scholarly journals Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior

2021 ◽  
Vol 22 (15) ◽  
pp. 8219
Author(s):  
Yosef Avchalumov ◽  
Alison D. Kreisler ◽  
Wulfran Trenet ◽  
Mahasweta Nayak ◽  
Brian P. Head ◽  
...  
Keyword(s):  
Fixed Ratio ◽  
Dorsal Striatum ◽  
Long Term Potentiation ◽  
Ratio Schedule ◽  
High Frequency Stimulation ◽  
Self Administration ◽  
Altered Expression ◽  
Caveolin 1 ◽  
Extended Access ◽  
Cav1 Expression

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

scholarly journals SCH23390 Reduces Methamphetamine Self-Administration and Prevents Methamphetamine-Induced Striatal LTD

2020 ◽  
Vol 21 (18) ◽  
pp. 6491
Author(s):  
Yosef Avchalumov ◽  
Wulfran Trenet ◽  
Juan Piña-Crespo ◽  
Chitra Mandyam
Keyword(s):  
Synaptic Transmission ◽  
Ex Vivo ◽  
Dorsal Striatum ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Self Administration ◽  
Striatal Slices ◽  
Extended Access

Extended-access methamphetamine self-administration results in unregulated intake of the drug; however, the role of dorsal striatal dopamine D1-like receptors (D1Rs) in the reinforcing properties of methamphetamine under extended-access conditions is unclear. Acute (ex vivo) and chronic (in vivo) methamphetamine exposure induces neuroplastic changes in the dorsal striatum, a critical region implicated in instrumental learning. For example, methamphetamine exposure alters high-frequency stimulation (HFS)-induced long-term depression in the dorsal striatum; however, the effect of methamphetamine on HFS-induced long-term potentiation (LTP) in the dorsal striatum is unknown. In the current study, dorsal striatal infusion of SCH23390, a D1R antagonist, prior to extended-access methamphetamine self-administration reduced methamphetamine addiction-like behavior. Reduced behavior was associated with reduced expression of PSD-95 in the dorsal striatum. Electrophysiological findings demonstrate that superfusion of methamphetamine reduced basal synaptic transmission and HFS-induced LTP in dorsal striatal slices, and SCH23390 prevented this effect. These results suggest that alterations in synaptic transmission and synaptic plasticity induced by acute methamphetamine via D1Rs could assist with methamphetamine-induced modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions and formation of habits, mediating escalation of methamphetamine self-administration and methamphetamine addiction-like behavior.

scholarly journals Knockdown of Hypocretin/Orexin Attenuates Extended-Access Cocaine Self-Administration in Rats

2017 ◽  
Author(s):  
Brooke E. Schmeichel ◽  
Alessandra Matzeu ◽  
Pascale Koebel ◽  
Leandro F. Vendruscolo ◽  
Brigitte L. Kieffer ◽  
...  
Keyword(s):  
Stress Responses ◽  
Viral Vector ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Self Administration ◽  
Adult Rats ◽  
Extended Access ◽  
Seeking Behavior ◽  
Melanin Concentrating Hormone

AbstractThe hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Longterm Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake during extended self-administration access, a model that mimics key features of compulsive cocaine-taking. In addition, Hcrt silencing decreased motivation for both cocaine and palatable food (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence to general measures of arousal-dependent behaviors. At the molecular level, longterm Hcrt knockdown moderately reduced the downstream expression of dynorphin (DYN) and melanin-concentrating hormone (MCH) in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.

scholarly journals Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice

2013 ◽  
Vol 231 (7) ◽  
pp. 1277-1287 ◽  
Author(s):  
Yong Zhang ◽  
Brandan Mayer-Blackwell ◽  
Stefan D. Schlussman ◽  
Matthew Randesi ◽  
Eduardo R. Butelman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Receptor Gene ◽  
Dorsal Striatum ◽  
Self Administration ◽  
Neurotransmitter Receptor ◽  
Extended Access ◽  
Receptor Gene Expression

scholarly journals Cocaine self-administration by rats is inhibited by cyclic GMP-elevating agents: involvement of epigenetic markers

2013 ◽  
Vol 16 (7) ◽  
pp. 1587-1597 ◽  
Author(s):  
Elodie Deschatrettes ◽  
Pascal Romieu ◽  
Jean Zwiller
Keyword(s):  
Prefrontal Cortex ◽  
Cyclic Gmp ◽  
Present Report ◽  
Fixed Ratio ◽  
Signal Transduction Pathway ◽  
Adult Brain ◽  
Ratio Schedule ◽  
Self Administration ◽  
Epigenetic Markers ◽  
Histone Deacetylase 2

Abstract The C-type natriuretic peptide (CNP) exerts its action via stimulation of the cyclic GMP (cGMP) signalling pathway, which includes the activation of cGMP-dependent protein kinases. The pathway can also be activated by inhibitors of phosphodiesterases (PDE) that hydrolyse cGMP. The present report shows that activation of the cGMP pathway by CNP, by bromo-cGMP, a cell-permeant cGMP analogue, or by the PDE inhibitor zaprinast dose dependently reduces intravenous cocaine self-administration by rats. The effect was found when the compounds were injected in situ into the prefrontal cortex, but not when they were injected into the nucleus accumbens. A decrease in the number of cocaine infusions performed by rats was obtained under the fixed ratio-1 schedule of reinforcement as well as under a progressive ratio schedule, which evaluates the motivation of the animals for the drug. Decrease in cocaine self-administration was accompanied with reduced expression of the epigenetic markers methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in dopaminergic projection areas. An increase in the acetylation level of histone H3, but not of histone H4, was also noticed. Since MeCP2 and HDAC2 are known to modulate dynamic functions in the adult brain, such as synaptic plasticity, our results showing that activation of the cGMP signal transduction pathway decreased both cocaine intake and expression of the epigenetic markers strongly suggest that the MeCP2/HDAC2 complex is involved in the analysis of the reinforcing properties of cocaine in the prefrontal cortex.

scholarly journals Dramatic increase in lever-pressing activity in rats after training on the progressive ratio schedule of cocaine self-administration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vladimir L. Tsibulsky ◽  
Andrew B. Norman
Keyword(s):  
Fixed Ratio ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Self Administration ◽  
The Press ◽  
Second Mode ◽  
Before And After ◽  
Lever Pressing ◽  
Remission Phase ◽  
Definition Of

AbstractTransition from the highest rate of lever-pressing activity during the unloading (extinction) phase of a cocaine self-administration session to an extremely low activity rate during the remission phase is in many cases gradual. This makes it difficult to assess the duration of the unloading phase after a fixed ratio 1 (FR1) or breakpoint after a progressive-ratio (PR) self-administration session. In addition, 3–5 days of training under the PR schedule results in a dramatic and persistent increase in the rate of presses during PR sessions and in the unloading phase following FR1 self-administration sessions. The goals of this study were to find the definition of the last press demarcating the border between the unloading and remission phases of the session and to determine if this border was also affected by PR training. Rats were trained to self-administer cocaine under the FR1 schedule and then under the PR schedule of drug delivery. Distributions of inter-press intervals (IPIs) during the unloading phase in sessions before and after PR training were compared. It was found that the distribution of cocaine-induced IPIs during the unloading phase was lognormal, bimodal, and independent of previously injected cocaine unit doses. The first mode represented intervals within the short bouts of stereotypic presses and the second mode represented intervals between bouts. The two modes were approximately 0.7 s and 21 s during unloading prior to and 0.6 s and 1.5 s after PR self-administration training. The total number of presses per unloading phase increased eightfold. When the FR1 schedule was restored, the intervals between bouts remained very short for at least 7–10 days and only then started a gradual increase towards baseline levels. The last unloading press was defined as the press followed by the IPI longer than the defined criterion. PR training resulted in a substantial and long-lasting increase in lever-pressing activity during unloading. The duration of the unloading phase did not depend on the rate of lever-pressing activity.

scholarly journals The Role of NMDA receptors in rat propofol self-administration

2020 ◽  
Author(s):  
Bei ping Chen ◽  
Xi-xi Huang ◽  
Dong-mei Dong ◽  
Hui Wu ◽  
Tian-qi Zhu ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Neural Plasticity ◽  
Fixed Ratio ◽  
Study Groups ◽  
Ratio Schedule ◽  
Self Administration ◽  
Mk 801 ◽  
Anesthetic Agents ◽  
Administration Methods

Abstract Aim Propofol is among the most frequently used anesthetic agents, and it has the potential for abuse. The N-methyl-D-aspartate (NMDA) receptors are key mediators of both neural plasticity and development, as well as of addiction and neurodegeneration. Herein we explored the role of these receptors in rat propofol self-administration. Methods Rats were trained to self-administer propofol (1.7 mg/kg/infusion) using an FR fixed ratio schedule of the course of 14 sessions (3 h/day). After training, rats were intraperitoneally administered the non-competitive NDMA receptor antagonist MK-801, and then 10 minutes later were subjected to a propofol self-administration session. Results: After training, rats had acquired the ability to self-administer propofol successfully, as evidenced by a significant and stable rise in active nose-pokes leading to propofol administration relative to control nose-pokes (P<0.01) and became stable. Relative to control rats, rats that had been injected with 0.2 mg/kg MK-801 exhibited significantly more propofol infusions (F(3, 28)=4.372, P<0.01), whereas infusions were comparable in the groups administered 0.1 mg/kg and 0.4 mg/kg. In addition, MK-801 failed to alter numbers of active (F(3, 28)=1.353, P>0.05) or inactive (F(3, 28)=0.047, P>0.05) responses in study groups. Animals administered 0.4 mg/kg MK-801 exhibited significantly fewer infusions than animals administered 0.2 mg/kg (P=0.006, P<0.01). In contrast, however, animals in the 0.4 mg/kg MK-801 group exhibited a significant reduction in the number of active nose poke responses (F(3, 20)=20.8673, P<0.01) and the number of sucrose pellets (F(3, 20)=23.77, P<0.01), with increased locomotor activity (F(3, 20)=22.812, P<0.01). Conclusion These findings indicate that NMDA receptors may play a role in regulating rat self-administration of propofol.

scholarly journals The Role of NMDA receptors in rat propofol self-administration

2020 ◽  
Author(s):  
Bei ping Chen ◽  
Xi-xi Huang ◽  
Dong-mei Dong ◽  
Hui Wu ◽  
Tian-qi Zhu ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Neural Plasticity ◽  
Fixed Ratio ◽  
Study Groups ◽  
Ratio Schedule ◽  
Self Administration ◽  
Mk 801 ◽  
Anesthetic Agents ◽  
Administration Methods

Abstract Aim Propofol is among the most frequently used anesthetic agents, and it has the potential for abuse. The N-methyl-D-aspartate (NMDA) receptors are key mediators of both neural plasticity and development, as well as of addiction and neurodegeneration. Herein we explored the role of these receptors in rat propofol self-administration. Methods Rats were trained to self-administer propofol (1.7 mg/kg/infusion) using an FR fixed ratio schedule of the course of 14 sessions (3 h/day). After training, rats were intraperitoneally administered the non-competitive NDMA receptor antagonist MK-801, and then 10 minutes later were subjected to a propofol self-administration session. Results: After training, rats had acquired the ability to self-administer propofol successfully, as evidenced by a significant and stable rise in active nose-pokes leading to propofol administration relative to control nose-pokes (P<0.01) and became stable. Relative to control rats, rats that had been injected with 0.2 mg/kg MK-801 exhibited significantly more propofol infusions (F(3, 28)=4.372, P<0.01), whereas infusions were comparable in the groups administered 0.1 mg/kg and 0.4 mg/kg. In addition, MK-801 failed to alter numbers of active (F(3, 28)=1.353, P>0.05) or inactive (F(3, 28)=0.047, P>0.05) responses in study groups. Animals administered 0.4 mg/kg MK-801 exhibited significantly fewer infusions than animals administered 0.2 mg/kg (P=0.006, P<0.01). In contrast, however, animals in the 0.4 mg/kg MK-801 group exhibited a significant reduction in the number of active nose poke responses (F(3, 20)=20.8673, P<0.01) and the number of sucrose pellets (F(3, 20)=23.77, P<0.01), with increased locomotor activity (F(3, 20)=22.812, P<0.01). Conclusion These findings indicate that NMDA receptors may play a role in regulating rat self-administration of propofol.

scholarly journals Protracted abstinence from extended cocaine self-administration is associated with hypodopaminergic activity in the VTA but not in the SNc

2020 ◽  
Author(s):  
Adélie Salin ◽  
Virginie Lardeux ◽  
Marcello Solinas ◽  
Pauline Belujon
Keyword(s):  
Dorsal Striatum ◽  
Cocaine Addiction ◽  
Substantia Nigra Pars Compacta ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Protracted Abstinence ◽  
Negative Emotional State ◽  
Chronic Cocaine ◽  
Extended Access ◽  
Altered Metabolism

Abstract The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown altered metabolism of DA-target structures, the ventral and dorsal striatum, between early and late abstinence. However, specific changes within the midbrain DA system were not investigated. Here, we investigated potential time and region-specific changes of activity in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in rats that had extended or limited access to cocaine and later underwent a period of abstinence. We found that DA activity is decreased only in the VTA in rats with extended access to cocaine, with no changes in SNc DA activity. These changes in VTA DA activity may participate in the negative emotional state and in the incubation of drug seeking that occur during abstinence from cocaine.

scholarly journals Effects of β-Phenylethylamine on Psychomotor, Rewarding, and Reinforcing Behaviors and Affective State: The Role of Dopamine D1 Receptors

2021 ◽  
Vol 22 (17) ◽  
pp. 9485
Author(s):  
In Soo Ryu ◽  
Oc-Hee Kim ◽  
Ji Sun Kim ◽  
Sumin Sohn ◽  
Eun Sang Choe ◽  
...  
Keyword(s):  
Affective State ◽  
Fixed Ratio ◽  
Dorsal Striatum ◽  
Place Preference ◽  
D1 Receptor ◽  
D1 Receptors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Schedules Of Reinforcement ◽  
Self Administration

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.

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