scholarly journals The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators

2019 ◽  
Author(s):  
Christina Gobin ◽  
Marek Schwendt
Keyword(s):  
Working Memory ◽  
Cognitive Function ◽  
Metabotropic Glutamate Receptor ◽  
Memory Performance ◽  
Repeated Treatment ◽  
Allosteric Modulators ◽  
Sprague Dawley ◽  
Self Administration ◽  
Cocaine Seeking ◽  
Prolonged Abstinence

AbstractRationaleCocaine use disorder (CUD) remains difficult to treat with no FDA-approved medications to reduce relapse. Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine seeking but may also further compromise cognitive function in long-term cocaine users.ObjectivesHere we assessed the effect of repeated administration of negative or positive allosteric modulators (NAM or PAM) of mGlu5 on both cognitive performance and (context+cue)-primed cocaine seeking after prolonged abstinence.MethodsAdult male Sprague-Dawley rats underwent 6 days of short-access (1 h/day) and 12 days of long-access (6 h/day) cocaine self-administration. Rats were then trained and tested in a delayed-match-to-sample (DMS) task to establish baseline working memory performance over a five-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM MTEP (3 mg/kg), mGlu5 PAM CDPPB (30 mg/kg) or vehicle prior to DMS testing during a block of five days, followed by a 5-day washout DMS testing block.ResultsMTEP and CDPPB decreased drug seeking in response to cocaine-associated cues after prolonged abstinence. However, repeated treatment with MTEP impaired working memory, while CDPPB had no effects on performance.ConclusionsThese results emphasize the relevance of evaluating cognitive function within the context of investigating pharmacotherapies to treat CUD. Further research is needed to determine how two mechanistically different pharmacological compounds can exert the same behavioral effects to reduce cocaine seeking.

scholarly journals Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking

2018 ◽  
Vol 33 (1) ◽  
pp. 132-144
Author(s):  
Tracey A Larson ◽  
Casey E O’Neill ◽  
Michaela P Palumbo ◽  
Ryan K Bachtell
Keyword(s):  
Dose Response ◽  
Extinction Training ◽  
Schedules Of Reinforcement ◽  
Sprague Dawley ◽  
Self Administration ◽  
Caffeine Consumption ◽  
Adult Rats ◽  
Sprague Dawley Rats ◽  
Cocaine Seeking ◽  
Administration Procedure

Background: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. Aim: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Methods: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62–82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Results: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. Conclusions: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.

scholarly journals Quantifying the inverted U: A meta-analysis of prefrontal dopamine, D1-receptors, and working memory

2021 ◽  
Author(s):  
Matthew A. Weber ◽  
Mackenzie M. Conlon ◽  
Hannah R. Stutt ◽  
Linder Wendt ◽  
Patrick Ten Eyck ◽  
...  
Keyword(s):  
Working Memory ◽  
Cognitive Function ◽  
Memory Performance ◽  
Meta Analysis ◽  
Quantitative Relationship ◽  
D1 Receptors ◽  
Hyperactivity Disorder ◽  
Human Disorders ◽  
High Level ◽  
And Behavior

Dopamine in the prefrontal cortex can be disrupted in human disorders that affect cognitive function such as Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Dopamine has a powerful effect on prefrontal circuits via the D1-type dopamine receptor (D1DR). It has been proposed that prefrontal dopamine has "inverted U-shaped" dynamics, with optimal dopamine and D1DR signaling required for optimal cognitive function. However, the quantitative relationship between prefrontal dopamine and cognitive function is not clear. Here, we conducted a meta-analysis of published manipulations of prefrontal dopamine and the effects on working memory, a high-level executive function in humans, primates, and rodents that involves maintaining and manipulating information over seconds to minutes. We reviewed 646 papers and found that 75 studies met criteria for inclusion. Our quantification of effect sizes for dopamine, D1DRs, and behavior revealed a negative quadratic slope. This is consistent with the proposed inverted U-shape of prefrontal dopamine and D1DRs and working memory performance, explaining 10% of the variance. Of note, the inverted quadratic fit was much stronger for prefrontal D1DRs alone, explaining 26% of the variance, compared to prefrontal dopamine alone, explaining 10% of the variance. Taken together, these data, derived from a variety of manipulations and systems, demonstrate that optimal prefrontal dopamine signalling is linked with higher cognitive function. Our results provide insight into the fundamental dynamics of prefrontal dopamine, which could be useful for pharmacological interventions targeting prefrontal dopaminergic circuits, and into the pathophysiology of human brain disease.

scholarly journals Heroin self-administration and extinction increases prelimbic cortical astroglia-synapse proximity and alters dendritic spine morphometrics that are reversed by N-acetylcysteine

2020 ◽  
Author(s):  
BM Siemsen ◽  
KN Hooker ◽  
EA Carpenter ◽  
ME Prescott ◽  
AG Brock ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Glutamate Release ◽  
Repeated Treatment ◽  
Spine Density ◽  
Sprague Dawley ◽  
Self Administration ◽  
Spine Head ◽  
Synaptic Markers

AbstractClinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astroglial glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observed increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astroglial plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astroglial complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at synapses. Additionally, these data demonstrate, for the first time, that NAC reverses PrL cortical heroin SA and extinction-induced adaptations in both astrocytes and corticostriatal neurons.

scholarly journals A subset of nucleus accumbens neurons receiving dense and functional prelimbic cortical input are required for cocaine seeking

2021 ◽  
Author(s):  
Benjamin M. Siemsen ◽  
Sarah M. Barry ◽  
Kelsey Vollmer ◽  
Lisa M. Green ◽  
Ashley G. Brock ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Glutamate Release ◽  
Sprague Dawley ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Cortical Input ◽  
Cortical Projections ◽  
Cocaine Seeking ◽  
Accumbens Core

AbstractBackgroundPrelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.MethodsMale Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, in vivo electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking.ResultsChemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines.ConclusionsWe identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.

Characteristics of Healthy Older Adults that Influence Self-rated Cognitive Function

2017 ◽  
Vol 24 (1) ◽  
pp. 57-66 ◽  
Author(s):  
Bryce P. Mulligan ◽  
Colette M. Smart ◽  
Sidney J. Segalowitz ◽  
Stuart W.S. MacDonald
Keyword(s):  
Older Adults ◽  
Working Memory ◽  
Cognitive Function ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Healthy Aging ◽  
Memory Performance ◽  
Short Term ◽  
Healthy Older Adults ◽  
Subjective Cognitive Function

AbstractObjectives: We sought to clarify the nature of self-reported cognitive function among healthy older adults by considering the short-term, within-person association (coupling) of subjective cognitive function with objective cognitive performance. We expected this within-person coupling to differ between persons as a function of self-perceived global cognitive decline and depression, anxiety, or neuroticism. Methods: This was an intensive measurement (short-term longitudinal) study of 29 older adult volunteers between the ages of 65 and 80 years without an existing diagnosis of dementia or mild cognitive impairment. Baseline assessment included neuropsychological testing and self-reported depression, anxiety, and neuroticism, as well as self- and informant-reported cognitive decline (relative to 10 years previously). Intensive within-person measurement occasions included subjective ratings of cognitive function paired with performance on a computerized working memory (n-back) task; each participant attended four or five assessments separated by intervals of at least one day. Statistical analysis was comprised of multilevel linear regression. Results: Comparison of models suggested that both neuroticism and self-rated cognitive decline explained unique variance in the within-person, across-occasion coupling of subjective cognitive function with objective working memory performance. Conclusions: Self-ratings of cognition may accurately reflect day-to-day variations in objective cognitive performance among older adults, especially for individuals lower in neuroticism and higher in self-reported cognitive decline. Clinicians should consider these individual differences when determining the validity of complaints about perceived cognitive declines in the context of otherwise healthy aging. (JINS, 2018, 24, 57–66)

scholarly journals Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence

2020 ◽  
Vol 117 (42) ◽  
pp. 26460-26469 ◽  
Author(s):  
Craig T. Werner ◽  
Swarup Mitra ◽  
Benjamin D. Auerbach ◽  
Zi-Jun Wang ◽  
Jennifer A. Martin ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Dorsal Hippocampus ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Activin A ◽  
Lateral Septum ◽  
Self Administration ◽  
Cocaine Seeking ◽  
Prolonged Abstinence

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or “incubates”) during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

scholarly journals Social Interaction With Relapsed Partner Facilitates Cocaine Relapse in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiqiu Meng ◽  
Wei Yan ◽  
Xiaoxing Liu ◽  
Yimiao Gong ◽  
Shanshan Tian ◽  
...  
Keyword(s):  
Social Interaction ◽  
Social Factors ◽  
Sprague Dawley ◽  
Self Administration ◽  
Facilitation Effect ◽  
Drug Seeking ◽  
Cocaine Seeking ◽  
Social Partners ◽  
Seeking Behavior ◽  
Drug Relapse

Social factors strongly contribute to drug use and relapse, and epidemiological studies have found that members of peer groups influence each other to use drugs. However, previous animal models mostly failed to incorporate social factors and demonstrate the effects of social partners on drug addiction and relapse. In the present study, we investigated the transfer of relapse to cocaine seeking between drug-addicted partners in rats. Male Sprague–Dawley rats were pair-housed and subjected to training and extinction of cocaine self-administration and conditioned place preference (CPP). 24 h after extinction test, the targeted rats interacted with a cocaine-primed (relapsed) partner or stranger, or saline-injected (unrelapsed) partner for 30 min, after which the targeted rats were tested for drug seeking behavior. We found that social interaction with a relapsed partner increased drug seeking behavior in cocaine self-administration and CPP models in rats, while social interaction with an unrelapsed partner or relapsed stranger had no effect on cocaine seeking. Moreover, the effect of social interaction on cocaine seeking could last for at least 1 day. Our findings demonstrate a facilitation effect of relapsed social partners on drug relapse in rats and provide a novel animal model for social transfer of drug relapse.

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