Faculty Bibliography

Recent studies have shown that the beta-blockers can be effective treatments for neuroleptic-induced akathisia. However, the relative contributions of beta-1 versus beta-2 blockade to the therapeutic effect of beta-blockers remains unclear. We treated nine patients who had neuroleptic-induced akathisia with low doses (25-100 mg/day) of the beta-blocker metoprolol. At these doses metoprolol causes selective blockade of beta-1 receptors. Seven patients improved after metoprolol; no further substantial changes were seen after subsequent treatment with propranolol. This finding suggests that neuroleptic-induced akathisia can be improved by selective beta-1 blockade

Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using [18F]N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of [18F]N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS

Injection of the dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (NPA; 5-40 micrograms) into anterior ventral striatal sites (either lateral (VL) or medial (VM) elicited dose-dependent oral and sniffing stereotypies of rapid onset, long duration and high intensity. In contrast, injection into anterior dorsolateral (DL) or posterior ventral (lateral (PL) or medial (PM] sites produced little oral and moderate sniffing behavior of slower onset, shorter duration and low intensity. Injection into the dorsomedial (DM) striatum produced intermediate effects. Intra-accumbens NPA elicited weak oral activity and moderate sniffing which was similar in onset, duration and intensity to the least sensitive striatal sites (DL, PM and PL). In other experiments, DA receptors were inactivated with the irreversible blocking agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 6 mg/kg) and behavioral recovery was monitored by challenge with 20 micrograms NPA into the VL or the nucleus accumbens (NA) at various times after EEDQ. Sniffing behavior recovered rapidly (normal by day 4 in both regions), whereas oral activity required 8 (NA) and 12 days (VL) to return to control levels. The results are discussed in terms of a possible topographic distribution of behavior in the striatum. Alternatively, heterogeneity of DA receptor density may account for these findings

The malaria parasite Plasmodium falciparum contains at least two genes related to the mammalian multiple drug resistance genes, and at least one of the P. falciparum genes is expressed at a higher level and is present in higher copy number in a strain that is resistant to multiple drugs than in a strain that is sensitive to the drugs.

The present study was undertaken to evaluate the potential usefulness of 11C-buprenorphine (bup) as a ligand for investigating opioid receptors in living primates, including humans, using positron-emission transaxial tomography (PETT). Because PETT studies of receptor function are best carried out under conditions of low receptor occupancy, the pharmacokinetics, uptake into brain, and specific binding to opioid receptors within brain of 3H-bup were examined in rats under conditions in which occupancy of opioid receptors by 3H-bup never exceeded 2% of sites in the brain at any time point examined. Male Sprague Dawley rats (weight range 140-220 grams) were injected s.c. with either naloxone (10 mg/kg) or saline. Five min later, a saline solution containing [15, 16-3H] bup (39 Ci/mmole) was injected into tail veins at a dose of 0.4 microgram/kg body weight. At least 90-95% of radioactivity was cleared from the blood in the first 5 min. In saline pretreated rats, total brain uptake 15 min after injection of 3H-bup was about 0.4% of the administered dose. Ligand specifically bound to receptors may be estimated by comparing the amount of radioactivity in the brain following injection of labeled ligand alone to that obtained when a high concentration of an unlabeled competitor is pre- or co-administered. In the present study, average levels obtained in brain (excluding cerebellum) were higher in saline pretreated rats than in naloxone pretreated rats at all time points and the difference increased with time indicating specific binding to opioid receptors. Specific binding may also be estimated by comparing radioactivity accumulated in brain areas rich in opioid receptors with 'background' levels achieved in areas known to be low in opioid receptors, e.g., the cerebellum in rats. In the present study, ratios of the amount of radioactivity in brain (excluding cerebellum) to the amount in the cerebellum increased with time (to about 4 after 60 min) in saline pretreated rats, but remained close to 1 in naloxone pretreated rats. The effects of biological variation were less when specific binding was estimated by the latter method since each animal served as its own control. Tissue distribution of radioactivity to other tissues (blood, skin, muscle, fat, liver, kidney) was similar in naloxone and saline pretreated rats. The results presented here suggest that 11C-bup or an 18F-labeled fluorinated derivative would be a useful ligand for PETT studies

Alprazolam added to stable doses of neuroleptics in nine schizophrenic patients was associated with a 20%-30% mean reduction in positive and negative symptoms, although clinical response was variable and in some patients particularly brisk. The authors examined the possibilities of a pharmacokinetic effect of alprazolam on neuroleptic plasma levels and of a clinical effect of alprazolam. The modest increase in mean neuroleptic plasma levels did not correlate with clinical change, but those patients with the highest alprazolam plasma levels tended to show more robust clinical responses

To assess the role of blockade of beta-receptor subpopulations in the treatment of neuroleptic-induced akathisia (NIA), the specific beta 2-antagonist ICI 118,551 was compared to placebo in a double-blind study. After a baseline evaluation on placebo, patients were treated with ICI 118,551 or placebo. Five of six patients treated with ICI 118,551 showed improvements in NIA, while only one of four patients improved on placebo. Patients were then treated openly with propranolol, a mixed beta 1, beta 2-antagonist. Compared to ICI 118,551, no further improvement on objective measures of akathisia was seen on propranolol. Mean subjective assessments of NIA declined on propranolol, but changes were variable and not statistically significant

Nine hospitalized schizophrenic patients with tardive dyskinesia were treated with the calcium-channel antagonist verapamil under single-blind conditions. The tardive dyskinesia and activation scores decreased, and the anxiety/depression scores increased. The changes were small but statistically significant