Improved ethical guidance for the return of results from psychiatric genomics research.

There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.

Effects of caffeine and PD 116,600 on the differential-reinforcement-of-low rate 72-S (DRL 72-S) schedule of reinforcement.

Caffeine and PD 116,600 were found to decrease the reinforcement rate and increase the response rate in rats performing under a differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule of reinforcement. In contrast, antidepressant drugs previously have been found to increase the reinforcement and decrease the response rate. Caffeine has been found to test similar to antidepressant drugs on at least one other behavioral screen, but caffeine does not possess clinical antidepressant properties. These results provide further support for the DRL 72-s schedule as a behavioral screen for antidepressant drugs.

Variability among brain regions in the specificity of 6-hydroxydopamine (6-OHDA)-induced lesions.

6-Hydroxydopamine (6-OHDA; 200 micrograms, 150 micrograms or 110 micrograms) or vehicle was infused stereotaxically into the lateral ventricles of rats, usually following pretreatment with desmethylimipramine (DMI). Various brain regions were then assayed for dopamine (DA), serotonin (5-HT) and norepinephrine (NE). As expected, 6-OHDA depleted DA in all brain regions examined. Unexpectedly, however, the two highest doses of 6-OHDA significantly decreased 5-HT levels in the hippocampus and increased 5-HT levels in the striatum. In addition, despite pretreatment with doses of DMI commonly considered adequate to block 6-OHDA-induced depletion of NE, all doses of 6-OHDA tested significantly reduced NE levels in the hippocampus, hypothalamus and septum. We interpret our data as suggesting that some brain regions are susceptible to nonspecific toxic effects of 6-OHDA at doses commonly employed. Furthermore, these nonspecific effects may or may not occur, depending on seemingly minor variations in experimental technique.

The effect of water-deprivation on locomotor activity in rats treated with 6-hydroxydopamine.

Male albino rats treated with 6-hydroxydopamine (6-OHDA) became more hyperactive than did vehicle-treated controls when both groups were water-deprived. Rats were treated with vehicle, 150 or 250 micrograms of 6-OHDA intraventricularly, after pretreatment with desmethylimpramine (25 mg/kg) and pargyline (50 mg/kg). Eleven days after these treatments, under ad libitum water conditions, the 6-OHDA-treated rats were slightly hypoactive. After several days of water-deprivation all three groups showed increased mean locomotor activity levels, but rats treated with 6-OHDA showed a much greater increase than did vehicle-treated rats. Under subsequent ad libitum and deprivation conditions, locomotor activity decreased and increased, respectively, in all 3 groups. Again, the changes in activity levels of the 6-OHDA-treated groups were greater than those of the vehicle-treated group. In addition, rats treated with 250 micrograms 6-OHDA seemed to become sensitized to the novel environment of the stabilimeter rather than habituating to it. Dopamine (DA) levels were decreased as a result of the injections of 6-OHDA, and significant correlations were found between DA levels in the caudate-putamen and nucleus accumbens, and locomotor activity levels. These results, as well as those obtained by others, suggest that there is an interaction among DA levels, deprivational states, and locomotor activity levels in rats.

Behavioral screen for antidepressants: the effects of drugs and electroconvulsive shock on performance under a differential-reinforcement-of-low-rate schedule.

Those antidepressant drugs that are in wide clinical use decrease response rate and increase reinforcement rate when administered to rats performing on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Drugs that are not antidepressants do not have this effect. In this experiment, the following were examined for their effects on a DRL 72-s schedule: trazodone, zimelidine, fluoxetine, and bupropion (atypical antidepressants); electroconvulsive shock (ECS, which is an effective treatment for depression); and haloperidol and clozapine (antipsychotic drugs). Trazodone (3.12-25.00 mg/kg), fluoxetine (10-20 mg/kg), and ECS decreased response rate and increased reinforcement rate. Zimelidine (20 mg/kg) increased reinforcement rate and nonsignificantly decreased response rate. At doses between 2.5 and 40 mg/kg, bupropion had no effect on reinforcement rate or response rate, but at 60 mg/kg response rate was increased and reinforcement rate was nonsignificantly decreased. At the higher dose, the effects of bupropion resemble those of a psychomotor stimulant. Haloperidol (0.04 mg/kg) and clozapine (2.5-10.0 mg/kg) decreased response rate and reinforcement rate. These results suggest that the DRL 72-s schedule may be useful for testing the antidepressant potential of new drugs.