Characteristics of Rainfall-Induced Slope Instability in Cisokan Region, Indonesia

A 25.5 km long access road has been constructed in a hilly area in Cisokan region. Several slope instabilities occurred during the rainy season, particularly at the end of heavy rainfall. A comprehensive study was performed to understand the characteristics of rainfall-induced slope instability. The study consisted of field observation, analyses of field and laboratory test data, and numerical analyses. The study revealed that in general there were two categories of slopes with instability characteristics: (i) slopes with a significant groundwater level increase during rainfall; (ii) slopes with an insignificant groundwater level increase during rainfall. In the first category, the slope instability was caused by a loss of matric suction and eventually the pore-water pressure, uw became positive as indicated by an increase of the groundwater level. In the second category, the slope instability was caused by a loss of matric suction without a rise in pore-water pressure, uw, to a positive magnitude. Two empirical curves of slope stability were developed as a preliminary guidance to assess slope stability during rainfall in the region.

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

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.

Chemogenetic Inhibition of Corticostriatal Circuits Reduces Cued Reinstatement of Methamphetamine Seeking

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

The gut microbiome is associated with cocaine behavior and predicts addiction vulnerability in adult male rats

The gut-brain axis is a bi-directional communication system through which microbial communities in the gut interact with the nervous system. Disruptions in microbiome composition, known as dysbiosis, appear to be associated with neuropsychiatric disorders, perhaps including drug abuse. This study used behavioral data and biological samples from the Cocaine Biobank to test the hypothesis that the gut microbiota can predict and reflect susceptibility to cocaine reinforcement. Adult male heterogenous (HS) rats were catheterized and allowed to self-administer cocaine in daily short-access sessions (2 hr/day, 10 days, 0.5 mg/kg per intravenous infusion), followed by progressive ratio (PR) testing. Rats were transitioned to daily long-access sessions (6 hr/day, 14 days), followed by a PR test and alternating blocks of footshock testing, long-access, and PR. Fecal samples were collected at three time points and bacterial 16s rRNA genes were sequenced to profile the microbiota and compare low vs. high responders to cocaine. Bacterial taxa identified in baseline samples in drug-naive animals were used to test whether specific bacterial abundance could predict future cocaine susceptibility. As expected, levels of cocaine-related behavior varied across individual subjects, such that a quartile split identified low and high responders on each measure, as well as an overall addiction index. Although beta diversity in the gut microbiota at baseline and after short access did not predict membership in high or low addiction quartiles, linear discriminant analysis (LDA) identified certain taxa that were more robustly represented in either low or high responders. Beta diversity after long access did reveal a difference in microbiota profiles between low and high responders, and LDA identified specific populations that differed between groups. Plotting baseline samples identified using LDA on a Receiver Operating Characteristic (ROC) curve revealed that high relative abundance of Akkermansia muciniphila predicted future low response rates. This study is the first to report that microbiota variability reflects levels of cocaine intake and that the microbiota might facilitate diagnosis and identify risk factors predictive of future drug vulnerability.

Cocaine-Seeking Behavior Induced by Orexin A Administration in the Posterior Paraventricular Nucleus of the Thalamus Is Not Long-Lasting: Neuroadaptation of the Orexin System During Cocaine Abstinence

Hypothalamic orexin (Orx) projections to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. Using an established model of cocaine dependence (i.e., long access [LgA] to cocaine), we previously showed that OrxA injections in the posterior PVT (pPVT) reinstated extinguished cocaine-seeking behavior in rats after an intermediate period of abstinence (2–3 weeks). Considering the long-lasting nature of drug-seeking behavior, the present study examined whether the priming effect of intra-pPVT OrxA administration was preserved after a period of protracted abstinence (4–5 weeks) in rats that self-administered cocaine under LgA conditions. Furthermore, to better understand whether a history of cocaine dependence affects the Orx system—particularly the hypothalamic Orx↔pPVT connection—the number of Orx-expressing cells in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) and number of orexin receptor 1 (OrxR1)- and OrxR2-expressing cells in the pPVT were quantified. Orexin A administration in the pPVT induced cocaine-seeking behavior after intermediate abstinence, as reported previously. At protracted abstinence, however, the priming effect of OrxA was absent. A higher number of cells that expressed Orx was observed in the LH/DMH/PFA at both intermediate and protracted abstinence. In the pPVT, the number of OrxR2-expressing cells was significantly higher only at intermediate abstinence, with no changes in the number of OrxR1-expressing cells. These data build on our previous findings that the hypothalamic Orx↔pPVT connection is strongly recruited shortly after cocaine abstinence and demonstrate that the priming effect of OrxA is not long lasting. Furthermore, these findings suggest that throughout abstinence, the Orx↔pPVT connection undergoes neuroadaptive changes, reflected by alterations of the number of OrxR2-expressing cells in the pPVT.

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

To 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.

Prolonged Withdrawal From Escalated Oxycodone Is Associated With Increased Expression of Glutamate Receptors in the Rat Hippocampus

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 h and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction analyses. Rats, given long-access (9 h per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 h per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6, and Grm8 subtypes of glutamate receptors after 31 days but not after 2 h of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

Prolonged Withdrawal from Escalated Oxycodone is Associated with Increased Expression of Glutamate Receptors in the Rat Hippocampus

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 hours and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction (qPCR) analyses. Rats, given long-access (9 hours per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 hours per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6 and Grm8 subtypes of glutamate receptors after 31 days but not after 2 hours of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.