48) Google Scholar) and thus the mechanism through which the brain signals reward (Box 1). The large DA increases triggered by phasic DA cell firing are necessary to stimulate D1 receptors (D1R) in the NAc.Box 1Modulation of VTA DA Neuronal FiringRecent pseudorabies virus-based methods for monosynaptic network tracing have shown that neurons from many brain areas synapse on distinct VTA DA neuron subpopulations (Lammel et al., 2014Lammel S. Lim B.K. Malenka R.C. Reward and aversion in a heterogeneous midbrain dopamine system.Neuropharmacology. 2014; 76 Pt B: 351-359Crossref PubMed Scopus (52) Google Scholar) and that neurons from the dorsal raphe (DR) provide the majority of monosynaptic inputs (Ogawa et al., 2014Ogawa S.K. Cohen J.Y. Hwang D. Uchida N. Watabe-Uchida M. Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems.Cell Rep. 2014; 8: 1105-1118Abstract Full Text Full Text PDF PubMed Google Scholar). Studies of the influence of these projections on DA neurons have been limited to a few brain structures (Paladini and Roeper, 2014Paladini C.A. Roeper J. Generating bursts (and pauses) in the dopamine midbrain neurons.Neuroscience. 2014; 282C: 109-121Crossref PubMed Scopus (11) Google Scholar). For instance, the control of tonic firing of VTA DA neurons involves the stria terminals and the ventral pallidum (Georges and Aston-Jones, 2001Georges F. Aston-Jones G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis.J. Neurosci. 2001; 21: RC160PubMed Google Scholar, Mahler et al., 2014Mahler S.V. Vazey E.M. Beckley J.T. Keistler C.R. McGlinchey E.M. Kaufling J. Wilson S.P. Deisseroth K. Woodward J.J. Aston-Jones G. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.Nat. Neurosci. 2014; 17: 577-585Crossref PubMed Scopus (19) Google Scholar), whereas the control of phasic firing of VTA DA neurons involves the pedunculo pontine tegmentum (PPT), the subthalamic nucleus (STN), and the laterodorsal tegmentum (Floresco et al., 2003Floresco S.B. West A.R. Ash B. Moore H. Grace A.A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.Nat. Neurosci. 2003; 6: 968-973Crossref PubMed Scopus (507) Google Scholar, Lodge and Grace, 2006Lodge D.J. Grace A.A. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons.Proc. Natl. Acad. Sci. USA. 2006; 103: 5167-5172Crossref PubMed Scopus (147) Google Scholar). VTA DA neurons receive GABAergic innervation from local GABAegic neurons, the NAc, globus pallidus, and rostromedial tegmental nucleus, among others. These GABAergic projections are implicated in the control of burst timing (Paladini and Roeper, 2014Paladini C.A. Roeper J. Generating bursts (and pauses) in the dopamine midbrain neurons.Neuroscience. 2014; 282C: 109-121Crossref PubMed Scopus (11) Google Scholar). It is likely that phasic and tonic changes in DA neuronal firing triggered by repeated drug administration, reflect neuroplastic changes in these regions and on inputs that relay to them. For example, the lateral habenula (LHb) indirectly inhibits VTA DA neurons via its inputs to GABA neurons in rostromedial tegmental nucleus (Ji and Shepard, 2007Ji H. Shepard P.D. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism.J. Neurosci. 2007; 27: 6923-6930Crossref PubMed Scopus (150) Google Scholar), eliciting aversion (Lammel et al., 2012Lammel S. Lim B.K. Ran C. Huang K.W. Betley M.J. Tye K.M. Deisseroth K. Malenka R.C. Input-specific control of reward and aversion in the ventral tegmental area.Nature. 2012; 491: 212-217Crossref PubMed Scopus (216) Google Scholar), and these inputs are modified by repeated cocaine administration (Meye et al., 2015Meye F.J. Valentinova K. Lecca S. Marion-Poll L. Maroteaux M.J. Musardo S. Moutkine I. Gardoni F. Huganir R.L. Georges F. Mameli M. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula.Nat. Neurosci. 2015; 18: 376-378Crossref PubMed Google Scholar). Thus, future studies will be able to assess their contribution to the dysphoria and enhanced stress reactivity in addiction.We recently showed abundant glutamatergic projections from the DR to VTA DA neurons that innervate the NAc, whose activation induced DA release in NAc and evoked reward (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). The DR is best known as a serotonergic structure that regulates emotional behaviors. However, findings on the role of DR serotonergic neurons in reward have been inconsistent (Cohen et al., 2015Cohen J.Y. Amoroso M.W. Uchida N. Serotonergic neurons signal reward and punishment on multiple timescales.eLife. 2015; 4: 4Google Scholar, Fonseca et al., 2015Fonseca M.S. Murakami M. Mainen Z.F. Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing.Curr. Biol. 2015; 25: 306-315Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, Liu et al., 2014Liu Z. Zhou J. Li Y. Hu F. Lu Y. Ma M. Feng Q. Zhang J.E. Wang D. Zeng J. et al.Dorsal raphe neurons signal reward through 5-HT and glutamate.Neuron. 2014; 81: 1360-1374Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, McDevitt et al., 2014McDevitt R.A. Tiran-Cappello A. Shen H. Balderas I. Britt J.P. Marino R.A. Chung S.L. Richie C.T. Harvey B.K. Bonci A. Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry.Cell Rep. 2014; 8: 1857-1869Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Miyazaki et al., 2014Miyazaki K.W. Miyazaki K. Tanaka K.F. Yamanaka A. Takahashi A. Tabuchi S. Doya K. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.Curr. Biol. 2014; 24: 2033-2040Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), which is likely to reflect, in part, the functional diversity of these neurons. In this regard, cellular recordings from DR serotonergic neurons in behaving mice have revealed that they convey reward information through tonic as well as phasic firing and that they signal reward and punishment on multiple timescales (Cohen et al., 2015Cohen J.Y. Amoroso M.W. Uchida N. Serotonergic neurons signal reward and punishment on multiple timescales.eLife. 2015; 4: 4Google Scholar). The DR also has glutamatergic and GABAergic neurons, some of which co-release serotonin, and thus future studies are necessary to tease apart the specific targets of the diverse serotonergic neurons and of their neighboring GABAergic and glutamatergic neurons (Liu et al., 2014Liu Z. Zhou J. Li Y. Hu F. Lu Y. Ma M. Feng Q. Zhang J.E. Wang D. Zeng J. et al.Dorsal raphe neurons signal reward through 5-HT and glutamate.Neuron. 2014; 81: 1360-1374Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, McDevitt et al., 2014McDevitt R.A. Tiran-Cappello A. Shen H. Balderas I. Britt J.P. Marino R.A. Chung S.L. Richie C.T. Harvey B.K. Bonci A. Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry.Cell Rep. 2014; 8: 1857-1869Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). In this regard, we recently showed that, within the VTA, DR neurons expressing the vesicular glutamate transport (VGluT3) preferentially establish synapses on DA neurons (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). These DR-VGluT3 neurons provide a major glutamatergic input to VTA DA neurons, including those that innervate the NAc. Selective activation of these DR-VGluT3 fibers results in VTA glutamate release, NAc DA release, and reward (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). Notably, these DR VGluT3-glutamatergic neurons (some of which may co-release serotonin) are highly interactive with the serotonergic system (Commons, 2009Commons K.G. Locally collateralizing glutamate neurons in the dorsal raphe nucleus responsive to substance P contain vesicular glutamate transporter 3 (VGLUT3).J. Chem. Neuroanat. 2009; 38: 273-281Crossref PubMed Scopus (25) Google Scholar). Thus, a better understanding of the function and connections of the diverse DR neurons will help us determine whether they serve as a link between reward and mood regulation and whether they contribute to the high co-morbidity between drug use and depression. Recent pseudorabies virus-based methods for monosynaptic network tracing have shown that neurons from many brain areas synapse on distinct VTA DA neuron subpopulations (Lammel et al., 2014Lammel S. Lim B.K. Malenka R.C. Reward and aversion in a heterogeneous midbrain dopamine system.Neuropharmacology. 2014; 76 Pt B: 351-359Crossref PubMed Scopus (52) Google Scholar) and that neurons from the dorsal raphe (DR) provide the majority of monosynaptic inputs (Ogawa et al., 2014Ogawa S.K. Cohen J.Y. Hwang D. Uchida N. Watabe-Uchida M. Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems.Cell Rep. 2014; 8: 1105-1118Abstract Full Text Full Text PDF PubMed Google Scholar). Studies of the influence of these projections on DA neurons have been limited to a few brain structures (Paladini and Roeper, 2014Paladini C.A. Roeper J. Generating bursts (and pauses) in the dopamine midbrain neurons.Neuroscience. 2014; 282C: 109-121Crossref PubMed Scopus (11) Google Scholar). For instance, the control of tonic firing of VTA DA neurons involves the stria terminals and the ventral pallidum (Georges and Aston-Jones, 2001Georges F. Aston-Jones G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis.J. Neurosci. 2001; 21: RC160PubMed Google Scholar, Mahler et al., 2014Mahler S.V. Vazey E.M. Beckley J.T. Keistler C.R. McGlinchey E.M. Kaufling J. Wilson S.P. Deisseroth K. Woodward J.J. Aston-Jones G. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.Nat. Neurosci. 2014; 17: 577-585Crossref PubMed Scopus (19) Google Scholar), whereas the control of phasic firing of VTA DA neurons involves the pedunculo pontine tegmentum (PPT), the subthalamic nucleus (STN), and the laterodorsal tegmentum (Floresco et al., 2003Floresco S.B. West A.R. Ash B. Moore H. Grace A.A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.Nat. Neurosci. 2003; 6: 968-973Crossref PubMed Scopus (507) Google Scholar, Lodge and Grace, 2006Lodge D.J. Grace A.A. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons.Proc. Natl. Acad. Sci. USA. 2006; 103: 5167-5172Crossref PubMed Scopus (147) Google Scholar). VTA DA neurons receive GABAergic innervation from local GABAegic neurons, the NAc, globus pallidus, and rostromedial tegmental nucleus, among others. These GABAergic projections are implicated in the control of burst timing (Paladini and Roeper, 2014Paladini C.A. Roeper J. Generating bursts (and pauses) in the dopamine midbrain neurons.Neuroscience. 2014; 282C: 109-121Crossref PubMed Scopus (11) Google Scholar). It is likely that phasic and tonic changes in DA neuronal firing triggered by repeated drug administration, reflect neuroplastic changes in these regions and on inputs that relay to them. For example, the lateral habenula (LHb) indirectly inhibits VTA DA neurons via its inputs to GABA neurons in rostromedial tegmental nucleus (Ji and Shepard, 2007Ji H. Shepard P.D. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism.J. Neurosci. 2007; 27: 6923-6930Crossref PubMed Scopus (150) Google Scholar), eliciting aversion (Lammel et al., 2012Lammel S. Lim B.K. Ran C. Huang K.W. Betley M.J. Tye K.M. Deisseroth K. Malenka R.C. Input-specific control of reward and aversion in the ventral tegmental area.Nature. 2012; 491: 212-217Crossref PubMed Scopus (216) Google Scholar), and these inputs are modified by repeated cocaine administration (Meye et al., 2015Meye F.J. Valentinova K. Lecca S. Marion-Poll L. Maroteaux M.J. Musardo S. Moutkine I. Gardoni F. Huganir R.L. Georges F. Mameli M. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula.Nat. Neurosci. 2015; 18: 376-378Crossref PubMed Google Scholar). Thus, future studies will be able to assess their contribution to the dysphoria and enhanced stress reactivity in addiction. We recently showed abundant glutamatergic projections from the DR to VTA DA neurons that innervate the NAc, whose activation induced DA release in NAc and evoked reward (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). The DR is best known as a serotonergic structure that regulates emotional behaviors. However, findings on the role of DR serotonergic neurons in reward have been inconsistent (Cohen et al., 2015Cohen J.Y. Amoroso M.W. Uchida N. Serotonergic neurons signal reward and punishment on multiple timescales.eLife. 2015; 4: 4Google Scholar, Fonseca et al., 2015Fonseca M.S. Murakami M. Mainen Z.F. Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing.Curr. Biol. 2015; 25: 306-315Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, Liu et al., 2014Liu Z. Zhou J. Li Y. Hu F. Lu Y. Ma M. Feng Q. Zhang J.E. Wang D. Zeng J. et al.Dorsal raphe neurons signal reward through 5-HT and glutamate.Neuron. 2014; 81: 1360-1374Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, McDevitt et al., 2014McDevitt R.A. Tiran-Cappello A. Shen H. Balderas I. Britt J.P. Marino R.A. Chung S.L. Richie C.T. Harvey B.K. Bonci A. Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry.Cell Rep. 2014; 8: 1857-1869Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Miyazaki et al., 2014Miyazaki K.W. Miyazaki K. Tanaka K.F. Yamanaka A. Takahashi A. Tabuchi S. Doya K. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.Curr. Biol. 2014; 24: 2033-2040Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), which is likely to reflect, in part, the functional diversity of these neurons. In this regard, cellular recordings from DR serotonergic neurons in behaving mice have revealed that they convey reward information through tonic as well as phasic firing and that they signal reward and punishment on multiple timescales (Cohen et al., 2015Cohen J.Y. Amoroso M.W. Uchida N. Serotonergic neurons signal reward and punishment on multiple timescales.eLife. 2015; 4: 4Google Scholar). The DR also has glutamatergic and GABAergic neurons, some of which co-release serotonin, and thus future studies are necessary to tease apart the specific targets of the diverse serotonergic neurons and of their neighboring GABAergic and glutamatergic neurons (Liu et al., 2014Liu Z. Zhou J. Li Y. Hu F. Lu Y. Ma M. Feng Q. Zhang J.E. Wang D. Zeng J. et al.Dorsal raphe neurons signal reward through 5-HT and glutamate.Neuron. 2014; 81: 1360-1374Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, McDevitt et al., 2014McDevitt R.A. Tiran-Cappello A. Shen H. Balderas I. Britt J.P. Marino R.A. Chung S.L. Richie C.T. Harvey B.K. Bonci A. Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry.Cell Rep. 2014; 8: 1857-1869Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). In this regard, we recently showed that, within the VTA, DR neurons expressing the vesicular glutamate transport (VGluT3) preferentially establish synapses on DA neurons (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). These DR-VGluT3 neurons provide a major glutamatergic input to VTA DA neurons, including those that innervate the NAc. Selective activation of these DR-VGluT3 fibers results in VTA glutamate release, NAc DA release, and reward (Qi et al., 2014Qi J. Zhang S. Wang H.L. Wang H. de Jesus Aceves Buendia J. Hoffman A.F. Lupica C.R. Seal R.P. Morales M. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.Nat. Commun. 2014; 5: 5390Crossref PubMed Scopus (12) Google Scholar). Notably, these DR VGluT3-glutamatergic neurons (some of which may co-release serotonin) are highly interactive with the serotonergic system (Commons, 2009Commons K.G. Locally collateralizing glutamate neurons in the dorsal raphe nucleus responsive to substance P contain vesicular glutamate transporter 3 (VGLUT3).J. Chem. Neuroanat. 2009; 38: 273-281Crossref PubMed Scopus (25) Google Scholar). Thus, a better understanding of the function and connections of the diverse DR neurons will help us determine whether they serve as a link between reward and mood regulation and whether they contribute to the high co-morbidity between drug use and depression. DA neurons in the VTA fire in either a tonic (1–8 Hz) or a transient ( 15 Hz), with the phasic mode resulting in larger DA increases than the tonic mode. Though it was initially believed that DA signaling in the brain encoded for reward, more recent findings have revealed that it encodes for a reward prediction signal. Specifically, these studies have shown that phasic DA firing is time locked to unexpected or novel reward but is also triggered by cues that predict reward. Moreover, the firing frequency of DA neurons triggered by cues is associated with the expected reward value and its probability of delivery, but if the expected reward does not materialize, DA cell firing is inhibited (Schultz, 2002Schultz W. Getting formal with dopamine and reward.Neuron. 2002; 36: 241-263Abstract Full Text Full Text PDF PubMed Scopus (1370) Google Scholar). Changes in the response patterns of DA cell firing are modulated by more distinct projections for tonic than for phasic firing (Box 1). Changes in phasic DA firing patterns modify the strength of cortico-striatal glutamatergic synapses, thus altering signaling in D1R- and D2R-expressing GABAergic medium spiny neurons (MSNs) (Paladini and Roeper, 2014Paladini C.A. Roeper J. Generating bursts (and pauses) in the dopamine midbrain neurons.Neuroscience. 2014; 282C: 109-121Crossref PubMed Scopus (11) Google Scholar). This is distinct from DA signaling in the NAc driven by release from tonic DA neuron firing, which results in lower DA increases than from phasic firing but that are sufficient to stimulate D2R signaling and have been mostly associated with motivational drive (Dreyer et al., 2010Dreyer J.K. Herrik K.F. Berg R.W. Hounsgaard J.D. Influence of phasic and tonic dopamine release on receptor activation.J. Neurosci. 2010; 30: 14273-14283Crossref PubMed Scopus (86) Google Scholar, Trifilieff et al., 2013Trifilieff P. Feng B. Urizar E. Winiger V. Ward R.D. Taylor K.M. Martinez D. Moore H. Balsam P.D. Simpson E.H. Javitch J.A. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.Mol. Psychiatry. 2013; 18: 1025-1033Crossref PubMed Scopus (31) Google Scholar). Though most studies link drug-induced neuroplasticity with the fast and large transient DA changes triggered by drugs, the contribution from the longer-lasting stimulation of D2R (also D3R and D4R) has been much less investigated. VTA DA neurons project predominantly to the NAc, where DA interacts with D1R, D2R, and D3R, which are mainly expressed in MSNs. Stimulatory striatal MSNs that express D1R (D1R-MSNs) signal through the direct striatal pathway, whereas those that express D2R (D2R-MSNs) signal through the striatal indirect pathway and act in an inhibitory manner. D3R mostly co-localize with D1R-MSNs, with which they heteromerize, potentiating their function (Marcellino et al., 2008Marcellino D. Ferré S. Casadó V. Cortés A. Le Foll B. Mazzola C. Drago F. Saur O. Stark H. Soriano A. et al.Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum.J. Biol. Chem. 2008; 283: 26016-26025Crossref PubMed Scopus (98) Google Scholar). The ventral striatal direct and indirect pathways have distinct roles in modulating reward and motivation. The direct pathway is associated with reward, whereas the indirect one is associated with punishment (Hikida et al., 2010Hikida T. Kimura K. Wada N. Funabiki K. Nakanishi S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.Neuron. 2010; 66: 896-907Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, Kravitz et al., 2012Kravitz A.V. Tye L.D. Kreitzer A.C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement.Nat. Neurosci. 2012; 15: 816-818Crossref PubMed Scopus (158) Google Scholar). Thus, DA receptor stimulation of the direct pathway directly mediates reward, whereas DA-receptor-mediated inhibition of the indirect pathway opposes aversive responses. This could explain why maximal drug reward is obtained when DA binds to both D1R and D2R. However, in contrast to the situation in the dorsal striatum, where the direct and indirect pathways are fully segregated, in the NAc, both D1R- and D2R-expressing MSNs project into the ventral globus pallidum (Smith et al., 2013bSmith R.J. Lobo M.K. Spencer S. Kalivas P.W. Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways).Curr. Opin. Neurobiol. 2013; 23: 546-552Crossref PubMed Scopus (37) Google Scholar). To be reinforcing, drug-induced DA increases need to be fast and sufficiently large to stimulate low-affinity D1R in addition to D2R, leading to the activation of the direct pathway and the inhibition of the indirect pathway. D1R stimulation in the NAc by itself is sufficient to produce drug reward (Caine et al., 2007Caine S.B. Thomsen M. Gabriel K.I. Berkowitz J.S. Gold L.H. Koob G.F. Tonegawa S. Zhang J. Xu M. Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice.J. Neurosci. 2007; 27: 13140-13150Crossref PubMed Scopus (78) Google Scholar), whereas D2R stimulation is not (Caine et al., 2002Caine S.B. Negus S.S. Mello N.K. Patel S. Bristow L. Kulagowski J. Vallone D. Saiardi A. Borrelli E. Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists.J. Neurosci. 2002; 22: 2977-2988PubMed Google Scholar, Durieux et al., 2009Durieux P.F. Bearzatto B. Guiducci S. Buch T. Waisman A. Zoli M. Schiffmann S.N. de Kerchove d’Exaerde A. D2R striatopallidal neurons inhibit both locomotor and drug reward processes.Nat. Neurosci. 2009; 12: 393-395Crossref PubMed Scopus (92) Goo
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