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The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue. In the present study, the effects of these sigma ligands on concentrations of prolactin and corticosterone in serum in the rat were investigated. In addition, the effects of these agents on the synthesis and/or release of dopamine from tuberoinfundibular and nigrostriatal neurons were determined. Concentrations of prolactin and corticosterone in serum were increased dose-dependently by BMY 14802, tiospirone, remoxipride and gevotriline. The activity of tyrosine hydroxylase within the terminals of tuberoinfundibular dopamine neurons in vivo also was increased by BMY 14802, tiospirone and gevotriline, but not by remoxipride. The extracellular concentrations of dopamine and dihydroxyphenylacetic acid in the striatum, as determined by in vivo microdialysis, were increased by BMY 14802 (5-20 mg/kg, s.c.) and remoxipride (3 mg/kg, s.c.). These data suggest the involvement of sigma receptors in the regulation of secretion of prolactin and corticosterone, as well as the activity of tuberoinfundibular and nigrostriatal dopamine neurons. Moreover, the pattern of neurochemical and neuroendocrinological responses to these sigma ligands resembled those which have been determined previously for atypical antipsychotics and support the contention that these sigma ligands may be antipsychotic agents with an atypical profile of action.

1. Previous studies conducted in our laboratory demonstrated that rats given a choice between a 0.1% saccharin solution or 10% ethanol/0.1% saccharin solution and repeatedly exposed on an unpredictable basis to stressful stimuli, consumed increasing quantities of the ethanol solution following cessation of stressor presentation as compared to nonstressed control rats. 2. Stressful stimuli potently activate the hypothalamic-pituitary-adrenocortical (HPA) axis, thus a systematic investigation of the HPA axis and its involvement in post-stress induced ethanol consummatory behavior was undertaken. 3. Exposure to repetitive unpredictable stressful stimuli did not induce the free-choice consumption of ethanol in either hypophysectomized rats or chronic dexamethasone treated rats. 4. Adrenalectomized rats exposed to chronic unpredictable stressful stimuli consumed increased quantities of ethanol following cessation of stressful stimuli in both a quantitative and qualitative manner which mirrored that of intact animals. 5. Repeated intravenous administration of exogenous adrenocorticotropin (ACTH1-39) on an unpredictable basis also induced ethanol consuming behavior, following the discontinuation of its administration. 6. These results suggest that elimination of the pituitary or pharmacological antagonism of stress-induced HPA activation will prevent post-stress induced ethanol consummatory behavior. 7. Conversely, activation of a functional hypothalamic-pituitary system or repeated administration of exogenous ACTH1-39 will initiate ethanol consumption in rats. 8. Thus, hormones secreted from the pituitary, namely ACTH, appear to play a crucial role in the post-stress induced initiation of ethanol consuming behavior in rats.

Single doses of d-amphetamine, chlorpheniramine or diazepam were combined with ethanol under two conditions: (i) in drug-naive mice and (ii) in mice which had been given a single dose of ethanol 72 hr previously. Ethanol was administered orally at doses of 6.0, 3.0 or 1.5 g/kg; doses of d-amphetamine, chlorpheniramine or diazepam were given intraperitoneally. Three parameters were measured; changes in rectal temperature, forced motor coordination, as evaluated by rotarod performance and concentrations of ethanol in blood. d-Amphetamine and chlorpheniramine attenuated the hypothermia induced by ethanol but had no effect on the motor-impairing effect of ethanol. Hypothermia induced by diazepam was unaffected by ethanol, but the combination appeared to impair maximally rotarod performance. Concentrations of ethanol in blood did not differ between ethanol-naive mice and mice which had received the same dose of ethanol 72 hr previously. Changes in body temperature and intoxication have been attributed to central actions of ethanol; however, the differential results obtained from the interactions between these drugs suggest differing sensitivities of the various systems which are affected by ethanol.

In an attempt to investigate whether a relationship exists between exposure to stressful stimuli and the consumption of CNS stimulants, rats were given continuous access to an 0.1% saccharin solution and either d-amphetamine (AMP), methamphetamine (MET) or phenylpropanolamine (PPA) at two concentrations. Animals were exposed to either isolation/novel environment or immobilization stress repetitively over a two week period on an irregular/unpredictable schedule. No differences were seen between control (non-stressed) and stressed animals with respect to the volume of AMP, MET or PPA consumed either during stress or in two weeks post-stress. All three drugs failed to demonstrate any oral reinforcing properties as evaluated by positional perseveration. In contrast to earlier work using ethanol, the data suggests that stress has very little influence over the oral ingestion of phenethylamines.

Administration of single doses of ethanol, 1-propanol, 1-butanol or 1-pentanol to mice caused hypothermia and impairment of rotarod performance. Repetitive doses, at 24-72 hr intervals led to development of tolerance to the hypothermic effects of ethanol but not of the other alcohols. No tolerance was seen in the impairment of rotarod performance with repeated doses of any of the alcohols. Ethanol did show an intersession tolerance on rotarod performance; at 20 and 80 min after injection, blood levels were similar, while performance was impaired at 20 but not at 80 min.