Effects of NMDA receptor antagonists on behavioral economic indices of cocaine self-administration.

BACKGROUND: Currently, there are no FDA-approved medications for the treatment of psychostimulant (e.g., cocaine) use disorders. Because the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor is an important mediator of addiction-like behaviors, the goal of the current study was to determine if the GluN2B-selective antagonist Ro 63-1908 is efficacious in attenuating cocaine self-administration. METHODS: Adult Sprague Dawley rats (24 males and 11 females) were implanted with indwelling catheters and were trained to self-administer cocaine (0.75 mg/kg/inf). Rats were then trained in a threshold procedure, in which the dose of cocaine decreased across six 6-min blocks (0.75, 0.27, 0.08, 0.03, 0.01, 0.003 mg/kg/inf). This procedure allowed for the quantification of behavioral economic indices of drug self-administration. Following training in the threshold procedure, rats were treated with the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Rats also received treatments of the NMDA receptor channel blocker MK-801 (0, 0.01, 0.03, 0.06 mg/kg; s.c.). RESULTS: Blocking NMDA receptors decreased initial intake (i.e., consumption during the first block), although Ro 63-1908 and MK-801 increased area under the curve (global measure of demand) and decreased demand elasticity, an effect observed primarily in males. Neither drug affected demand intensity (i.e., consumption of cocaine at a minimally constrained price). CONCLUSIONS: While blocking the NMDA receptor decreases initial intake of cocaine, NMDA receptor antagonists make cocaine more inelastic with increasing price. These results suggest that NMDA receptor antagonists can exacerbate addiction-like behaviors during self-administration during extinction-like conditions that are observed in later blocks of the threshold procedure.

The association between risky decision making and cocaine conditioned place preference is moderated by sex.

BACKGROUND: Excessive risk taking is a characteristic trait of several psychiatric conditions, including substance use disorders. High risk-taking (HiR) rats self-administer more cocaine compared to low risk-taking (LoR) rats. However, research has not determined if risk taking is associated with enhanced cocaine conditioned place preference (CPP). METHODS: Male and female Sprague Dawley rats (n = 48 each sex) were first tested in the risky decision task (RDT), in which a response on one lever resulted in safe delivery of one food pellet, and a response on a different lever resulted in delivery of two pellets and probabilistic delivery of foot shock. Following RDT training, rats were tested for cocaine CPP. The first session was a pretest that measured rats' preference for three compartments that provided different visual and tactile cues. Rats then learned to associate one compartment with cocaine (either 10.0 mg/kg or 20.0 mg/kg; i.p.) and one compartment with saline (1.0 ml/kg; i.p.) across eight conditioning sessions. Finally, rats explored all three compartments in a drug-free state. RESULTS: Sex significantly moderated the association between risky decision making and cocaine CPP. While increased risk aversion was somewhat positively associated with cocaine CPP in males, increased risk taking was positively correlated with cocaine CPP in females. CONCLUSIONS: These results highlight the moderating role of sex on the relationship between risky decision making and cocaine reward.

Draft Genome Sequences of Three Shewanella sp. Strains Isolated from Urban Freshwaters in the Ohio River Valley, USA.

Draft genome sequences of three Shewanella sp. strains are reported. The strains NKUCC01_JLK, NKUCC05_KAH, and NKUCC06_TVS were isolated from freshwater sources in the Ohio River Valley, USA. These genome sequences provide insights into Shewanella adaptation to urban freshwaters and may help to elucidate their roles in biogeochemical cycling.

Effects of the GluN2B-selective antagonist Ro 63-1908 on acquisition and expression of methamphetamine conditioned place preference in male and female rats.

BACKGROUND: Methamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl-d-aspartate (NMDA) GluN2B-selective antagonist Ro 63-1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP). METHODS: Two main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63-1908 (1.0-10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63-1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP. RESULTS: Ro 63-1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63-1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63-1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63-1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6). CONCLUSIONS: The results of this study show that Ro 63-1908 is able to decrease the conditioned rewarding effects of methamphetamine.

Differential effects of glutamate N-methyl-D-aspartate receptor antagonists on risky choice as assessed in the risky decision task.

RATIONALE: Risky choice can be measured using the risky decision task (RDT). In the RDT, animals choose between a large, risky option that is paired with probabilistic foot shock and a small, safe option that is never paired with shock. To date, studies examining the neurochemical basis of decision-making in the RDT have focused primarily on the dopaminergic system but have not focused on the glutamatergic system, which has been implicated in risky decision-making. OBJECTIVES: Because glutamate is known to play a critical role in decision-making, we wanted to determine the contribution of the glutamatergic system to performance in the RDT. METHODS: In the experiment, 32 rats (16 male; 16 female) were tested in the RDT. The probability of receiving a foot shock increased across the session (ascending schedule) for half of the rats but decreased across the session (descending schedule) for half of the rats. Following training, rats received injections of the N-methyl-D-aspartate (NMDA) receptor competitive antagonist CGS 19755 (0, 1.0, 2.5, 5.0 mg/kg; s.c.) and the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). RESULTS: CGS 19755 (2.5 and 5.0 mg/kg) increased risky choice in males and females trained on the ascending schedule. Ro 63-1908 (1.0 mg/kg) decreased risky choice, but only in male rats trained on the ascending schedule. CONCLUSIONS: Although NMDA receptor antagonists differentially alter risky choice in the RDT, the current results show that NMDA receptors are an important mediator of decision-making involving probabilistic delivery of positive punishment.

Pair housing, but not using a controlled reinforcer frequency procedure, attenuates the modulatory effect of probability presentation order on amphetamine-induced changes in risky choice.

Probability discounting is often measured with independent schedules. Independent schedules have several limitations, such as confounding preference for one alternative with frequency of reward presentation and generating ceiling/floor effects at certain probabilities. To address this potential caveat, a controlled reinforcer frequency schedule can be used, in which the manipulandum that leads to reinforcement is pseudo-randomly determined before each trial. This schedule ensures subjects receive equal presentations of the small and large magnitude reinforcers across each block of trials. A total of 24 pair-housed and 11 individually housed female Sprague Dawley rats were tested in a controlled reinforcer frequency procedure. For half of the rats, the odds against (OA) receiving the large magnitude reinforcer increased across the session (ascending schedule); the OA decreased across the session for half of the rats (descending schedule). Following training, rats received treatments of amphetamine (AMPH; 0, 0.25, 0.5, 1.0 mg/kg; s.c.). For pair-housed rats, AMPH (0.5 mg/kg) increased risky choice, regardless of probability presentation order, whereas a higher dose of AMPH (1.0 mg/kg) decreased discriminability of reinforcer magnitude for rats trained on the descending schedule only. For individually housed rats, probability presentation order modulated the effects of AMPH on probability discounting, as AMPH (0.25 and 0.5 mg/kg) increased risky choice in rats trained on the ascending schedule but not on the descending schedule. These results show that pair-housing animals, but not using a controlled reinforcer frequency procedure, attenuates the modulatory effects of probability presentation order on drug effects on risky choice.

Effects of d-amphetamine and MK-801 on impulsive choice: Modulation by schedule of reinforcement and delay length.

Procedural modifications can modulate drug effects in delay discounting, such as signaling the delay to reinforcement and altering the order in which delays are presented. Although the schedule of reinforcement can alter the rate at which animals discount a reinforcer, research has not determined if animals trained on different schedules of reinforcement are differentially affected by pharmacological manipulations. Similarly, research has not determined if using different delays to reinforcement can modulate drug effects in delay discounting. Male Sprague Dawley rats (n = 36) were split into four groups and were trained in a delay-discounting procedure. The schedule of reinforcement (fixed ratio [FR] 1 vs. FR 10) and delays to reinforcement (0, 5, 10, 20, and 50 s vs. 0, 10, 30, 60, 100 s) were manipulated for each group. Following behavioral training, rats were treated with d-amphetamine (0, 0.25, 0.5, and 1.0 mg/kg) and MK-801 (0, 0.03, and 0.06 mg/kg). Results showed that amphetamine decreased impulsive choice when a FR 1 schedule was used, but only when the short delay sequence was used. Conversely, amphetamine decreased impulsive choice when a FR 10 schedule was used, but only when rats were trained on the long delay sequence. MK-801 decreased impulsive choice in rats trained on a FR 1 schedule, regardless of delay sequence, but did not alter choice in rats trained on a FR 10 schedule. These results show that schedule of reinforcement and delay length can modulate drug effects in delay discounting.

Group I metabotropic glutamate receptor antagonists impair discriminability of reinforcer magnitude, but not risky choice, in a probability-discounting task.

The glutamatergic system has been identified as an important mediator of risky choice. However, previous studies have focused primarily on ionotropic glutamate receptors (e.g., NMDA receptors). Little research has examined the contribution of metabotropic glutamate receptors (mGluRs) on risky choice. The goal of the current experiment was to determine the effects of mGluR1 and mGluR5 antagonism on risky choice as assessed in probability discounting (PD). Male Sprague Dawley rats (n = 24) were trained in PD, in which consistently choosing a large, probabilistic reward (LR) reflects risky choice. For half of the rats, the odds against (OA) receiving the LR increased across blocks of trials, whereas the OA decreased across the session for half of the rats. Following training, rats received injections of the mGluR1 antagonist JNJ 16,259,685 (JNJ; 0, 0.1, 0.3, or 1.0 mg/kg; i.p) and the mGluR5 antagonist MTEP (0, 1.0, 3.0, or 10.0 mg/kg; i.p.). Regardless of which schedule was used, JNJ and MTEP decreased preference for the LR when its delivery was guaranteed. In contrast to delay discounting, in which blocking the mGluR1 has been shown to alter impulsive choice, these results show that the Group I mGluR family does not selectively alter risky choice. Instead, blocking these receptors appears to impair discriminability of reinforcers of varying magnitudes in PD.