Influence of dietary fats on Ecstasy-induced hyperthermia.

BACKGROUND AND PURPOSE: Studies were designed to examine the effects of dietary fats on metabolic effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). These effects included hyperthermia, expression of uncoupling protein (UCP1 and 3) in brown adipose tissue or skeletal muscle and plasma free fatty acid (FFA) levels. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were fed either a high-fat diet (HFD, 60% kcal) or a lower fat isocaloric controlled diet (LFD, 10% kcal) for 28 days before MDMA challenge. KEY RESULTS: No significant differences were observed between LFD and HFD groups in terms of body weight, plasma thyroxine (T4) levels and expression of brown fat UCP1 or skeletal muscle UCP3 protein. HFD significantly raised levels of circulating FFA and potentiated the thermogenesis induced by MDMA (10 mg kg(-1), s.c.), compared to the effects of the LFD. Moreover, 30 and 60 min after MDMA administration, plasma FFA levels decreased in HFD animals, but were markedly elevated in the LFD group. CONCLUSIONS AND IMPLICATIONS: These results indicate that high-fat feeding regulates MDMA-induced thermogenesis by augmenting the activation of UCP rather than its expression.

Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors.

Leu100Ile, Val106Ala and Val108Ile are mutations in HIV-1 reverse transcriptase (RT) that are observed in the clinic and give rise to resistance to certain non-nucleoside inhibitors (NNRTIs) including the first-generation drug nevirapine. In order to investigate structural mechanisms of resistance for different NNRTI classes we have determined six crystal structures of mutant RT-inhibitor complexes. Val108 does not have direct contact with nevirapine in wild-type RT and in the RT(Val108Ile) complex the biggest change observed is at the distally positioned Tyr181 which is > 8 A from the mutation site. Thus in contrast to most NNRTI resistance mutations RT(Val108Ile) appears to act via an indirect mechanism which in this case is through alterations of the ring stacking interactions of the drug particularly with Tyr181. Shifts in side-chain and inhibitor positions compared to wild-type RT are observed in complexes of nevirapine and the second-generation NNRTI UC-781 with RT(Leu100Ile) and RT(Val106Ala), leading to perturbations in inhibitor contacts with Tyr181 and Tyr188. Such perturbations are likely to be a factor contributing to the greater loss of binding for nevirapine compared to UC-781 as, in the former case, a larger proportion of binding energy is derived from aromatic ring stacking of the inhibitor with the tyrosine side-chains. The differing resistance profiles of first and second generation NNRTIs for other drug resistance mutations in RT may also be in part due to this indirect mechanism.

Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.

BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

The effect of aging on experience-dependent plasticity of hippocampal place cells.

The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i. e., there was "phase precession," as reported by others). The net phase shift did not differ between age groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, so that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.

Deciphering the hippocampal polyglot: the hippocampus as a path integration system.

Hippocampal 'place' cells and the head-direction cells of the dorsal presubiculum and related neocortical and thalamic areas appear to be part of a preconfigured network that generates an abstract internal representation of two-dimensional space whose metric is self-motion. It appears that viewpoint-specific visual information (e.g. landmarks) becomes secondarily bound to this structure by associative learning. These associations between landmarks and the preconfigured path integrator serve to set the origin for path integration and to correct for cumulative error. In the absence of familiar landmarks, or in darkness without a prior spatial reference, the system appears to adopt an initial reference for path integration independently of external cues. A hypothesis of how the path integration system may operate at the neuronal level is proposed.