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Insulin-like growth factor 1 (IGF-1) is an anabolic hormone with several biological activities, such as proliferation, mitochondrial protection, cell survival, tissue growth and development, anti-inflammatory, antioxidant, antifibrogenic and antiaging. This hormone plays an important role in embryological and postnatal states, being essential for normal foetal and placental growth and differentiation. During gestation, the placenta is one of the major sources of IGF-1, among other hormones. This intrauterine organ expresses IGF-1 receptors and IGF-1 binding proteins (IGFBPs), which control IGF-1 activities. Intrauterine growth restriction (IUGR) is the second most frequent cause of perinatal morbidity and mortality, defined as the inability to achieve the expected weight for gestational age. Different studies have revealed that IUGR infants have placental dysfunction and low circulating levels of insulin, IGF-1, IGF-2 and IGFBPs. Such data suggest that IGF-1 deficiency in gestational state may be one of the major causes of foetal growth retardation. The aim of this review is to study the epidemiology, physiopathology and possible causes of IUGR. Also, it intends to study the possible role of the placenta as an IGF-1 target organ. The purpose is to establish if IUGR could be considered as a novel condition of IGF-1 deficiency and if its treatment with low doses of IGF-1 could be a suitable therapeutic strategy.

Rationale: Despite decades of research specifying harmful effects produced by 3,4-methylenedioxymethamphetamine (MDMA; a principal component of 'ecstasy' pills), young people (and adults) continue to use it. In an attempt to model human MDMA consumption patterns, preclinical investigators have sought to establish reliable patterns of intravenous MDMA self-administration in rodents., Objective: The objective of this report is to offer a critical review of published data (including our own novel findings) that reveal MDMA self-administration in rodents., Results: The data indicate that MDMA serves as a reinforcer in rodents, though the responses are not similar to those previously reported for psychostimulants (i.e., cocaine). Important differences between rodent models and human use patterns include frequency of dosing and dosage exposure, routes of administration, tolerance that develops to MDMA after repeated exposure, polydrug use in humans but not by rodents, limits on the repertoire of behaviors that can be exhibited by rodents undergoing IV self-administration procedures, and the question of neurotoxicity as it relates to models of self-administration., Conclusions: While MDMA is not as potent a reinforcer as other drugs of abuse, the fact remains that young people and adults continue to use the drug, and therefore, additional research is needed to determine why drugs with low reinforcing effects continue to be abused.

Rationale: To determine the association between MDMA misuse and neurocognition using meta-analysis., Objective: Separate analyses were conducted based on two sets of inclusion/exclusion criteria. A relatively stringent set required that the subjects be matched on important moderator variables, whereas the other did not. The study participants' performance in the following neurocognitive domains was reviewed: attention/concentration, verbal and nonverbal learning and memory, psychomotor speed and executive systems functioning., Results: In the 11 studies meeting the relatively stringent inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Similarly, in the 23 studies meeting the relatively lenient inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Small to medium effect sizes were generally observed. A comparison of the effect sizes across the two sets of analyses did not reveal significant differences., Conclusions: The findings from this review reveal that MDMA use is associated with neurocognitive deficits. The implications of these findings are discussed.

Rationale: Methamphetamine dependence is a growing problem for which no medication treatments have proven effective., Objectives: We evaluated bupropion, an antidepressant with beneficial effects for the treatment of nicotine dependence, in patients with methamphetamine dependence, to assess the safety and tolerability of methamphetamine administration during bupropion treatment., Methods: Twenty-six participants entered the study and 20 completed the protocol. Participants received intravenous methamphetamine (0, 15, and 30 mg) before and after randomization to twice-daily bupropion (150 mg SR) or matched placebo. Dependent measures included cardiovascular effects of methamphetamine, methamphetamine and amphetamine pharmacokinetics, and peak and trough plasma concentrations of bupropion and its metabolites., Results: Bupropion treatment was well tolerated, with bupropion- and placebo-treated groups reporting similar rates of adverse events. Methamphetamine administration was associated with expected stimulant cardiovascular effects, and these were not accentuated by bupropion treatment. Instead, there was a trend for bupropion to reduce methamphetamine-associated increases in blood pressure and a statistically significant reduction in methamphetamine-associated increases in heart rate. Pharmacokinetic analysis revealed that bupropion treatment reduced the plasma clearance of methamphetamine and also reduced the appearance of amphetamine in the plasma. Methamphetamine administration did not alter the peak and trough plasma concentrations of bupropion or its metabolites., Conclusions: Methamphetamine administration was well tolerated during bupropion treatment. There was no evidence of additive cardiovascular effects when the drugs were coadministered. This study provides initial evidence for the safety of prescribing bupropion for the treatment of methamphetamine abuse and dependence. The impact of bupropion treatment in patients who abuse larger doses of methamphetamine remains undetermined.

Rationale: Drug challenges in "intact" and p-chlorophenylalanine (p-CPA)-treated animals can be used to distinguish agents that act as direct serotonin (5-HT) agonists from agents that function as 5-HT releasers., Objectives: The objective of the study was to investigate the effect of p-CPA treatment on the capacity of racemic 3,4-methylenedioxymethamphetamine (MDMA) and its stereoisomers to induce the head twitch response, hyperthermia, and locomotor stimulation in mice., Methods: Pretreatments with either 100 mg/kg p-CPA or equivolume saline were administered for three consecutive days. The following day, mice were either euthanized (to quantify 5-HT tone), tested with various doses of racemic MDMA or one of its enantiomers in the head twitch assay, or challenged with 32 mg/kg racemic MDMA or one of its enantiomers, while temperature and locomotor activity were monitored via radiotelemetry., Results: p-CPA reduced cortical 5-HT turnover by >70% without altering dopamine turnover. Racemic MDMA did not induce a significant head twitch response in intact or p-CPA-treated mice. S(+)-MDMA and R(-)-MDMA elicited similar head twitch curves in intact mice; p-CPA treatment attenuated this response when induced by S(+)-MDMA but not when elicited by R(-)-MDMA. Neither the hyperthermic nor locomotor-stimulant effects of racemic MDMA were altered by p-CPA treatment. The hyperthermic effects, but not the locomotor-stimulant effects, of S(+)-MDMA were attenuated in mice treated with p-CPA. R(-)-MDMA did not alter core temperature or induce significant locomotor stimulation in intact or p-CPA-treated mice., Conclusions: The effects of S(+)-MDMA on core temperature and head twitch behavior are consistent with a mechanism involving 5-HT release, whereas the effects of R(-)-MDMA on head twitch behavior are consistent with a direct agonist mechanism of action. The actions of the racemate on core temperature and locomotor activity likely involve a combination of 5-HT release and direct agonism at 5-HT receptors.

Rationale: Non-steroidal anti-inflammatory drugs (NSAIDs) counteract stress hormone and pro-inflammatory cytokine activation, and are being considered as therapeutics for Alzheimer's and Parkinson's disease, and multiple sclerosis. Previous data from our laboratory revealed that repeated treatment with the NSAID diclofenac attenuated lipopolysaccharide (LPS)-induced alterations to reward behavior, implicating a role for NSAIDs in alleviating depressive-like behavior., Objectives: To extend these findings, we sought to determine whether acute treatment with diclofenac would attenuate LPS-induced alterations to basic reward behavior, as well as neuroendocrine and neuroimmune function., Methods: Male, Wistar rats (n=8-9/grp) pressed a lever for sucrose pellet reward and after establishing a steady baseline were exposed to an injection of saline (1 ml/kg, SC) or diclofenac (2.5 mg/kg, SC) 30 min prior to a second injection of saline or LPS (20 microg/kg, IP)., Results: In saline pre-treated rats, LPS significantly reduced rate of sucrose pellet self-administration and total reinforcers obtained, suggestive of an anhedonia response. In addition, LPS increased corticosterone release, increased plasma intereleukin (IL)-1beta release, increased IL-1beta and IL-6 mRNA in hippocampus, increased corticotropin releasing hormone (CRH) mRNA in pituitary, and decreased CRH-1 mRNA in pituitary. Importantly, the behavioral and neuroendocrine effects, but not neuroimmune effects, produced by LPS were significantly attenuated in rats pre-treated with diclofenac., Conclusions: These new data provide a comprehensive assessment of the acute effects of diclofenac on LPS exposure in rats and confirm a role for NSAIDs in attenuating endotoxin-induced anhedonia. Of particular importance, the data reveal that the observed effects are mediated via the hypothalamic pituitary adrenal axis at the level of the pituitary or above.

Serotonin (5-HT) afferents may modulate the dopamine mesoaccumbens circuit, which has been shown to be critically involved in the locomotor stimulatory, discriminative stimulus, and rewarding properties of cocaine. In the present study, we investigated the role of 5-HT1A receptors in the ventral tegmental area (VTA) in mediating the discriminative stimulus effects of cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task. After acquiring the cocaine-saline discrimination, rats were stereotaxically implanted with bilateral guide cannulae into the VTA or adjacent substantia nigra reticulata (SNR). Intraperitoneal administration of cocaine (0.625-10 mg/kg) produced a dose-related increase in drug-lever responding. Both intra-VTA and intra-SNR infusion of cocaine (12.5-50 microg/0.5 microl/side) engendered primarily saline-like responding. Microinjection of the 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (DPAT; 0.1-10 microg/0.5 microl/side) or the 5-HT1A antagonist WAY 100635 (0.01-1.0 microg/0.5 microl/side) into the VTA or SNR did not substitute for the systemic cocaine cue. Further, intra-VTA or intra-SNR DPAT or WAY 100635 in combination with systemic doses of cocaine did not alter (i.e., attenuate or potentiate) the systemic cocaine cue. Overall, these data indicate that 5-HT1A receptors in the VTA do not mediate or modulate the discriminative stimulus effects of cocaine in the rat.

Dopamine (DA) D1 and D2 receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accumbens DA D1 receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625-20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5-40 micrograms) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 microliter/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D1 antagonist SCH 23390 (3-12 micrograms/kg) completely antagonized (< 20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025-0.4 microgram) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D1 receptors in modulating this behavior.

The present study was designed to assess the discriminative stimulus properties of cocaine in pigeons. Six pigeons were trained to discriminate IM injections of cocaine (2 mg/kg) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. Cocaine, d-amphetamine, and l-cathinone substituted completely for the training dose of cocaine in all pigeons. When nicotine (0.25-4.0 mg/kg), apomorphine (0.03-1.0 mg/kg), procaine (4-32 mg/kg), and lidocaine (4-16 mg/kg) were substituted, both partial substitutions and individual differences between pigeons were observed. Oxazepam (0.5-4.0 mg/kg) and pentobarbital (2-8 mg/kg) failed to substitute for the training dose of cocaine. Discriminative stimulus control by cocaine was greatest when the drug was administered 10-40 min prior to the session and the effects disappeared after 2 h. The substitution results indicate drug class specificity of the cocaine cue but, in addition, suggest its multidimensional nature.