Effect of sustained postnatal systemic inflammation on hippocampal volume and function in mice.

BACKGROUND: Premature infants are at risk for persistent neurodevelopmental impairment. Children born preterm often exhibit reduced hippocampal volumes that correlate with deficits in working memory. Perinatal inflammation is associated with preterm birth and brain abnormalities. Here we examine the effects of postnatal systemic inflammation on the developing hippocampus in mice. METHODS: Pups received daily intraperitoneal injections of lipopolysaccharide (LPS) or saline between days 3 and 13. Ex vivo magnetic resonance imaging (MRI) and microscopic analysis of brain tissue was performed on day 14. Behavioral testing was conducted at 8-9 wk of age. RESULTS: MR and microscopic analysis revealed a 15-20% reduction in hippocampal volume in LPS-treated mice compared with controls. Behavioral testing revealed deficits in hippocampal-related tasks in LPS-treated animals. Adult mice exposed to LPS during the postnatal period were unable to select a novel environment when re-placed within a 1-min delay, were less able to remember a familiar object after a 1-h delay, and had impaired retention of associative fear learning after 24 h. CONCLUSION: Systemic inflammation sustained during the postnatal period contributes to reduced hippocampal volume and deficits in hippocampus-dependent working memory. These findings support the novel and emerging concept that sustained systemic inflammation contributes to neurodevelopmental impairment among preterm infants.

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications.

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2-32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained (0.001-0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment.

Impulsivity as a behavioral measure of withdrawal of orally delivered PCP and nondrug rewards in male and female monkeys.

BACKGROUND: Withdrawal of phencyclidine (PCP), ethanol (ETOH), and other drugs reduces operant responding maintained by food. OBJECTIVES: Experiment 1 examined the effects of withdrawing daily short access (2 h) to drug on impulsivity for saccharin (SACC) using a delay discounting task and comparing male and female rhesus monkeys. Experiment 2 examined the effects of withdrawing a nondrug substance (e.g., food or SACC) on impulsivity for PCP. MATERIALS AND METHODS: In experiment 1, either PCP or ETOH was available daily with water for 2 h under a fixed ratio 16 (FR 16) or FR 8 schedule, respectively. In a second component, SACC was available for 45 min under a delay discounting schedule. Next, water was substituted, and drug access was then restored. In experiment 2, PCP was available under a delay discounting schedule during food satiation or restriction or during concurrent SACC vs water access. RESULTS: In experiment 1, withdrawal of 0.5 mg/ml PCP increased impulsivity for SACC, but not SACC intake, in males and females. During 16% ETOH access, impulsivity for SACC was elevated compared to baseline water access, and it returned to baseline levels during ETOH withdrawal. In experiment 2, food restriction resulted in increased PCP intake in males and females and increases in impulsivity for PCP that were greater in males than in females. SACC withdrawal had no effect on impulsivity for PCP or PCP intake. CONCLUSIONS: Withdrawal of PCP and reduced food access increased impulsivity for SACC or PCP, respectively. Impulsivity is a sensitive indicator of drug dependence.

Contribution of fat-free mass and fat mass to bone mineral density among reproductive-aged women of white, black, and Hispanic race/ethnicity.

The objective of the study was to evaluate the contribution of fat-free mass (FFM) and fat mass (FM) to bone mineral density (BMD) and bone mineral apparent density (BMAD) among reproductive-aged women. Dual-energy X-ray absorptiometry scans were performed on 708 healthy black, white, and Hispanic women, 16-33 yr of age. The independent effect of FFM and FM on BMD and BMAD and the interaction of body composition measurements with race/ethnicity and age, were evaluated. FFM correlated more strongly than FM with BMD at the lumbar spine (r=0.52 vs r=0.39, p<0.01) and the femoral neck (r=0.54 vs r=0.41, p<0.01). There was a significant positive association between bone density measures [ln(BMD) and ln(BMAD)] and both ln(FFM) and ln(FM). The association of FFM with spinal BMD was stronger in 16-24-yr-old women than in 25-33-yr-old women (p<0.006). The effect of FFM on femoral neck BMD was greater in blacks (p<0.043) than Hispanics, whereas the effect of FM on spinal BMD was less (p<0.047). Both FM and FFM are important contributors to bone density although the balance of importance is slightly different between BMD and BMAD.

Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task.

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.

Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys.

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of a paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement during both the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration were significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP.

Effects of menstrual cycle phase on the reinforcing effects of phencyclidine (PCP) in rhesus monkeys.

Substantive evidence indicates that there are sex differences in the reinforcing effects of drugs, and gonadal steroid hormones, such as estrogen and progesterone, likely contribute to these differences. Among females, subjective effects of drugs differ as a function of menstrual cycle phase. The purpose of the present study was to compare oral self-administration of phencyclidine (PCP) in female rhesus monkeys (Macaca mulatta) across different phases of the menstrual cycle. Since the 28-day menstrual cycle of non-human primates is similar to that of humans, this model could provide important evidence supporting the implication that changes in the levels of gonadal hormones across menstrual phase can alter a drug's reinforcing effects. Oral self-administration of several concentrations of PCP (0.125, 0.25, and 0.5 mg/ml) was examined in three sexually mature female monkeys during 3-h experimental sessions. Menstrual cycle phase was determined by onset of menses and verified by examining vaginal cytology. PCP self-administration was greater during the luteal phase at the 0.125 and 0.25 mg/ml concentrations, which is normally characterized by high levels of progesterone and moderate levels of estrogen, than during the follicular phase, when levels of estrogen are increasing and progesterone levels are low. When examined within each phase, numbers of PCP deliveries were highest during the mid-luteal phase, compared to the early and mid-follicular phases. No differences in self-administration were observed between early and mid-follicular phases, but a significant difference in PCP deliveries was found between mid- and late luteal phases at the lowest concentration of PCP tested. The results from this study suggest that PCP's reinforcing effects in female monkeys differ as a function of menstrual cycle phase.

Reinforcing effects of smoked methamphetamine in rhesus monkeys.

RATIONALE: The occurrence of methamphetamine (METH) use by the smoking route is increasing. A nonhuman primate model for examining the reinforcing effects of smoked METH would be valuable for testing potential interventions for treating METH abuse disorders. OBJECTIVE: The purpose of the present study was to examine the reinforcing effects of smoked METH in monkeys. MATERIALS AND METHODS: Four rhesus monkeys were trained to smoke cocaine (COC) under a chain fixed-ratio (FR) 64 lever press, FR 5 inhalation schedule of reinforcement. Upon observing stable levels of self-administration, METH was substituted for COC and a dose-response function for METH (0.08-0.8 mg/kg) was determined. Subsequently, the number of deliveries of COC (1 mg/kg), and 0.2 and 0.8 mg/kg METH were examined across increasing response requirements. RESULTS: METH was dose-dependently self-administered. Higher doses of METH (0.2, 0.4, and 0.8 mg/kg) produced asymptotic levels of responding that were slightly lower than those obtained with 1 mg/kg COC. Numbers of deliveries of COC and METH decreased as response requirement increased. METH, however, maintained fewer deliveries than 1 mg/kg COC at most response requirements. CONCLUSIONS: METH is readily self-administered by smoking in rhesus monkeys when substituted for COC. METH may have a lower reinforcing strength than COC, but further research is needed to fully characterize its relative reinforcing strength.

Effects of memantine, haloperidol, and cocaine on primary and conditioned reinforcement associated with cocaine in rhesus monkeys.

RATIONALE: The N-methyl-D-aspartate (NMDA) receptor has been implicated in mediating the reinforcing effects of abused drugs. Some reports indicate the uncompetitive NMDA antagonist, memantine, modulates the conditioned and unconditioned effects of stimulants in rats. OBJECTIVE: The objective of this study was to evaluate the effects of memantine on the primary and conditioned reinforcing effects of cocaine in the rhesus monkey. METHODS: Rhesus monkeys were trained to press levers reinforced with either cocaine-associated stimuli (brief stimuli, BS) or 30-microg/kg cocaine infusion during daily, 75-min experimental sessions in which the reinforcers were independently available in separate components according to identical progressive ratio (PR) schedules. Memantine (0.3-10 mg/kg), and as comparators, haloperidol (0.001-0.1 mg/kg) and cocaine (0.01-1 mg/kg), were administered 5 min before experimental sessions. RESULTS: Memantine (0.3-3 mg/kg) produced decreases in responding maintained by BS presentations at some doses which failed to affect cocaine self-administration when measured during equivalent periods early in the experimental session. Memantine (3 mg/kg) increased cocaine self-administration, however, later in the session. A low dose of haloperidol (0.001 mg/kg) increased the number of BS presentations, whereas higher doses decreased their number. Cocaine self-administration was not significantly affected by haloperidol until a behaviorally suppressant dose (0.1 mg/kg) was administered. Pretreatment with high doses of cocaine (0.3 and 1 mg/kg) decreased responding maintained by both reinforcers. CONCLUSION: These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.

Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys.

Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a mu-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphine-dependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through mu-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects.

Modulation of the locomotor activating effects of the noncompetitive NMDA receptor antagonist MK801 by dopamine D2/3 receptor agonists in mice.

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.

Heroin discriminative stimulus effects of methadone, LAAM and other isomers of acetylmethadol in rats.

RATIONALE: LAAM (alpha- l-acetylmethadol) is a derivative of the synthetic mu-opiate agonist methadone and is one of the four isomers of acetylmethadol. Methadone and LAAM have similar pharmacological properties and both are approved medications for the treatment of heroin dependency disorders. Few studies have reported on the pharmacology of acetylmethadol's other isomers and most of these have focused on their potential analgesic activity. OBJECTIVES: The purpose of the present investigation was to examine the discriminative stimulus effects of LAAM, the other isomers of acetylmethadol, and methadone in rats trained to discriminate heroin from water, and to compare the duration of the discriminative stimulus effects of heroin, methadone, and LAAM. METHODS: Long-Evans rats were trained to discriminate 0.3 mg/kg heroin from water under a fixed ratio 10 (FR10) schedule of food reinforcement. Dose-response functions for heroin, methadone, LAAM, three other isomers of acetylmethadol: alpha- d-acetylmethadol, beta- d-acetylmethadol, beta- l-acetylmethadol, and its precursor, beta- l-methadol were examined. Additionally, the time course effects for heroin, methadone, and LAAM were examined. RESULTS: LAAM and methadone dose-dependently occasioned heroin-like discriminative stimulus effects. Two of acetylmethadol's isomers, alpha- d-acetylmethadol and beta- d-acetylmethadol, were more potent than LAAM in producing heroin-like effects. The beta- l-methadol precursor and beta- l-acetylmethadol did not fully substitute for heroin's discriminative stimulus. LAAM elicited heroin-like discriminative stimulus effects for at least 6 h and generated partial generalization up to 36 h following administration. CONCLUSIONS: Methadone, LAAM, beta- d-acetylmethadol and alpha- d-acetylmethadol, but not beta- l-acetylmethadol and beta- l-methadol evoke heroin-like discriminative stimulus effects.