Jasper Heinsbroek | Medical University of South Carolina (original) (raw)
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Highlights d Nuclear HDAC5 in the NAc attenuates relapse-like drugseeking behaviors d ChIP-seq re... more Highlights d Nuclear HDAC5 in the NAc attenuates relapse-like drugseeking behaviors d ChIP-seq revealed numerous HDAC5-associated target genes including Npas4 d NPAS4 in NAc is induced in subset of FOS+ neurons during cocaine-context learning d HDAC5 and NPAS4 in NAc are involved in cocaineconditioned behaviors SUMMARY
Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relaps... more Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/ reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in 1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapit-ulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction.
Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs)... more Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accum-bens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1-and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1-or D2-MSNs. Because D1-and D2-MSNs inner-vate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1-versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTD GABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information ... more The nucleus accumbens is a major input
structure of the basal ganglia and integrates information
from cortical and limbic structures to mediate goaldirected
behaviors. Chronic exposure to several classes of
drugs of abuse disrupts plasticity in this region, allowing
drug-associated cues to engender a pathologic motivation
for drug seeking.Anumber of alterations in glutamatergic
transmission occur within the nucleus accumbens after
withdrawal from chronic drug exposure. These druginduced
neuroadaptations serve as the molecular basis
for relapse vulnerability. In this review, we focus on the
role that glutamate signal transduction in the nucleus
accumbens plays in addiction-related behaviors. First, we
explore the nucleus accumbens, including the cell types
and neuronal populations present as well as afferent
and efferent connections. Next we discuss rodent models
of addiction and assess the viability of these models
for testing candidate pharmacotherapies for the
prevention of relapse. Then we provide a review of
the literature describing how synaptic plasticity in the
accumbens is altered after exposure to drugs of abuse
and withdrawal and also how pharmacological
manipulation of glutamate systems in the accumbens
can inhibit drug seeking in the laboratory setting.
Finally, we examine results from clinical trials in
which pharmacotherapies designed to manipulate
glutamate systems have been effective in treating
relapse in human patients. Further elucidation of how
drugs of abuse alter glutamatergic plasticity within the
accumbens will be necessary for the development of
new therapeutics for the treatment of addiction across
all classes of addictive substances.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information ... more The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
Neuropsychopharmacology, 2015
Rats that have self-administered methamphetamine (meth) under long access, but not short access, ... more Rats that have self-administered methamphetamine (meth) under long access, but not short access, conditions do not recognize novel objects. The perirhinal cortex is critical for novelty detection, and perirhinal metabotropic glutamate 5 receptors (mGlu5) are downregulated after long-access meth. The novel positive allosteric modulator (PAM) 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, or DPFE, demonstrates improved solubility compared with other mGlu5 PAMs, thus allowing brain-site-specific pharmacological studies. Infusion of DPFE into perirhinal cortex restored novel object recognition in long-access meth rats. To investigate the impact of these cognitive enhancing effects on relapse, we tested the effects of DPFE infusions into perirhinal cortex on meth-seeking under two different test conditions. In the standard cue relapse test, perirhinal DPFE infusions did not alter meth-seeking in the presence of meth cues. However, in a novel cue relapse test, wherein animals were allowed to allocate responding between a novel cue and meth-conditioned cue, perirhinal DPFE infusions shifted the pattern of responding in long-access rats toward a profile resembling short-access rats, which respond equally for novel and meth cues. Perirhinal mGlu5 are thus a promising pharmacological target for the restoration of cognitive function in meth addicts. Targeting these receptors may also reduce relapse, particularly in situations where novel stimuli compete with conditioned stimuli for control over meth seeking.Neuropsychopharmacology advance online publication, 21 October 2015; doi:10.1038/npp.2015.283.
Nature Neuroscience, 2015
It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their informat... more It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.
Nature Neuroscience, 2015
It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their informat... more It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.
Highlights d Nuclear HDAC5 in the NAc attenuates relapse-like drugseeking behaviors d ChIP-seq re... more Highlights d Nuclear HDAC5 in the NAc attenuates relapse-like drugseeking behaviors d ChIP-seq revealed numerous HDAC5-associated target genes including Npas4 d NPAS4 in NAc is induced in subset of FOS+ neurons during cocaine-context learning d HDAC5 and NPAS4 in NAc are involved in cocaineconditioned behaviors SUMMARY
Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relaps... more Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/ reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in 1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapit-ulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction.
Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs)... more Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accum-bens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1-and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1-or D2-MSNs. Because D1-and D2-MSNs inner-vate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1-versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTD GABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information ... more The nucleus accumbens is a major input
structure of the basal ganglia and integrates information
from cortical and limbic structures to mediate goaldirected
behaviors. Chronic exposure to several classes of
drugs of abuse disrupts plasticity in this region, allowing
drug-associated cues to engender a pathologic motivation
for drug seeking.Anumber of alterations in glutamatergic
transmission occur within the nucleus accumbens after
withdrawal from chronic drug exposure. These druginduced
neuroadaptations serve as the molecular basis
for relapse vulnerability. In this review, we focus on the
role that glutamate signal transduction in the nucleus
accumbens plays in addiction-related behaviors. First, we
explore the nucleus accumbens, including the cell types
and neuronal populations present as well as afferent
and efferent connections. Next we discuss rodent models
of addiction and assess the viability of these models
for testing candidate pharmacotherapies for the
prevention of relapse. Then we provide a review of
the literature describing how synaptic plasticity in the
accumbens is altered after exposure to drugs of abuse
and withdrawal and also how pharmacological
manipulation of glutamate systems in the accumbens
can inhibit drug seeking in the laboratory setting.
Finally, we examine results from clinical trials in
which pharmacotherapies designed to manipulate
glutamate systems have been effective in treating
relapse in human patients. Further elucidation of how
drugs of abuse alter glutamatergic plasticity within the
accumbens will be necessary for the development of
new therapeutics for the treatment of addiction across
all classes of addictive substances.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information ... more The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
Neuropsychopharmacology, 2015
Rats that have self-administered methamphetamine (meth) under long access, but not short access, ... more Rats that have self-administered methamphetamine (meth) under long access, but not short access, conditions do not recognize novel objects. The perirhinal cortex is critical for novelty detection, and perirhinal metabotropic glutamate 5 receptors (mGlu5) are downregulated after long-access meth. The novel positive allosteric modulator (PAM) 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, or DPFE, demonstrates improved solubility compared with other mGlu5 PAMs, thus allowing brain-site-specific pharmacological studies. Infusion of DPFE into perirhinal cortex restored novel object recognition in long-access meth rats. To investigate the impact of these cognitive enhancing effects on relapse, we tested the effects of DPFE infusions into perirhinal cortex on meth-seeking under two different test conditions. In the standard cue relapse test, perirhinal DPFE infusions did not alter meth-seeking in the presence of meth cues. However, in a novel cue relapse test, wherein animals were allowed to allocate responding between a novel cue and meth-conditioned cue, perirhinal DPFE infusions shifted the pattern of responding in long-access rats toward a profile resembling short-access rats, which respond equally for novel and meth cues. Perirhinal mGlu5 are thus a promising pharmacological target for the restoration of cognitive function in meth addicts. Targeting these receptors may also reduce relapse, particularly in situations where novel stimuli compete with conditioned stimuli for control over meth seeking.Neuropsychopharmacology advance online publication, 21 October 2015; doi:10.1038/npp.2015.283.
Nature Neuroscience, 2015
It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their informat... more It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.
Nature Neuroscience, 2015
It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their informat... more It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.