Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen—two brain regions involved in cognitive function and motoric behavior—identified in a whole brain analysis. Six adult male squirrel monkeys self-administered cocaine (0.32 mg/kg/inj) over 140 sessions. Six additional monkeys that had not received any drug treatment for ~1.5 years served as drug-free controls. Resting-state fMRI imaging sessions at 9.4 Tesla were conducted under isoflurane anesthesia. Functional connectivity maps were derived using seed regions placed in the left dACC or putamen. Results show that cocaine maintained robust self-administration with an average total intake of 367 mg/kg (range: 299–424 mg/kg). In the cocaine group, functional connectivity between the dACC seed and regions primarily involved in motoric behavior was weaker, whereas connectivity between the dACC seed and areas implicated in reward and cognitive processing was stronger. In the putamen seed, weaker widespread connectivity was found between the putamen and other motor regions as well as with prefrontal areas that regulate higher-order executive function; stronger connectivity was found with reward-related regions. dACC connectivity was associated with total cocaine intake. These data indicate that functional connectivity between regions involved in motor, reward, and cognitive processing differed between subjects with recent histories of cocaine self-administration and controls; in dACC, connectivity appears to be related to cumulative cocaine dosage during chronic exposure.

Background: Serotonin 5-HT2A receptor antagonists and 5-HT2C receptors agonists have been proposed as important candidates for the development of pharmacotherapies for psychostimulant abuse, with evidence suggesting that those receptors may act together to control behavior. However, the role of 5-HT2A receptors on the reinforcing effects of psychostimulant drugs has not been fully elucidated. Methods: In the present study, we investigated the effects of the selective 5HT2A receptor antagonist M100907 alone or in combination with the selective 5HT2C agonist WAY 163909 on intravenous methamphetamine self-administration in rhesus macaques (N = 3). Methamphetamine self-administration (0.01-0.03 mg/kg/inf) was evaluated under a fixed-ratio 20-schedule of reinforcement, and acute pretreatments were conducted 1h (M100907) or 45min (WAY 163909) prior to the beginning of self-administration sessions at the EDMax dose of methamphetamine once stability criteria were met. Results: Pretreatment with M100907 (0.03-0.3 mg/kg, i.m.) dose-dependently attenuated methamphetamine self-administration, with the highest dose significantly decreasing response rates compared to vehicle. Combined administration of ineffective doses of M100907 and WAY 163909 had no effects on methamphetamine self-administration. Conclusions: Our study indicates that acute selective 5-HT2A receptor blockade decreases peak methamphetamine intake in nonhuman primates. Combination approaches with sub-threshold doses of 5-HT2A receptor antagonists and 5-HT2C receptor agonists, on the other hand, do not seem to be effective in decreasing methamphetamine reinforcement. Further studies are needed in order to investigate the effects of chronic treatments with M100 on complete METH SA dose-response curves.

3,4-Methylenedioxymethamphetamine (MDMA) affects monoaminergic pathways that play a critical role in sleep-wake cycles. Dopaminergic mechanisms are thought to mediate the sleep-disrupting effects of stimulant drugs. However, the mechanisms underlying the effects of MDMA on sleep-wake cycles and the effects of (-) MDMA, a stereoisomer that lacks dopaminergic activity, on sleep remain unknown. The aim of the present study was to investigate the effects of racemic MDMA and(-) MDMA on daytime activity and sleep-like parameters evaluated with actigraphy in adult rhesus macaques (, = 6). Actiwatch monitors were attached to the monkeys' collars and actigraphy recording was conducted during baseline conditions and after the administration of acute intramuscular injections of saline (vehicle), racemic MDMA (0.3, 1.0, or 1.7 mg/kg), or(-) MDMA (0.3, 1.0, or 1.7 mg/kg) at 9 or 16 h (3 h before "lights off"). Morning treatments had no effects on sleep-like parameters. Racemic MDMA decreased general daytime activity during the first hour after injection and increased daytime activity at 3 hr posttreatment. Although afternoon administration of racemic MDMA increased sleep latency, it improved other sleep parameters, decreasing wake time after sleep onset (WASO) and increasing sleep efficiency for subjects with low baseline sleep efficiency. Afternoon treatment with R(-) MDMA improved sleep measures, increasing sleep efficiency and decreasing sleep latency and WASO, while having no effects on daytime activity. The stimulant and sleep-disrupting effects of racemic MDMA are likely mediated by dopaminergic and noradrenergic mechanisms, while serotonergic pathways appear to be involved in the sleep-promoting effects of MDMA. (PsycINFO Database Record

No abstract

Cocaine use disorder represents a prominent health concern in the United States, and there are currently no accepted pharmacotherapies for the treatment of ongoing cocaine use. Additionally, the occurrence of stressors early in life, such as physical abuse and neglect, is a major predictor in the emergence of cocaine abuse later in life. Rhesus monkeys demonstrate a similar prevalence rate of infant abuse and rejection as humans, and serve as ideal candidates to examine the relationship between early life stress (ELS) and cocaine use. Finally, previous data suggest serotonin 2C (5HT2C) agonists may be viable candidates in the treatment of ongoing drug use. Accordingly, the effectiveness of the 5HT‐2C agonist WAY 163909 (WAY) to decrease cocaine self‐administration was examined in male and female rhesus macaques.Subjects were 8 adolescent male and female rhesus macaques who experienced infant maltreatment (MALT) or competent maternal care (MALT males n=4; MALT females, n=2; Control males, n=0; Control females, n=2). During adolescence, animals were trained to respond under a fixed‐ratio 20 response (FR 20) schedule of reinforcement to receive an infusion of cocaine (0.01–0.1 mg/kg/infusion). After meeting criteria for stable self‐administration (SA), animals progressed through a full dose‐effect curve to establish the dose that engendered the highest response rate (EDMax), and were then examined under maintenance conditions. During each testing week, WAY pretreatments (3 consecutive daily treatments administered 45 minutes prior to sessions) were preceded by normal maintenance sessions without any pretreatments, which provided a baseline of responding. Each WAY dose (0.1–1 mg/kg IM) was tested weekly interspersed by weeks of vehicle treatment.WAY dose‐dependently decreased cocaine self‐administration in males and females, with males demonstrating significantly lower response rates in comparison to females at 0.3 mg/kg WAY. MALT animals also demonstrated an overall lower response rate across doses of WAY in comparison to control subjects.These preliminary data suggest that females may be more resistant to serotonergic interventions of ongoing cocaine SA, given that females from MALT and Control groups were less sensitive to the effects of WAY in comparison to males. Furthermore, MALT animals overall showed a lower response rate in comparison to control animals across doses of WAY, suggesting that MALT subjects may be uniquely sensitive to serotonergic interventions aimed at decreasing ongoing drug use. The addition of male controls will be critical in determining whether robust sex differences persist, and if male controls demonstrate a similar response pattern as female controls.Support or Funding InformationThis research was supported by USPHS grants DA 038588 (MMS/LLH), DA 010344 (LLH), DA 031246 (LLH), and P51OD11132 (YNPRC).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.