Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents

Major depressive disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA(A) agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism

A Disintegrating Minor Planet Transiting a White Dwarf

White dwarfs are the end state of most stars, including the Sun, after they exhaust their nuclear fuel. Between 1/4 and 1/2 of white dwarfs have elements heavier than helium in their atmospheres1,2, even though these elements should rapidly settle into the stellar interiors unless they are occasionally replenished3–5. The abundance ratios of heavy elements in white dwarf atmospheres are similar to rocky bodies in the Solar system6,7. This and the existence of warm dusty debris disks8–13 around about 4% of white dwarfs14–16 suggest that rocky debris from white dwarf progenitors’ planetary systems occasionally pollute the stars’ atmospheres17. The total accreted mass can be comparable to that of large asteroids in the solar system1. However, the process of disrupting planetary material has not yet been observed. Here, we report observations of a white dwarf being transited by at least one and likely multiple disintegrating planetesimals with periods ranging from 4.5 hours to 4.9 hours. The strongest transit signals occur every 4.5 hours and exhibit varying depths up to 40% and asymmetric profiles, indicative of a small object with a cometary tail of dusty effluent material. The star hosts a dusty debris disk and the star’s spectrum shows prominent lines from heavy elements like magnesium, aluminium, silicon, calcium, iron, and nickel. This system provides evidence that heavy element pollution of white dwarfs can originate from disrupted rocky bodies such as asteroids and minor planets.Astronom

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania

Physiological and pharmacological bases for the diverse properties of benzodiazepines and their congeners.

Benzodiazepines (BZs), which have been marketed by pharmaceutical companies since the sixties, are the most commonly prescribed psychotropic drugs. Diazepam, the prototype of this class of drugs, has a vast spectrum of therapeutic indications. It possesses, over a narrow dose-range, the well-known neuropsychopharmacological profile consisting of anxiolytic, anticonvulsant, sedative, and muscle relaxant effects, and CNS depression. Recently, BZ ligands that retain anxiolytic and antiepileptic properties at doses that are unable to produce a CNS depression have been developed. The pharmacological profiles of these drugs are discussed in light of: the heterogeneity of the structure of the GABAA receptor complex; intrinsic efficacy of the ligand; action of the BZ ligand on the mitochondrial BZ receptor

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature

Characterization of [3H]-imidazenil binding to rat brain membranes.

1. The binding of [3H]-imidazenil, an imidazobenzodiazepine carboxamide, to rat cerebellar membranes was characterized at different temperatures. 2. Specific binding was linear with tissue concentrations and reached maximum after 90, 30 and 5 min incubation at 0, 21 and 37 degrees C, respectively. The binding was of high affinity, specific and saturable; non linear regression and Scatchard analysis of the data was compatible with the presence of a single population of receptor sites with Bmax of 0.74 +/- 0.020, 0.90 +/- 0.011 and 1.0 +/- 0.036 pmol mg-1 protein at 0, 21 and 27 degrees C, respectively. Binding affinity decreased with increasing temperature: Kd were 0.29 +/- 0.051 nM (0 degrees C), 1.0 +/- 0.080 nM (21 degrees C) and 2.4 +/- 0.38 nM (37 degrees C). 3. At all tested temperatures, [3H]-imidazenil binding was reversible and the Kd calculated from the dissociation and association rate constants approximated the equilibrium Kd. 4. In the presence of gamma-aminobutyric acid (GABA), Kd increased 4 fold at 0 degrees C, whereas Bmax increased, albeit slightly, at all temperatures. 5. Benzodiazepines (BZDs), imidazopyridines and methyl-beta-carboline-3-carboxylate (beta CCM) were effective inhibitors of [3H]-imidazenil binding. Conversely, GABAA antagonists, barbiturates, picrotoxin and peripheral BZD receptor ligands were devoid of any activity. 6. Comparing [3H]-imidazenil to [3H]-flumazenil binding in various brain areas, similar densities of recognition sites as well as like regional differences in the distribution of binding sites for both radioligands were observed (cortex = striatum > cerebellum > spinal cord). 7. The present results indicate that [3H]-imidazenil specifically binds to the BZD sites of GABAA receptors. Furthermore, the effects of GABA and temperature differentiate imidazenil from classicalBZDs. It is suggested that the characteristics of imidazenil binding may be relevant to the in vivo pharmacology of the drug