Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

Background

Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug''s consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit.

Methodology/Principal Findings

We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine.

Conclusions/Significance

Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus–nearly perfectly correlated with the infusion–likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse.     

Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding

Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that influence the antiviral potency of two such gp41 inhibitors, C37 and 5-Helix. Employing a series of C37 and 5-Helix variants, we investigated the physical properties of gp41 inhibition, including the ability of inhibitor-bound gp41 to recover its fusion activity once inhibitor was removed from solution. Our results indicated that antiviral activity critically depended upon irreversible deactivation of inhibitor-bound gp41. For C37, which targets the N-terminal region of the gp41 ectodomain, deactivation was a slow process that depended on chemokine receptor binding to Env. For 5-Helix, which targets the C-terminal region of the gp41 ectodomain, deactivation occurred rapidly following inhibitor binding and was independent of chemokine receptor levels. Due to this kinetic disparity, C37 inhibition was largely reversible, while 5-Helix inhibition was functionally irreversible. The fundamental difference in deactivation mechanism points to an unappreciated asymmetry in gp41 following inhibitor binding and impacts the development of improved fusion inhibitors and HIV-1 vaccines. The results also demonstrate how the activities of intermediate state inhibitors critically depend upon the final disposition of inhibitor-bound states.     

An altered oxidant defense system in red blood cells affects their ability to release nitric oxide-stimulating ATP

A novel microflow technique is used to demonstrate that a weakened oxidant defense system found in diabetic erythrocytes leads to decreased levels of deformation-induced release of adenosine triphosphate (ATP) from erythrocytes. Addition of an oxidant to rabbit erythrocytes resulted in a 63% decrease in deformation-induced ATP release before eventually recovering to a value that was statistically equivalent to the initial value. Inhibition of glucose-6-phosphate dehydrogenase prevents recovery from the oxidant attack. Finally, results indicated that the ATP release from the erythrocytes of type II diabetics (91 nM +/- 10 nM) was less than half of that measured from the erythrocytes of healthy controls (190 +/- 10 nM). These data suggest that the antioxidant status of erythrocytes is a critical determinant in the ability of these cells to release ATP, a known nitric oxide stimulus.     

The pathology of embryo death caused by the male-killing Spiroplasma bacterium in Drosophila nebulosa

Background

Inherited bacteria that kill male offspring, male-killers, are known to be common in insects, but little is understood about the mechanisms used by male-killing bacteria to kill males. In this paper we describe the tempo and changes that occur during male-killing by Spiroplasma bacteria in the host Drosophila nebulosa.

Results

Spiroplasma infected D. nebulosa males were developmentally retarded from 6–8 h into embryonic development at 25°C, and arrested at between stages 12 and 13 of embryogenesis (10–12 h). Dying males were characterized by a failure to form segments, and ultimately disintegration of the normal oval embryonic shape. Prior to death, dying males exhibited widespread apoptosis, as testified by TUNEL staining.

Conclusion

The Spiroplasma kills male Drosophila in a narrow developmental period, shortly after the formation of the host dosage compensation complex that is required for male-killing. Male death is preceded by widespread apoptosis, but it is uncertain if this is primary or secondary apoptosis.     

Ileal bile acid transporter inhibition,CYP7A1 induction,and antilipemic action of 264W94

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 micro M [(3)H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC(50)s of 0.24 micro M and 0.41 micro M, and had a competitive profile with K(i) of 0.2 micro M against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1-10 micro M of 264W94 rapidly decreased uptake of 3mM TC by 24-39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-(75)Se-homocholic acid taurine ((75)SeHCAT; quantitated in feces), with ED(30) of 0.02 mg/kg bid. (75)SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of (75)SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03-1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL cholesterol up to 61%. In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.     

Paraquat Suicide in a Young Woman: Results of Therapy Directed Against the Superoxide Radical

The clinical course of a young woman following two separate suicide attempts using the herbicide paraquat is reported. The patient survived an intramuscular injection of paraquat almost asymptomatically, but later exhibited a typical fatal course with fulminant proliferative pulmonary fibrosis after an intravenous injection. Fibrosis and death occurred despite a therapeutic regimen based upon a known action of paraquat, the generation of superoxide (O₂[unk]), using superoxide dismutase, α-tocopherol, and ascorbic acid in conjunction with forced diuresis and prednisone. While treatment failed explanations for the failure of therapy in this case and current therapeutic alternatives are discussed so that they may be considered when future cases are encountered.     

Theory for why dioecious plants have equal length sex chromosomes

Dioecy and sex chromosomes almost certainly evolved from ancestral hermaphrodites that only possessed autosomes. There is a growing body of evidence that genes for female or male function were then epigenetically suppressed in some of these hermaphrodites, creating the first males or females and nascent sex chromosomes. The incipient sex-determining epigenetic signals, such as cytosine methylation, then drove Muller's ratchet in many animals, resulting in shorter Y chromosomes. Based on this theory of sex chromosome evolution and limited data on gametophyte gene expression, I argue that plants should be largely immune from Muller's ratchet and therefore retain their ancestral state of equal length sex chromosomes, unless they incur chromosomal rearrangements or large-scale insertions of duplicated genomes. Usually heteromorphic sex chromosomes canalize dioecy, but extensive polyploidy or polysomy can provide an escape from this canalized dioecy. This theory implies that dioecy due to heteromorphic sex chromosomes should be evolutionarily ephemeral in bryophytes and homosporous pteridophytes because of their extraordinarily high incidences of polyploidy. And, if anything, these very high incidences of polyploidy are responsible for translocation or gradual addition of beneficial genes, rather than gradual reduction in the length of a sex chromosome.     

Conformational selection during weak binding at the actin and myosin interface

The molecular mechanism of the powerstroke in muscle is examined by resonance energy transfer techniques. Recent models suggesting a pre-cocking of the myosin head involving an enormous rotation between the lever arm and the catalytic domain were tested by measuring separation distances among myosin subfragment-2, the nucleotide site, and the regulatory light chain in the presence of nucleotide transition state analogs. Only small changes (<0.5 nm) were detected that are consistent with internal conformational changes of the myosin molecule, but not with extreme differences in the average lever arm position suggested by some atomic models. These results were confirmed by stopped-flow resonance energy transfer measurements during single ATP turnovers on myosin. To examine the participation of actin in the powerstroke process, resonance energy transfer between the regulatory light chain on myosin subfragment-1 and the C-terminus of actin was measured in the presence of nucleotide transition state analogs. The efficiency of energy transfer was much greater in the presence of ADP-AlF(4), ADP-BeF(x), and ADP-vanadate than in the presence of ADP or no nucleotide. These data detect profound differences in the conformations of the weakly and strongly attached cross-bridges that appear to result from a conformational selection that occurs during the weak binding of the myosin head to actin.     

Population dynamics of a diverse rodent assemblage in mixed grass-shrub habitat, southeastern Colorado, 1995-2000

We followed seasonal and year-to-year population dynamics for a diverse rodent assemblage in a short-grass prairie ecosystem in southeastern Colorado (USA) for 6 yr. We captured 2,798 individual rodents (range, one to 812 individuals per species) belonging to 19 species. The two most common species, deer mice (Peromyscus maniculatus) and western harvest mice (Reithrodontomys megalotis), generally had population peaks in winter and nadirs in summer; several other murid species demonstrated autumn peaks and spring nadirs; heteromyids were infrequently captured in winter, and populations generally peaked in summer or autumn. Inter-annual trends indicated an interactive effect between temperature and precipitation. Conditions associated with low rodent populations or population declines were high precipitation during cold periods (autumn and winter) and low precipitation during warm periods (spring and summer). Severity of adverse effects varied by species. Heteromyids, for example, were apparently not negatively affected by the hot, dry spring and summer of 2000. Cross-correlations for the temporal series of relative population abundances between species pairs (which are affected by both seasonal and interannual population dynamics) revealed positive associations among most murids and among most heteromyids, but there were negative associations between murids and heteromyids. These results have important implications for those attempting to model population dynamics of rodent populations for purposes of predicting disease risk.