Psychopharmacology

Gora-Maslak, Grazyna; McClearn, Gerald; Crabbe, John; Phillips, Tamara; Belknap, John; Plomin, Robert

doi: 10.1007/BF02245643pmid: 1780413

213 104 104 4 4 Grazyna Gora-Maslak Gerald E. McClearn John C. Crabbe Tamara J. Phillips John K. Belknap Robert Plomin Center for Developmental and Health Genetics Pennsylvania State University 16802 University Park PA USA VA Medical Center and Departments of Medical Psychology and Pharmacology Oregon Health Sciences University 97201 Portland OR USA Abstract Unlike simple Mendelian characteristics, individual differences in complex quantitative phenotypes studied in psychopharmacology are generally distributed continuously and are likely to be influenced by many genes. Recombinant inbred (RI) strains are valuable not only for their traditional use of detecting major gene segregation and linkage but also for identifying associations between quantitative traits and quantitative trait loci (QTL) that account for relatively small amounts of variation in phenotypes as well as loci that account for greater amounts of variation. When applied to published data on genetic markers and on amphetamine, alcohol, and morphine responses in BXD RI strains (RI strains developed from the cross between C57BL/6J and DBA/2J progenitor inbred strains), the RI QTL approach identified several significant associations beyond known major gene effects. Together, significant associations explain more than half of the genetic variance for these measures. The RI QTL approach is especially valuable for investigating the QTL underpinnings of genetic correlations among measures. It is recommended that psychopharmacogenetic research focus on the BXD RI strains. The cumulative and integrative nature of such a program of research is the major benefit of the RI QTL association approach for molecular genetic analysis of psychopharmacological processes, their physiological infrastructure, and their interface with other behavioral and biological systems.

Witkin, J.; Schindler, C.; Tella, S.; Goldberg, S.

doi: 10.1007/BF02245644pmid: 1838199

213 104 104 4 4 J. M. Witkin C. W. Schindler S. R. Tella S. R. Goldberg Preclinical Pharmacology Branch NIDA Addiction Research Center P.O. Box 5180 21224 Baltimore MD USA Abstract Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the FI at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001–0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Nagatani, Tadashi; Yamamoto, Tsuneyuki; Takao, Katsuyuki; Hashimoto, Shinji; Kasahara, Kenichi; Sugihara, Taisuke; Ueki, Showa

doi: 10.1007/BF02245645pmid: 1723527

213 104 104 4 4 Tadashi Nagatani Tsuneyuki Yamamoto Katsuyuki Takao Shinji Hashimoto Kenichi Kasahara Taisuke Sugihara Showa Ueki Department of Pharmacology, Nobeoka Medicines Laboratory, Life Science Research Laboratories Asahi Chemical Industry Asahi-machi 6-2700 882 Nobeoka, Miyazaki Japan Department of Pharmacology Faculty of Pharmaceutical Sciences Kyushu University 62 Fukuoka 812 Japan Abstract AP159 ((N-cyclohexyl-1,2,3,4-tetrahydrobenzo(b)thieno(2,3c)pyridine)-3-carboamide,hydrochloride) showed clear anti-conflict activity in rats in the absence of effects on muscle relaxation, potentiation of anesthesia (in mice) or anticonvulsant activity (in mice). This anticonflict effect was antagonized by treatment with Ro15-1788. By contrast with the deficits produced by diazepam, AP159 did not impair passive avoidance. The latter drug also improved scopolamine-induced amnesia in the same task. AP159 did not inhibit 3 H-flunitrazepam binding, but potently inhibited 3 H-8OH-DPAT binding. This compound increased serotonin and 5HIAA content of the midbrain raphe nuclei and of the amygdala centralis. AP159 has been shown to be a novel non-BZP anxiolytic agent with no side effects in laboratory animals; it could be a clinically effective anxiolytic agent.

Ansseau, Marc; Olié, Jean-Piérre; Frenckell, Remy; Jourdain, Gonzague; Stehle, Brigitte; Guillet, Philippe

doi: 10.1007/BF02245646pmid: 1685793

213 104 104 4 4 Marc Ansseau Jean-Piérre Olié Remy von Frenckell Gonzague Jourdain Brigitte Stehle Philippe Guillet Psychiatric Unit, Centre Hospitalier Universitaire du Sart Tilman (B35) B-4000 Liège Belgium Hôpital Sainte-Anne 1 rue Cabanis F-75014 Paris France Spécia Laboratories 16 rue E. Clisson F-75013 Paris France Rhône-Poulenc Rorer 20 avenue Raymond Aron F-92165 Antony France Abstract The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54–59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Wada, Takeo; Fukuda, Naohisa

doi: 10.1007/BF02245647pmid: 1685794

213 104 104 4 4 Takeo Wada Naohisa Fukuda Biology Research Laboratories, Research and Development Division Takeda Chemical Industries 17-85, Jusohonmachi 2-chome, Yodogawa-ku 532 Osaka Japan Abstract In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5–20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug. In conclusion, the present experiment revealed that the anxiolytic effect of DN-2327 in this test was clear, whereas buspirone showed no apparent effect.

Grant, Kathleen; Barrett, James

doi: 10.1007/BF02245648pmid: 1780414

213 104 104 4 4 Kathleen A. Grant James E. Barrett Unit for Special Projects, National Institute on Alcohol Abuse and Alcoholism 12501 Washington Avenue 20852 Rockville MD USA Department of Psychiatry Uniformed Services University of the Health Sciences Bethesda MD USA Abstract The ability of selective 5-HT 3 receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT 3 receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT 3 receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT 3 receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT 2 receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT 3 mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT 3 receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT 3 activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.

George, Frank; Porrino, Linda; Ritz, Mary; Goldberg, Steven

doi: 10.1007/BF02245649pmid: 1838200

213 104 104 4 4 Frank R. George Linda J. Porrino Mary C. Ritz Steven R. Goldberg Department of Psychology, Center on Alcoholism, Substance Abuse and Addictions University of New Mexico 87131 Albuquerque NM USA Preclinical Pharmacology Branch, National Institute on Drug Abuse, Addiction Research Center 4940 Eastern Avenue 21224 Baltimore MD USA Unit on Brain Imaging, National Institute on Neurological Disorders and Stroke 20892 Bethesda MD USA Abstract Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D 1 and D 2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

Carey, Robert

doi: 10.1007/BF02245650pmid: 1780415

213 104 104 4 4 Robert J. Carey Research and Development Service, VA Medical Center, and Department of Psychiatry SUNY Health Sciences Center at Syracuse 800 Irving Avenue 13210 Syracuse NY USA Abstract Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

Jensen, E.; Schmidt, E.; Pedersen, B.; Dahl, R.

doi: 10.1007/BF02245651pmid: 1780416

213 104 104 4 4 E. J. Jensen E. Schmidt B. Pedersen R. Dahl Department of Respiratory Medicine University Hospital, Noerrebrogade DK-8000 Aarhus C Denmark Abstract In a randomized smoking cessation study 211, 203 and 82 persons were supported with nicotine, silver acetate and ordinary chewing gum, respectively. After 26 weeks there was no overall difference in number of abstainers between treatments. Participants were divided into subsets with low and high weighted packyears consumption (WPY) which modifies tobacco consumption by nicotine content. Abstainer rates in the total population controlled for treatment decreased with increasing WPY ( P <0.005). In participants with low WPY abstainer rate was higher in the silver acetate group compared to the nicotine ( P <0.0005) and ordinary ( P <0.05) chewing gum groups. Nicotine chewing gum was more effective than silver acetate ( P <0.05) and ordinary ( P <0.05) chewing gum in smokers with high WPY. Ratings on some inconveniences experienced during earlier attempts to quit smoking influenced the ability to break the habit but had no influence on chewing gum effects. This study indicated that through consideration of smoking history it should be possible to individualize pharmacological support to smokers wanting to quit, with silver acetate chewing gum most effective for smokers with a low WPY and nicotine chewing gum most effective for smokers with a high WPY.

Paris, Joseph; Cunningham, Kathryn

doi: 10.1007/BF02245652pmid: 1780417

213 104 104 4 4 Joseph M. Paris Kathryn A. Cunningham Department of Pharmacology and Toxicology University of Texas Medicla Branch 77550 Galveston TX USA Abstract The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT 3 ). Behavioral evidence suggests that 5-HT 3 receptors interact with mesolimbic dopamine (DA) systems and that 5-HT 3 antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT 3 receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT 3 antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats ( N =16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313–10 mg/kg), ICS 205930 (2–24 mg/kg), and MDL 72222 (2–16 mg/kg) were conducted. Cocaine produced a doserelated increase in cocaine-appropriate responding while the 5-HT 3 antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT 3 antagonists were given in combination with cocaine. The results indicate that although 5-HT 3 antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.