Sex and housing conditions modify the effects of adolescent caffeine exposure on anxiety-like and depressive-like behavior in the rat Previously observed antidepressant-like effects of caffeine in adolescent rats have been shown in individually housed (IH) rats. Because IH presents a social stressor that may create depressant-like effects in control animals, this study sought to compare the effects of chronic caffeine in IH and pair-housed (PH) adolescent male and female rats. Housing conditions began on postnatal day 24 (P24) and half of the rats were provided caffeine (0.25 g/l) in their drinking water beginning on P28. Open-field behavior was assessed on P42, a light/dark test was conducted on P43, and a forced swim test was conducted on P44–P45. PH and caffeine separately increased behavior in the open-field test and females reared more than males. In the light/dark test, IH animals and males showed greater anxiety-like behavior than PH animals and females, respectively. In the forced swim test, PH animals showed less overall immobility and caffeine decreased immobility in IH rats and PH females but increased immobility in PH males. Swimming behavior was higher in PH rats overall and caffeine increased swimming in IH rats but decreased swimming in PH rats. Climbing behavior was increased by caffeine in all groups except PH males with the greatest increase in PH females. We conclude that the effects of caffeine on depressive-like and anxiety-like behavior in adolescents are dependent on sex and housing conditions.

A single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress Many people suffer from a major depressive disorder, and chronic pain conditions are often associated with depressive symptoms. Neurotropin, an extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been used for pain relief. Decrease of brain-derived neurotrophic factor (BDNF) in the brain is one of the proposed mechanisms for the major depressive disorders, and Neurotropin has been reported to restore the decreased BDNF in the hippocampus. In this experiment, we examined whether Neurotropin had an antidepressant-like effect in a model of fibromyalgia and whether BDNF in the brain was altered after repeated cold stress (RCS) and Neurotropin treatment. Rats were exposed to RCS because these animals have been used as a model for fibromyalgia syndrome. Depression-like behavior was evaluated using elongation of immobility time in a forced swimming test. Change in expression of BDNF in the brain was also examined by western blot analysis of several brain areas. Depression-like behavior in the forced swimming test was significantly increased 10–14 days after RCS, and this increase was reversed by a single injection of an antidepressant, imipramine, but not by PBS. Increased depression-like behavior was also dose-dependently suppressed by a single administration of Neurotropin (50–200 NU/kg, subcutaneously). BDNF expression was not changed in the brain areas examined (hippocampus, amygdala, prefrontal cortex, and striatum) either after RCS or by Neurotropin injected after RCS. These results suggest that RCS induced a depression-like state in rats, and Neurotropin reversed this state. However, we did not observe a BDNF-related mechanism for these effects.

Repeated administration of synthetic cathinone 3,4-methylenedioxypyrovalerone persistently increases impulsive choice in rats 3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0–30.0 mg/kg), MDPV (0.1–3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.

Locomotor sensitization in male Sprague-Dawley rats following repeated concurrent treatment with 4-methylmethcathinone and 3,4-methylenedioxymethamphetamine Recreational abuse of illicit synthetic cathinones is an ongoing public health concern. Recent studies indicate that the methcathinone derivative 4-methylmethcathinone (4-MMC) produces behavioral and neurochemical effects similar to the entactogen 3,4-methylenedioxymethamphetamine (MDMA). Whereas polysubstance abuse is common, most preclinical studies of drug abuse liability only evaluate the effects of single drugs. Utilizing the locomotor sensitization paradigm, the present study assessed the combined locomotor stimulant effects of 4-MMC and MDMA for induction of sensitization following repeated administration and for expression of sensitization to a challenge dose of either substance alone after a 10-day period of drug abstinence. Male Sprague-Dawley rats received once daily intraperitoneal injections of saline, 4-MMC (1.0 mg/kg or 5.0 mg/kg), MDMA (3.0 mg/kg), or a mixture containing 4-MMC (1.0 mg/kg or 5.0 mg/kg) + MDMA (3.0 mg/kg) for 7 consecutive days. Following a 10-day drug-free period, rats were given a single intraperitoneal injection of either saline, 4-MMC (1.0 or 5.0 mg/kg), or 3.0 mg/kg MDMA. Activity was recorded for 1 h immediately before and 1 h immediately after injections on days 1, 7, and 17. 4-MMC treatment failed to induce locomotor sensitization, but, when combined with MDMA, sensitization was induced to a greater extent than with MDMA alone. Furthermore, the expression of sensitization to a subsequent challenge dose of MDMA was observed only in animals previously exposed to MDMA or a 5.0 mg/kg 4-MMC + MDMA mixture. In consideration of these findings along with the fact that 4-MMC has similar neurochemical actions to MDMA, further research may be warranted to determine the abuse liability of drug mixtures including 4-MMC and MDMA.

PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.

Effect of amphetamine dose on wheel-running functioning as reinforcement or operant behavior on a multiple schedule of reinforcement Does the effect of amphetamine on behavior (wheel running) differ depending on the functional role (operant, reinforcement) of that behavior? This study addressed this question using a multiple schedule of reinforcement in which wheel running served as reinforcement for lever pressing in one component and as operant behavior for sucrose reinforcement in the other component. Seven female Long–Evans rats were exposed to a multiple schedule in which pressing a lever on a variable ratio 10 schedule produced the opportunity to run for 15 revolutions in one component and running 15 revolutions produced a drop of 15% sucrose solution in the other component. Doses of 0.5, 1.0, and 2.0 mg/kg D-amphetamine were administered by intraperitoneal injection 20 min prior to a session. As amphetamine dose increased, wheel running decreased in both components – showing no evidence that the effect of the drug on wheel running depended on the function of wheel activity. Notably, lever pressing for wheel-running reinforcement also decreased with amphetamine dose. Drug dose increased the initiation of operant lever pressing, but not the initiation of operant wheel running. We propose that amphetamine dose had common effects on wheel running regardless of its function (reinforcement vs. operant) because wheel-running generates automatic reinforcement and the automatic-reinforcement value of wheel activity is modulated by drug dose.

The effects of Engelhardtia chrysolepis Hance on long-term memory and potential dopamine involvement in mice Engelhardtia chrysolepis Hance (ECH) is a perennial plant used in traditional medicine. A major active ingredient of ECH is astilbin (ASB), which has recently been shown to have neuroprotective effects as well as to affect catecholamine neurotransmissions in brain areas such as the prefrontal cortex. In this study, we investigated the effects of ECH and ASB on long-term memory in mice using a battery of behavioral tests. Acute ECH treatments dose-dependently facilitated nonspatial, but not spatial, memory. ECH treatments also upregulated expression of tyrosine hydroxylase, the enzyme mediating catecholamine synthesis, in neuroblastoma cell culture. Acute ASB treatments similarly improved nonspatial memory, whereas chronic ASB treatments improved both nonspatial and spatial memory. In accordance with such behavioral effects, the increased ratio of tissue concentrations of dopamine metabolites over dopamine in striatal regions was observed in mice with chronic ASB treatments. These results suggest that ECH and its active ingredient ASB may facilitate long-term memory by modulating catecholamine transmission.

Differential effects of d-amphetamine and atomoxetine on risk-based decision making of Lewis and Fischer 344 rats Individuals with attention-deficit/hyperactivity disorder tend to make risker choices during probabilistic-discounting procedures. Thus, how common attention-deficit/hyperactivity disorder medications affect probabilistic discounting is of interest. In general, d-amphetamine increases risk-taking while atomoxetine has produced mixed effects in rats. Results from previous studies may result from genetic factors. Lewis and F344 rats have neurochemical differences that may be relevant to probabilistic discounting and how drugs affect such behavior. In this study, we evaluated dose-dependent effects of d-amphetamine and atomoxetine on probabilistic discounting of Lewis and F344. Male Lewis and F344 chose between one food pellet delivered 100% of the time and three food pellets delivered following decreasing probabilities of delivery (i.e. 100%, 66.7%, 33.3%, 16.5%, and 8.25%). Saline, d-amphetamine (0.1–1.8 mg/kg), and atomoxetine (0.1–7.8 mg/kg) were tested acutely. Lewis and F344 did not differ in choice at baseline. d-Amphetamine increased risky choice for both rat strains at low-to-moderate doses, although it did so at a lower dose (0.1 and 0.3 mg/kg) for F344 as compared to Lewis (0.3 mg/kg only). At high doses (1.0 and 1.8 mg/kg), d-amphetamine disrupted choice, increased frequencies of omitted trials, and reduced reinforcer sensitivity. Although atomoxetine increased frequencies of omitted trials at high doses (5.6 and 7.8 mg/kg), it had no effect on probabilistic discounting for either rat strain. Although Lewis and F344 differ in various types of impulsivity (i.e. motor, choice), with Lewis being the more impulsive of the two, the present results suggest that Lewis and F344 do not differ in risk-based decision-making. Effects of d-amphetamine on probabilistic discounting may be biology-dependent and differ from effects of atomoxetine.

Effects of progesterone treatment during adulthood on consummatory and motivational aspects of sexual behavior in male rats In males of a variety of species, administration of progesterone during adulthood has been shown to decrease the expression of consummatory sexual behaviors and androgen receptors. However, it remains to be determined if the progesterone-induced decrease in androgen-receptor signaling and consummatory sexual behaviors correspond with less of a preference for a sexually receptive female relative to another male, a behavioral phenotype indicative of sexual motivation. Consistent with the effects of progesterone reported in males of other species, progesterone-treated rats, relative to vehicle-treated rats, exhibited fewer intromissions and ejaculations. Correspondingly, the weights of the androgen sensitive bulbourethral glands were lighter in progesterone-treated rats. In addition, unlike vehicle-treated rats, progesterone-treated rats did not exhibit a preference for a female rat during the early stages of testing. However, across the entire test, both treatment groups exhibited a preference for a female rat, and consequently, there were no differences between the conditions in overall sexual motivation. Progesterone treatment did not alter activity or anxiety-like behaviors. The results of the current study suggest that the lower levels of androgen-receptor signaling and consummatory sexual behaviors in males following progesterone treatment are associated with a transient deficit in the preference for a female sexual incentive.