We have recently undertaken an extensive examination of the effects of chronic dietary lithium treatment on levels of brain leucine-enkephalin immunoreactivity (1-enk-IR), release of endogenous 1-enk-IR from globus pallidus prisms in vitro and behavioral responsiveness to pain. Two LiCl containing diets were used. Rats on the lower strength diet attained brain Li levels of 0.40-0.55 mEq/L, while those on the higher strength diet attained levels of 0.70-1.0 mEq/L. In one series of experiments, we sought to relate alterations of K+-stimulated, Ca++-dependent release of 1-enk-IR to alterations of the content of the peptide. After 1 week on the lower strength diet, neither measure was affected in any of the brain regions examined. Following 2 or 3 weeks of feeding with the lower strength diet, 1-enk-IR levels in the globus pallidus and nucleus accumbens were elevated. However, 3 weeks of the high strength Li diet did not lead to alterations of 1-enk-IR content. In contrast, the release of 1-enk-IR was potentiated but only in subjects in which the brain lithium exceeded a threshold level. In another series of studies, we observed that hot-plate escape latency was significantly elevated in rats fed the high strength Li diet for 3 weeks. Also, the Li-treated animals had a greater morphine-induced elevation of escape latency than controls; this effect was less effectively blocked by naltrexone. These findings suggest that chronic exposure to Li leads to transiently elevated levels of 1-enk, and, when brain Li levels are greater than 0.5 mEq/L, to a potentiation of endogenous enkephalin release. The analgesia in Li-treated subjects may eventually be related to these influences of the anti-manic drug on enkephalinergic neurotransmission.

Analgesia↗

PubMedDate not supplied

Morphological and functional correlates of VIP neurons in cerebral cortex.

Vasoactive Intestinal Polypeptide (VIP) promotes the hydrolysis of 3H-glycogen newly synthesized from 3H-glucose by mouse cortical slices. This effect occurs rapidly, approximately 50% of the maximal effect being reached within one minute. The maximal effect is achieved after 5 minutes and maintained for at least 25 minutes. Furthermore the glycogenolytic effect of VIP is reversible, and pharmacologically specific. Thus several neuropeptides present in cerebral cortex such as cholecystokinin-8, somatostatin-28, somatostatin-14, met-enkephalin, leu-enkephalin, do not affect 3H-glycogen levels. VIP fragments 6-28, 16-28 and 21-28 are similarly inactive. Furthermore, among the peptides which share structural homologies with VIP, such as glucagon, secretin, PHI-27 and Gastric Inhibitory Peptide, only secretin and PHI-27 promote 3H-glycogen hydrolysis, with EC50 of 500 and 300 nM respectively, compared to an EC50 of 25 nM for VIP. Immunohistochemical observations indicate that each VIP-containing bipolar cell is identified with a unique radical cortical volume, which is generally between 15-60 micrograms in diameter and overlaps with the contiguous domains of neighbouring VIP-containing bipolar cells. Thus this set of biochemical and morphological observations support the notion that VIP neurons have the capacity to regulate the availability of energy substrates in cerebral cortex locally, within circumscribed, contiguous, radial domains.

Animals↗

PubMedDate not supplied

Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol.

Small angle X-ray diffraction analysis of Alzheimer's disease (AD) lipid membranes extracted from cortical gray matter showed significant, reproducible structure changes relative to age-matched control samples. Specifically, there was an average 4 A reduction in the lipid bilayer width and significant changes in the membrane electron density profiles of AD cortical samples. There were no significant structure differences in the membrane bilayers isolated from an unaffected region (cerebellum) of the AD brain. Lipid and protein analysis of 6 AD and 6 age-matched controls showed that the phospholipid:protein mass ratio was unchanged but that the unesterified cholesterol:phospholipid (C:PL) mole ratio decreased by 30% in the AD temporal gyrus relative to age-matched controls. By contrast, the C:PL mole ratio in the cerebellum did not change significantly. X-ray diffraction analysis of a cholesterol enriched AD sample demonstrated a virtual restoration of the normal membrane bilayer width and electron density profile, suggesting that the cholesterol deficit played a major role in the AD lipid membrane structure perturbation. Alterations in the composition and structure of the membrane bilayer may play an important role in the pathophysiology of AD by altering the activity and catabolism of membrane-bound proteins, including the beta-amyloid precursor protein.

Aged↗

PubMedDate not supplied

Prefrontal levels of 5-HIAA, but not dopamine, predict alcohol consumption in male Wistar rats following 6-OHDA lesions.

To examine the effects of dopamine (DA) on alcohol consumption, male Wistar rats were subjected either to 6-OHDA lesions of the frontal cortex (MPFC) or to a sham lesion/no lesion. Following surgery, rats were trained to drink alcohol on a sucrose-fading paradigm over the course of 6 weeks, at the completion of which they consumed a solution of 3% sucrose/10% alcohol. Daily consumption of alcohol was computed for each rat. Animals were sacrificed and the MPFC, nucleus accumbens (NA), and ventral tegmentum (VTA) were removed. Levels of DA and its metabolites (i.e., HVA and DOPAC), norepinephrine (NE), and serotonin (5-HT) and its metabolite (i.e., 5-HIAA) were measured for each brain region using HPLC with electrochemical detection. Post hoc analyses were run examining the relationship of DA and its metabolites, 5-HT and its metabolite (5-HIAA), and norepinephrine (NE) in the MPFC, NA, and VTA with alcohol consumption. The 6-OHDA lesions depleted DA to 74.5% of control levels in the MPFC, but did not significantly affect alcohol consumption. Post hoc analyses found that the "high" alcohol consumption group had significantly reduced levels of MPFC 5-HIAA in comparison to the "low" consumption group, but that there was no relationship of 5-HIAA levels in the VTA or NA to alcohol consumption. These findings suggest that MPFC DA is not critically involved in the regulation of alcohol consumption. They further suggest that MPFC serotonergic systems may play an important role in the regulation of alcohol consumption, although future experimentation directly manipulating 5-HT systems in the MPFC will be required to fully assess these findings.

Alcohol Drinking↗