Psychopharmacology

Ljungberg, T.; Ungerstedt, U.

doi: 10.1007/BF00432845pmid: 26097

213 56 56 3 3 T. Ljungberg U. Ungerstedt Department of Histology Karolinska Institutet Stockholm Sweden Abstract Apomorphine 5 mg/kg given s.c. induces two different behaviours that can be separately measured in a special test box: one characterized by increased locomotion and one characterized by strong compulsive gnawing. Six different neuroleptic drugs with different clinical profiles (metaclopramide, haloperidol, chlorpromazine, thioridazine, clozapine, and sulpiride) were tested for their ability to antagonize either of these two different behaviours. We found that the neuroleptic drugs causing high incidences of extrapyramidal side effects (metoclopramide and haloperidol) predominantly antagonized the apomorphine-induced compulsive gnawing, while the ‘atypical’ neuroleptic drugs causing low incidences of extrapyramidal side effects (thioridazine, clozapine, sulpiride) instead antagonized the apomorphine-induced locomotion. When the drugs were rank-ordered according to their relative potencies in antagonizing gnawing as compared to locomotion, the rank order paralleled clinical data concerning the incidence of extrapyramidal side effects. The findings are tentatively explained by the existence of two different dopamine receptors. The test may be useful for the screening of new neuroleptic drugs because it seems possible to distinguish drugs producing extrapyramidal side effects from drugs that do not.

Hansl, Nikolaus; Mead, Beverley

doi: 10.1007/BF00432846pmid: 418433

213 56 56 3 3 Nikolaus R. Hansl Beverley T. Mead Department of Medicinal Chemistry and Department of Psychiatry Creighton University 68178 Omaha Nebraska USA Abstract The effect of 3-(2-benzylmethylaminoethyl) benzoic acid methyl ester hydrochloride (PRL-8-53) on learning and on retention of verbal information in human subjects was investigated. Using the serial anticipation method under double-blind conditions it was found that PRL-8-53 causes slight improvement of acquisition. Retention of verbal information was found improved to a statistically significant degree (most P values better than 0.01, some better than 0.001). No significant changes were found for either visual reaction time or motor control after drug when compared with placebo values.

Meltzer, Herbert; Fessler, Richard; Simonovic, Miljana; Fang, Victor

doi: 10.1007/BF00432847pmid: 148665

213 56 56 3 3 Herbert Y. Meltzer Richard G. Fessler Miljana Simonovic Victor S. Fang Departments of Psychiatry, Medicine, and Pharmacology and Physical Sciences University of Chicago Pritzker School of Medicine and the Illinois State Psychiatric Institute 950 E. 59th Street 60637 Chicago Illinois USA Abstract The hallucinogenic indoleamine drugs N,N-dimethyltryptamine (N,N-DMT), psilocybin, bufotenin, 5-methoxy-N,N-dimethyltryptamine, and N-methyltryptamine, increased rat plasma prolactin (PRL) levels. The increase in plasma PRL produced by N,N-DMT, psilocybin, and bufotenin was inhibited by methysergide, a serotonin receptor blocker. Parachlorophenylalanine (PCPA), an inhibitor of serotonin synthesis, significantly potentiated the increase in PRL produced by N,N-DMT, and psilocybin. Parachloroamphetamine, a relatively selective toxin for serotonin neurons, also stimulated the increase in PRL produced by N,N-DMT. These results suggest that the indole hallucinogens stimulate PRL secretion by a serotonergic agonist mechanism. Bufotenin has been reported to pass the blood-brain barrier poorly, but of the indoles studied it had the most potent effect on PRL secretion. This raises the possibility that the serotonin receptors which promote PRL secretion may be outside the blood-brain barrier or that the central 5-HT receptors which mediate PRL secretion may be especially responsive to bufotenin.

Mallari, C.; Klemm, W.

doi: 10.1007/BF00432848pmid: 418434

213 56 56 3 3 C. G. Mallari W. R. Klemm Department of Biology Texas A&M University 77843 College Station Texas USA Abstract Previous studies have indicated that morphine alters nerve impulse activity differently in various brain areas of intact animals. Because morphine has profound effects on visceral organs and on the spinal cord, cervically transected preparations, in which hypothermia was prevented, were used for recording spontaneous impulse activity before and for 30 min after morphine simultaneously from six regions of the brain: caudate (Cau), midbrain reticular formation (MBRF), central grey (CG), cingulate cortex (CC), hippocampus (Hip), and substantia nigra (SN). Morphine (5 and 15 mg/kg, i.p.) caused a naloxonepreventable depression of impulse activity in most brain areas. The depression was, however, especially pronounced in the CG, more so with the lower than the higher dose; naloxone completely blocked the low-dose effect. The MBRF responded with increased impulse activity after 5 mg/kg, but with depression after 15 mg/kg; naloxone blocked both responses. Activity in both the Hip and CC was depressed by the low dose of morphine, but not by the high dose; naloxone blocked the depression. Both doses of morphine generally depressed the variance in impulse activity, with a clear preferential depression of CG variance; naloxone blocked the CG variance effect, but not that of other brain areas.

Nakamura, Hideo; Ishii, Katsumi; Shimizu, Masanao

doi: 10.1007/BF00432849pmid: 26098

213 56 56 3 3 Hideo Nakamura Katsumi Ishii Masanao Shimizu Department of Pharmacology, Research Laboratories Dainippon Pharmaceutical Co., Ltd. 564 Suita/Osaka Japan Abstract This investigation examined whether or not physical dependence or other abnormalities were detectable 1–3months after withdrawal in dependent rats that had been treated with the morphine (maintenance dose of 100×2mg/kg/day,s.c.) for 7 weeks. When narcotic antagonists were administered on the 32nd day after withdrawal, nalorphine caused a dose-dependent increase in spontaneous locomotor activity and a complete inhibition of wet-dog shakes and the writhing syndrome. Naloxone was ineffective. A remarkable increase in spontaneous locomotor activity on the 67th day and a significant increase in body weight on the 69th and 92nd day after withdrawal occurred after an acute injection of morphine (10 mg/kg, s.c.). When morphine (10 mg/kg) was administered for 3 days from the 92nd day after withdrawal, withdrawal from morphine produced a significant decrease in body weight. When morphine (10 mg/kg) was administered for 3 days from the 102nd day after withdrawal, a levallorphan injection caused a significant decrease in spontaneous locomotor activity and an increase in the frequency of the diarrheal syndrome. These abnormal responses, not observed in the naive rats, suggest the remains of some behavioral and biochemical abnormalities 3 months after morphine withdrawal.

Taylor, D.; Fennessy, M.

doi: 10.1007/BF00432850pmid: 418435

213 56 56 3 3 D. A. Taylor M. R. Fennessy Department of Pharmacology University of Melbourne 3052 Parkville Victoria Australia Abstract The development of tolerance to Δ 9 -tetrahydrocannabinol (Δ 9 -THC) was examined. Rats with permanently indwelling intravenous catheters were injected daily with Δ 9 -THC, 2 mg/kg, for up to 10 days and on each day subjective behaviour and body weight of each rat were noted. Tolerance appeared to develop to both the exciatory and depressant behavioural effects of Δ 9 -THC, whereas the rate of gain, in body weight of Δ 9 -THC treated rats, was retarded and tolerance to this phenomenon did not develop over the experimental period. On days 1, 2, 3, 5, 6 and 10 body temperature was recorded continuously for at least 2 h after Δ 9 -THC and in other groups of rats the brain levels of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured spectrophotofluorimetrically 1 h after Δ 9 -THC. Tolerance developed to the Δ 9 -THC-induced hypothermia by day 3, and on days 6 and 10 hyperthermia, was observed. Δ 9 -THC did not markedly affect the brain levels of NA or DA over the experimental period. The brain levels of 5-HT were unchanged, on days 1–5 but there was a decrease on days 6 and 10. On days 1, 2, and 3 brain levels of 5-HIAA were raised, whereas on day 6 there was a decrease. These results show that Δ 9 -THC induces tolerance to the hypothermia and elevation of brain 5-HIAA levels in a linear manner. An inverse relationship appears to exist between these two parameters.

Geisler, Robert; Hunter, Bruce; Walker, Don

doi: 10.1007/BF00432851pmid: 418436

213 56 56 3 3 Robert F. Geisler Bruce E. Hunter Don W. Walker Veterans Administration Hospital University of Florida 32602 Gainesville Florida USA Department of Neuroscience, College of Medicine University of Florida 32602 Gainesville Florida USA Abstract Electrodes were chronically implanted in the dorsal hippocampus of rats. Pretreatment levels of neural excitability were assessed by determining the duration of direct hippocampal electrical stimulation sufficient to induce forelimb clonus in each rat. Following baseline measurements the rats were administered an alcohol or sucrose-containing liquid diet and 19–22 days later were withdrawn. Two postwithdrawal stimulation sessions were conducted on each animal. Separate groups of ethanol-dependent and control rats were given primary stimulation sessions at 8 h, 24 h, 72 h, or 1 week postwithdrawal. Secondary stimulation sessions were conducted 1 week or 2 weeks postwithdrawal. The results from the primary stimulations indicated that ethanol-dependent animals exhibited significant neural hyperexcitability for at least 72 h, but not 1 week, postwithdrawal. Results from the secondary stimulations demonstrated the presence of a relative neural hypoexcitability in ethanol-dependent groups as compared to controls. The pattern of results suggests, however, that the observed relative neural hypoexcitability was not the direct result of ethanol withdrawal.

Ellison, Gaylord; Eison, Michael; Huberman, Harris

doi: 10.1007/BF00432852pmid: 418437

213 56 56 3 3 Gaylord Ellison Michael S. Eison Harris S. Huberman Department of Psychology University of California Los Angeles, 405 Hilgard Avenue 90024 Los Angeles California USA Abstract Rats in colonies were observed for 7 days after half of them were implanted with slow-release silicone pellets containing d -amphetamine base. The drug-implanted animals were initially hyperactive and exploratory, but this gradually evolved over the next 24 h into motor stereotypies of an increasingly more circumscribed nature. On the 4th day after amphetamine implantation they transiently withdrew to the burrows area; thereafter they were characterized by heightened startle responses and increased social behaviors such as fighting and fleeing. During the last phase some of the drug-implanted animals tended to focus their fighting behaviors on one other drug-implanted animal. This late phase of constant amphetamine intoxication in rats has a number of similarities to amphetamine psychosis in humans, and can serve as a useful animal model for the study of its biochemical correlates.

Morley, Barbara; Russin, Raymond

doi: 10.1007/BF00432853pmid: 418438

213 56 56 3 3 Barbara J. Morley Raymond Russin Neurosciences Program University of Alabama Medical School 35294 Birmingham Alabama USA Department of Psychiatry and Behavioral Sciences University of Oklahoma Medical School 73104 Oklahoma City Oklahoma USA Abstract The effects of scopolamine hydrobromide on baseline extinction levels and spontaneous recovery were assessed. Rats were trained on one of four reinforcement schedules (CRF, FR 10, FR 20, FR 40) with either food or water reinforcement. Scopolamine increased response rates in extinction and spontaneous recovery following training on all four schedules when the reinforcer was water, but had no effect on responding previously maintained by food. The results are discussed in terms of the limitations of a general theory of a cholinergic system mediating all suppressed behavior and the effects of anticholinergic drugs on central thirst mechanisms and consummatory behavior.

Eichelman, Burr; Orenberg, Elaine; Hackley, Pamela; Barchas, Jack

doi: 10.1007/BF00432854pmid: 418439

213 56 56 3 3 Burr Eichelman Chief of Psychiatry Elaine Orenberg Pamela Hackley Jack Barchas Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine 94305 Stanford California USA William S. Middleton Memorial Veterans Hospital 2500 Overlook Terrace 53705 Madison Wisconsin USA Abstract The methylxanthines caffeine and aminophylline, in daily doses of 100 mg/kg, facilitated shock-induced aggression in the rat. Under the limited parameters of this study, there was no induction of mouse-killing behavior or alteration of jump thresholds. Additional studies showed the optimal dose and time course for the facilitation of shock-induced aggression by caffeine to be 50 mg/kg administered i.p. 4 h prior to testing. Facilitation of a central adrenergic system may be the mechanism of action.