Self-administration of intravenous amphetamine: effect of nucleus accumbens CCK B receptor activation on fixed-ratio responding

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

Download Full-text

Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

Author(s):

Atul P Daiwile ◽

Subramaniam Jayanthi ◽

Bruce Ladenheim ◽

Michael T McCoy ◽

Christie Brannock ◽

...

Keyword(s):

Sex Differences ◽

Nucleus Accumbens ◽

Fixed Ratio ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Self Administration ◽

Male And Female ◽

Orexin Receptors ◽

Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

Download Full-text

2Hz-Electroacupuncture Attenuates Conditioned Cue-Evoked Heroin-Seeking Behavior and Increase CB2-Rs Expression in Relapse-Relevant Brain Regions in Heroin-Addicted Rats

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.998-999.164 ◽

2014 ◽

Vol 998-999 ◽

pp. 164-168 ◽

Cited By ~ 2

Author(s):

Lin Chen ◽

Bao Miao Ma ◽

Kai Yue ◽

Qin Ru ◽

Xiang Tian ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Rat Model ◽

Fixed Ratio ◽

Brain Regions ◽

Inhibitory Effect ◽

Control Group ◽

Self Administration ◽

Seeking Behavior

In order to investigate the influence of electroacupuncture on heroin seeking behavior and the expression of CB2-Rs in the relapse-relevant brain regions, heroin self-administration rat model which represents the heroin relapse behaviors was developed with progressive fixed ratio program. The model rats were randomly divided into 3 groups: control group, heroin-addicted group and 2Hz electroacupuncture group (stimulating on acupoints zusanli and sanyinjiao). The expression of CB2-Rs in the relapse-relevant brain regions were assessed with immunohistochemistry technologies. The reinstatement of heroin seeking behavior induced by conditioned cue priming showed that compared with the heroin-addicted group, active pokes in the 2Hz electroacupuncture group decreased significantly (p<0.05). Compared with the control group, the expression of CB2-Rs in prefrontal cortex (PFC) and nucleus accumbens (NAc) was significantly decreased (p<0.05) in heroin-addicted group and increaseed significantly recover (p<0.05) in the 2Hz electroacupuncture group. Our present results showed that 2Hz-electroacupuncture could attenuate the conditioned cue-evoked heroin-seeking behavior and the inhibitory effect was mediated partially by the increase CB2-Rs expression in relapse-relevant brain regions in heroin-addicted rats.

Download Full-text

Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement

Neuropharmacology ◽

10.1016/j.neuropharm.2016.04.010 ◽

2016 ◽

Vol 108 ◽

pp. 14-23 ◽

Cited By ~ 15

Author(s):

Jocelyn M. Richard ◽

Howard L. Fields

Keyword(s):

Nucleus Accumbens ◽

Alcohol Consumption ◽

Opioid Receptor ◽

Receptor Activation ◽

Mu Opioid Receptor ◽

Self Administration ◽

Mu Opioid

Download Full-text

Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.787362 ◽

2021 ◽

Vol 15 ◽

Author(s):

Margaret A. Minnig ◽

Tayun Park ◽

Maria Echeveste Sanchez ◽

Pietro Cottone ◽

Valentina Sabino

Keyword(s):

Nucleus Accumbens ◽

Alcohol Drinking ◽

Fixed Ratio ◽

Loss Of Function ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Pac1 Receptor ◽

Excessive Alcohol Consumption ◽

Excessive Alcohol ◽

Shrna Knockdown

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.

Download Full-text

Neuronal spike activity in rat nucleus accumbens during cocaine self-administration under different fixed-ratio schedules

Neuroscience ◽

10.1016/0306-4522(96)00144-3 ◽

1996 ◽

Vol 74 (2) ◽

pp. 483-497 ◽

Cited By ~ 23

Author(s):

J.-Y Chang ◽

J.M Paris ◽

S.F Sawyer ◽

A.B Kirillov ◽

D.J Woodward

Keyword(s):

Nucleus Accumbens ◽

Spike Activity ◽

Fixed Ratio ◽

Self Administration ◽

Neuronal Spike ◽

Rat Nucleus Accumbens

Download Full-text

Kisspeptin-8 Induces Anxiety-Like Behavior and Hypolocomotion by Activating the HPA Axis and Increasing GABA Release in the Nucleus Accumbens in Rats

Biomedicines ◽

10.3390/biomedicines9020112 ◽

2021 ◽

Vol 9 (2) ◽

pp. 112

Author(s):

Katalin Eszter Ibos ◽

Éva Bodnár ◽

Zsolt Bagosi ◽

Zsolt Bozsó ◽

Gábor Tóth ◽

...

Keyword(s):

Nucleus Accumbens ◽

Ex Vivo ◽

Gaba Release ◽

Receptor Activation ◽

Ambulatory Activity ◽

Corticosterone Concentration ◽

Reproductive Axis ◽

Neuropeptide Ff ◽

Serum Lh ◽

Anxiogenic Effect

Kisspeptins (Kp) are RF-amide neuropeptide regulators of the reproductive axis that also influence anxiety, locomotion, and metabolism. We aimed to investigate the effects of intracerebroventricular Kp-8 (an N-terminally truncated octapeptide) treatment in Wistar rats. Elevated plus maze (EPM), computerized open field (OF), and marble burying (MB) tests were performed for the assessment of behavior. Serum LH and corticosterone levels were determined to assess kisspeptin1 receptor (Kiss1r) activation and hypothalamic-pituitary-adrenal axis (HPA) stimulation, respectively. GABA release from the nucleus accumbens (NAc) and dopamine release from the ventral tegmental area (VTA) and NAc were measured via ex vivo superfusion. Kp-8 decreased open arm time and entries in EPM, and also raised corticosterone concentration, pointing to an anxiogenic effect. Moreover, the decrease in arm entries in EPM, the delayed increase in immobility accompanied by reduced ambulatory activity in OF, and the reduction in interactions with marbles show that Kp-8 suppressed exploratory and spontaneous locomotion. The increase in GABA release from the NAc might be in the background of hypolocomotion by inhibiting the VTA-NAc dopaminergic circuitry. As Kp-8 raised LH concentration, it could activate Kiss1r and stimulate the reproductive axis. As Kiss1r is associated with hyperlocomotion, it is more likely that neuropeptide FF receptor activation is involved in the suppression of locomotor activity.

Download Full-text

Shifting motivational states: The effects of nucleus accumbens dopamine and opioid receptor activation on a modified effort-based choice task

Behavioural Brain Research ◽

10.1016/j.bbr.2020.112999 ◽

2021 ◽

Vol 399 ◽

pp. 112999

Author(s):

Hannah N. Carlson ◽

Carolyn Murphy ◽

Wayne E. Pratt

Keyword(s):

Nucleus Accumbens ◽

Opioid Receptor ◽

Receptor Activation ◽

Choice Task ◽

Motivational States

Download Full-text

Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22052397 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2397

Author(s):

Chrysostomos Charalambous ◽

Tereza Havlickova ◽

Marek Lapka ◽

Nina Puskina ◽

Romana Šlamberová ◽

...

Keyword(s):

Conditioned Place Preference ◽

Fixed Ratio ◽

Place Preference ◽

Self Administration ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor ◽

Addiction Therapy ◽

Significant Efficacy ◽

Lever Pressing

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

Download Full-text