More Cocaine—More Glutamate—More Addiction

Gipson, Cassandra D.; Kalivas, Peter W.

doi:10.1016/j.biopsych.2014.08.010

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…In more recent work, it has been shown that MMP‐2 and ‐9 are involved in synaptic changes occurring in the striatum of cocaine‐extinguished and ‐reinstated animals (Smith et al ., ). In particular, the number and/or size of postsynaptic processes for glutamatergic synapses is increased with cocaine‐related plasticity, a finding consistent with accumulating evidence that glutamatergic signalling becomes critical in the addicted state (Doyle et al ., ; Gipson & Kalivas, ).…”

Section: Discussionmentioning

confidence: 99%

Dopamine increases NMDA‐stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase‐dependent mechanism

Partridge

Berger

et al. 2016

Eur J of Neuroscience

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Dopamine (DA) is a potent neuromodulator known to influence glutamatergic transmission in striatal medium spiny neurons (MSNs). It acts on D1- and D2-like DA receptors that are expressed on two distinct subpopulations. MSNs projecting to the sub-stantia nigra express D1 receptors (D1Rs), while those projecting to the lateral globus pallidus express D2 receptors (D2Rs). D1R signalling in particular can increase excitatory transmission through varied protein kinase A-dependent, cell-autonomous pathways. Mechanisms by which D1R signalling could increase excitatory transmission in D2R-bearing MSNs have been relatively less explored. Herein, the possibility is considered that D1R agonists increase levels of soluble factors that subsequently influence N-methyl-D-aspartate (NMDA)-stimulated calcium flux in D2R neurons. This study focuses on matrix metalloproteinases (MMPs) and MMP-generated integrin binding ligands, important soluble effectors of glutamatergic transmission that may be elevated in the setting of excess DA. It was observed that DA and a D1R agonist, SKF81297, increase MMP activity in extracts from striatal slices, as determined by cleavage of the substrate β-dystroglycan. Using mice engineered to express the calcium indicator GCaMP3 in striatopallidal D2R-bearing neurons, it was also observed that SKF81297 pretreatment of slices (60 min) potentiates NMDA-stimulated calcium increases in this subpopulation. Effects are diminished by pretreatment with an antagonist of MMP activity or an inhibitor of integrin-dependent signalling. Together, results suggest that DA signalling can increase excitatory transmission in D2R neurons through an MMP-dependent mechanism. Future studies may be warranted to determine whether D1R-stimulated MMP-dependent processes contribute to behaviours in which increased activity in striatopallidal MSNs plays a role.

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Section: Discussionmentioning

confidence: 99%

Dopamine increases NMDA‐stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase‐dependent mechanism

Partridge

Berger

et al. 2016

Eur J of Neuroscience

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“…Since cocaine-enhanced extracellular DA and glutamate are positively correlated with reinstatement responding to cocaine (Gipson and Kalivas, 2014), a reduction in cocaine-enhanced extracellular DA and glutamate may directly lead to a reduction in relapse to drug-seeking behavior. Furthermore, mGluR2-KO rats displayed higher basal levels of extracellular DA and glutamate, which may also contribute to attenuated relapse since drug craving and relapse have been shown to be associated with a reduction in basal levels of extracellular DA and glutamate or in basal glutamate transmission in the NAc after chronic cocaine administration (Kalivas, 2009; Thomas and Malenka, 2003).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats

Yang

Zhang

et al. 2017

Cell Reports

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Summary Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2-mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available, and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2-mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use, but could actually protect against addiction by reducing sensitivity to cocaine reward.

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“… 41 The reasons for this discrepancy remain unclear, but could reflect pre-existing traits, protracted withdrawal effects in those with extensive histories of substance abuse or a shift from DA to other neurobiological substrates mediating heightened behavioral responses to various challenges. 50 , 51 , 52 Together, these findings highlight the need to study systematically DA (cross) sensitization mechanisms in clinical samples with various levels of prior drug exposure to further understand the relevance of DA (cross)sensitization in the onset and relapse of drug dependence/abuse.…”

Section: Discussionmentioning

confidence: 95%

Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers

et al. 2016

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Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean±s.d.=22.1±3.4 years) [11C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg−1, by mouth; n=8) or placebo (3 × lactose, by mouth; n=9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P⩽0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P<0.04), and voxel-based analyses showed larger stress-induced decreases in [11C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [11C]raclopride binding, primarily in the sensorimotor striatum (P<0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

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More Cocaine—More Glutamate—More Addiction

Cited by 6 publications

References 9 publications

Dopamine increases NMDA‐stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase‐dependent mechanism

Dopamine increases NMDA‐stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase‐dependent mechanism

Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats

Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers

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