scholarly journals Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory deficits in rats

2019 ◽  
Author(s):  
Sara R. Westbrook ◽  
Megan R. Dwyer ◽  
Laura R. Cortes ◽  
Joshua M. Gulley
Keyword(s):  
Nmda Receptor ◽  
Drug Use ◽  
Expression Profiles ◽  
D1 Receptor ◽  
Receptor Expression ◽  
Cognitive Test ◽  
Adult Onset ◽  
Sprague Dawley ◽  
Self Administration ◽  
Long Access

AbstractIndividuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.

scholarly journals Chronic Fentanyl Self-Administration Generates a Shift toward Negative Affect in Rats during Drug Use

2021 ◽  
Vol 11 (8) ◽  
pp. 1064
Author(s):  
Angela N. Dao ◽  
Nicholas J. Beacher ◽  
Vivian Mayr ◽  
Annalisa Montemarano ◽  
Sam Hammer ◽  
...  
Keyword(s):  
Drug Use ◽  
Negative Affect ◽  
Positive Affect ◽  
Chronic Exposure ◽  
Negative Reinforcement ◽  
Affective State ◽  
Sprague Dawley ◽  
Self Administration ◽  
Initial Exposure ◽  
Long Access

Drug addiction is thought to be driven by negative reinforcement, and it is thought that a shift from positive affect upon initial exposure to negative affect after chronic exposure to a drug is responsible for maintaining self-administration (SA) in addicted individuals. This can be modeled in rats by analyzing ultrasonic vocalizations (USVs), a type of intraspecies communication indicative of affective state based on the frequency of the emission: calls in the 22 kHz range indicate negative affect, whereas calls in the 50 kHz range indicate positive affect. We employed a voluntary chronic, long-access model of fentanyl SA to analyze affective changes in the response to chronic fentanyl exposure. Male Sprague-Dawley rats self-administered either fentanyl (N = 7) or saline (N = 6) for 30 consecutive days and USVs were recorded at four different time points: the day before first SA session (PRE), the first day of SA (T01), the last day of SA (T30), and the first day of abstinence (ABS). At T01, the ratio of 50 to 22 kHz calls was similar between the fentanyl and saline groups, but at T30, the ratio differed between groups, with the fentanyl group showing significantly fewer 50 kHz calls and more 22 kHz calls relative to saline animals. These results indicate a shift toward a negative affect during drug use after chronic exposure to fentanyl and support negative reinforcement as a main driving factor of opioid addiction.

FC29-03 - Effects of chronic oral treatment with aripiprazole on expression of nmda receptor subunits and binding sites in rat brain

2011 ◽  
Vol 26 (S2) ◽  
pp. 1979-1979
Author(s):  
M. Zink ◽  
N. Segnitz ◽  
T. Ferbert ◽  
A. Schmitt ◽  
P. Gass ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Negative Symptoms ◽  
Oral Treatment ◽  
Antipsychotic Agents ◽  
Brain Regions ◽  
Relative Increase ◽  
Receptor Expression ◽  
Sprague Dawley ◽  
Adult Type ◽  
Mk 801

IntroductionThe glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.ObjectivesThe partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.AimsTo evaluate effects of APZ on NR mRNA and protein expressionMethodsWe treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.ResultsIncreased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.ConclusionsThe effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.

scholarly journals Changes in Glutamate/NMDA Receptor Subunit 1 Expression in Rat Brain after Acute and Subacute Exposure to Methamphetamine

2009 ◽  
Vol 2009 ◽  
pp. 1-4 ◽  
Author(s):  
Walailuk Kerdsan ◽  
Samur Thanoi ◽  
Sutisa Nudmamud-Thanoi
Keyword(s):  
Nmda Receptor ◽  
Frontal Cortex ◽  
Behavioral Sensitization ◽  
Hippocampal Formation ◽  
Receptor Expression ◽  
Receptor Subunit ◽  
Sprague Dawley ◽  
Acute Group ◽  
And Control ◽  
Subacute Exposure

Methamphetamine (METH) is a psychostimulant drug of abuse that produces long-term behavioral changes including behavioral sensitization, tolerance, and dependence. METH has been reported to induce neurotoxic effects in several areas of the brain via the dopaminergic system. Changes of dopamine function can induce malfunction of the glutamatergic system. Therefore, the aim of the present study was to examine the effects of METH administration on the expression of glutamate N-methyl-D-aspartate receptor subunit 1 (NMDAR1) in frontal cortex, striatum, and hippocampal formation after acute and subacute exposure to METH by western blotting. Male Sprague-Dawley rats were injected intraperitoneally with a single dose of 8 mg/kg METH, 4 mg/kg/day METH for 14 days and saline in acute, subacute, and control groups, respectively. A significant increase in NMDAR1 immunoreactive protein was found in frontal cortex in the subacute group (P=.036) but not in the acute group (P=.580). Moreover, a significant increase in NMDAR1 was also observed in striatum in both acute (P=.025) and subacute groups (P=.023). However, no significant differences in NMDAR1 in hippocampal formation were observed in either acute or subacute group. The results suggest that an upregulation of NMDA receptor expression may be a consequence of glutamatergic dysfunction induced by METH.

scholarly journals Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration

2018 ◽  
Author(s):  
Alex B. Kawa ◽  
Alec C. Valenta ◽  
Robert T. Kennedy ◽  
Terry E. Robinson
Keyword(s):  
Nucleus Accumbens ◽  
Drug Use ◽  
In Vivo Microdialysis ◽  
Group Differences ◽  
Self Administration ◽  
The Core ◽  
Intermittent Access ◽  
High Motivation ◽  
Long Access

Recent studies suggest that the temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self-administered cocaine to produce addiction-like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self-administration, which is widely used to model the transition to addiction, with Intermittent Access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of self-administered cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction-like behavior. IntA experience was more effective than LgA in producing addiction-like behavior- a drug experience-dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue-induced reinstatement, despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate, but a single self-administered IV injection of cocaine increased DA in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or Short Access (ShA) experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high DA response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper-responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.

scholarly journals Oxycodone self-administration activates the mitogen-activated protein kinase/ mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christopher A. Blackwood ◽  
Michael T. McCoy ◽  
Bruce Ladenheim ◽  
Jean Lud Cadet
Keyword(s):  
Protein Kinase ◽  
Histone H3 ◽  
Dorsal Striatum ◽  
Mitogen Activated Protein Kinase ◽  
Sprague Dawley ◽  
Self Administration ◽  
Molecular Analyses ◽  
Sprague Dawley Rats ◽  
Mitogen Activated Protein ◽  
Long Access

AbstractTo identify signaling pathways activated by oxycodone self-administration (SA), Sprague–Dawley rats self-administered oxycodone for 20 days using short—(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized 2 h after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs, in the LgA-H rats. GluA3, but not GluA2, mRNA expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. These findings suggest that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation and increases in striatal gene expression. These observations offer potential avenues for interventions against oxycodone addiction.

scholarly journals Oxycodone self-administration activates the mitogen-activated protein kinase/mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum

2020 ◽  
Author(s):  
Christopher A. Blackwood ◽  
Michael T. McCoy ◽  
Bruce Ladenheim ◽  
Jean Lud Cadet
Keyword(s):  
Protein Kinase ◽  
Histone H3 ◽  
Dorsal Striatum ◽  
Mitogen Activated Protein Kinase ◽  
Sprague Dawley ◽  
Self Administration ◽  
Pharmacological Interventions ◽  
Sprague Dawley Rats ◽  
Mitogen Activated Protein ◽  
Long Access

ABSTRACTTo identify signaling pathways activated by oxycodone self-administration (SA), Sprague-Dawley rats self-administered oxycodone for 20 days using short-access (ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized two hours after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs in the LgA-H rats. GluA3, but not GluA2, expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. Our findings indicate that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation, which promoted increases in striatal gene expression. Our observations offer novel avenues for pharmacological interventions against oxycodone addiction.

scholarly journals Differential Effects of Insufflated, Subcutaneous, and Intravenous Growth Hormone on Bone Growth, Cognitive Function, and NMDA Receptor Subunit Expression

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4418-4427 ◽  
Author(s):  
Sung Won Park ◽  
Sooyoung Shin ◽  
Chi Hwa Kim ◽  
Ah-ra Ko ◽  
Min Jung Kwak ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Nmda Receptor ◽  
Bone Growth ◽  
Inflammatory Responses ◽  
Escape Latency ◽  
Growth Promotion ◽  
Receptor Expression ◽  
Learning Ability ◽  
Sprague Dawley ◽  
Subunit Expression

The objective of this study was to characterize the effect of inhalable growth hormone (GH) delivered by an insufflator to the lungs of hypophysectomized Sprague Dawley rats. In the first cohort, the safety and efficacy of the insufflated GH were evaluated. Three experimental groups (n = 7 per group) were treated with GH for 15 d: One group received sc injection of GH daily at 200 μg/kg (SC200). Two other groups received GH by insufflation daily: 200 μg/kg (INS 200) and 600 μg/kg (INS 600). In the second set of experiments, GH was administered in three routes [SC200, INS200, intravenous (IV200)] (n=10) for 5 d, and escape latency and N-methyl D-aspartate (NMDA) receptor expression were evaluated. In the first cohort, INS200 showed similar bioactivity as SC200 in growth promotion, tibial growth, as well as escape latency on the 12th day of treatment. Insufflated GH was well tolerated without significant inflammatory responses. In the second cohort, expression of the NMDA receptor 1 and 2B in hippocampus measured after 3 or 6 d of daily treatments were significantly higher in INS200 as compared to IV200, consistent with the improvement of the escape latency. In summary, the inhalable form of GH delivered by intratracheal insufflation was safe, and its bioactivity was comparable to sc injection both in promotion of growth and acquisition of learning ability. If applied properly to human, inhalable GH would be effective for growth promotion and possibly for several disorders caused by underexpression of NMDA receptors.

Functional MHCI deficiency induces ADHD-like symptoms with increased dopamine D1 receptor expression

2021 ◽  
Author(s):  
Hong-Rui Meng ◽  
Toshiko Suenaga ◽  
Mitsuhiro Edamura ◽  
Atsuo Fukuda ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Receptor Expression

scholarly journals Transcriptional and Epigenetic Substrates of Methamphetamine Addiction and Withdrawal: Evidence from a Long-Access Self-Administration Model in the Rat

2014 ◽  
Vol 51 (2) ◽  
pp. 696-717 ◽  
Author(s):  
Jean Lud Cadet ◽  
Christie Brannock ◽  
Subramaniam Jayanthi ◽  
Irina N. Krasnova
Keyword(s):  
Self Administration ◽  
Long Access
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