Psychopharmacology

Parrino, L.; Terzano, M.

doi: 10.1007/BF02246405pmid: 8853211

213 126 126 1 1 L. Parrino M. G. Terzano Istituto di Neurologia Università degli Studi Via del Quartiere, 4 I-43100 Parma Italy Abstract This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.

Schenk, S.; Worley, C.; McNamara, C.; Valadez, A.

doi: 10.1007/BF02246406pmid: 8853212

213 126 126 1 1 S. Schenk C. M. Worley C. McNamara A. Valadez Department of Psychology Texas A&M University 77843 College Station TX USA Abstract Previously, we demonstrated that caffeine dose-dependently reinstated extinguished cocaine-taking behavior in rats. In the present study, we determined whether this effect of caffeine would extinguish with repeated exposures. Rats were first trained to self-administer cocaine intravenously. Once reliable self-administration was obtained, the pumps that delivered cocaine were turned off and the lever-pressing behavior was extinguished. Every 4 days the rats were given an injection of caffeine (20.0 mg/kg) and its ability to reinstate responding was measured. Some rats received each of four exposures to caffeine in the previously cocaine-associated environment. Other rats received the first three exposures to caffeine in the home cage and the last exposure to caffeine in the previously cocaine-associated environment. The results indicated that although caffeine was an effective cue for reinstatement of extinguished cocaine taking, the effect was reduced when repeated exposures occurred in the test environment. In addition, when 4 drug-free days were interspersed between self-administration and reinstatement testing, the caffeine effect was greater than when testing was conducted 1 day following the last self-administration session. Thus, extended withdrawal increases the priming effects of caffeine. The results are discussed in terms of the effectiveness of cue exposure as an adjunct to current therapies for cocaine abuse.

Coccaro, E.; Kavoussi, R.; Oakes, M.; Cooper, T.; Hauger, R.

doi: 10.1007/BF02246407pmid: 8853213

213 126 126 1 1 E. F. Coccaro R. J. Kavoussi M. Oakes T. B. Cooper R. Hauger Clinical Neuroscience Research Unit, Department of Psychiatry Medical College of Pennsylvania 3200 Henry Avenue 19129 Philadelphia PA USA Analytical Psychopharmacology Laboratory, Department of Psychiatry, College of Physicians and Surgeons Columbia University New York NY USA Neuroendocrine Research Laboratory, Department of Psychiatry University of California San Diego CA USA Abstract Prolactin responses to d -fenfluramine ( d -FEN) challenge (0.5 mg/kg PO) were examined after pre-treatment with and without the 5-HT 2a/2c receptor antagonist amesergide in eight physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with amesergide completely blocked the prolactin (PRL) response to d -FEN challenge in all subjects. These data are consistent with data demonstrating a complete blockade of the PRL response to d -FEN with the 5-HT 2a/2c receptor antagonist ritanserin, and suggest that the PRL response to d -FEN challenge in humans may largely be due to activation of the 5-HT 2a/2c receptor.

Ulrichsen, J.; Bech, B.; Ebert, B.; Diemer, N.; Allerup, P.; Hemmingsen, R.

doi: 10.1007/BF02246408pmid: 8853214

213 126 126 1 1 J. Ulrichsen B. Bech B. Ebert N. H. Diemer P. Allerup R. Hemmingsen Neuropsychiatric Research Group, Department of Psychiatry O-6234 Rigshospitalet, Belgdamsvej 9 DK-2100 Copenhagen Denmark Department of Medicinal Chemistry The Royal Danish School of Pharmacy Universitetsparken 2 DK-2100 Copenhagen Denmark Molecular Neurophathology Laboratory, Institute of Neuropathology University of Copenhagen Frederik V's vej 11, 6 DK-2100 Copenhagen Denmark The Danish National Institute for Educational Research Hermodsgade 28 DK-2200 Copenhagen Denmark Department of Psychiatry Bispebjerg Hospital Bispebjerg Bakke 23 DK-2400 Copenhagen NV Denmark Abstract During repeated alcohol withdrawal, convulsive withdrawal behaviour has been shown to be increased in a kindling-like manner in both clinical and experimental studies. In the present experiment, quantitative autoradiography was used to investigate binding of tritiated ligands to glutamate receptor subtypes and the benzodiazepine/GABA (BZ/GABA) receptor complex in rats exposed to 14 episodes of alcohol withdrawal. Seizures were detected in 25% of the animals during withdrawal episode 10–13. Repeated alcohol withdrawal resulted in a decrease in the number of ( 3 H)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (( 3 H)-AMPA) binding sites in striatum and subregions of the entorhinal cortex, the cerebellum and the hippocampus, while the ( 3 H)-flunitrazepam binding was down-regulated in the frontal cortex. There was no differences between the controls and the multiple withdrawal animals regarding the ( 3 H)-dizocilpine (( 3 H)-MK801) binding and the ( 3 H)-kainic acid binding. However, within the latter group, those animals in which withdrawal seizures were observed had increased ( 3 H)-MK801 binding sites in focal regions of entorhinal cortex and hippocampus, compared to those in which seizures were not observed. The decreased AMPA binding suggested impaired glutamate neurotransmission. As such, this receptor probably did not contribute to alcohol withdrawal kindling, but rather was involved in seizure protective mechanisms during this process.

Powell, K.; Dykstra, L.

doi: 10.1007/BF02246409pmid: 8853215

213 126 126 1 1 K. R. Powell L. A. Dykstra Department of Psychology University of North Carolina at Chapel Hill 27599-3270 Chapel Hill NC USA Department of Pharmacology Emory University School of Medicine 30322 Atlanta GA USA Abstract This experiment was conducted to determine whether drugs acting on brain serotonin modulate the effects of the mu opioid, morphine, as measured by the squirrel monkey shock titration procedure and, if so, whether serotonergic modulation is mediated via specific 5HT receptor subtypes. Under this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-s shock period terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The intensity below which monkeys maintained shock 50% of the time (median shock level or MSL) and rate of responding (RR) in the presence of shock were determined under control conditions and after administration of morphine alone and in combination with various serotonergic compounds. Morphine increased median shock level and decreased rate of responding in a dose-dependent manner. These effects of morphine were attenuated by the 5HT 1A receptor agonists, 8-OH-DPAT ((+)-8-hydroxy-2(di- n -propylamino tetralin HBr) and ipsapirone. The effects of morphine were not altered by the 5HT 1A receptor antagonist, NAN-190 (1-(2-methoxyphenyl)-4-(4-(2-phthalimido) butyl) piperazine HBr), the 5HT 2 receptor antagonist, ketanserin, the 5HT 3 receptor antagonist, MDL 72222 (3-tropanyl-3,5-dichlorobenzoate), the alpha 2 adrenergic antagonist, yohimbine, or the alpha 2 adrenergic agonist, clonidine. These results suggest that 5HT 1A receptors may be involved in the effects of morphine in the shock titration procedure, whereas 5HT 2 , 5HT 3 and alpha 2 adrenergic receptors do not appear to play a role in morphine's effects in this procedure.

Sharpley, A.; Williamson, D.; Attenburrow, M.; Pearson, G.; Sargent, P.; Cowen, P.

doi: 10.1007/BF02246410pmid: 8853216

213 126 126 1 1 A. L. Sharpley D. J. Williamson M. E. J. Attenburrow G. Pearson P. Sargent P. J. Cowen University Department of Psychiatry Littlemore Hospital OX4 4XN Oxford UK Abstract We studied the effect of acute (1 day) and subacute (16 days) administration of the new antidepressant, nefazodone (400 mg daily), and the selective serotonin re-uptake inhibitor (SSRI), paroxetine (30 mg daily), on the sleep polysomnogram of 37 healthy volunteers using a random allocation, double-blind, placebo-controlled design. Compared to placebo, paroxetine lowered rapid eye movement (REM) sleep and increased REM latency. In addition, paroxetine increased awakenings and reduced Actual Sleep Time and Sleep Efficiency. In contrast, nefazodone did not alter REM sleep and had little effect on measures of sleep continuity. We conclude that in contrast to typical SSRIs, nefazodone administration has little effect on sleep architecture in healthy volunteers.

Roullet, P.; Ammassari-Teule, M.; Mele, A.

doi: 10.1007/BF02246411pmid: 8853217

213 126 126 1 1 P. Roullet M. Ammassari-Teule A. Mele Laboratoire de Psychophysiologie Université de Tours Tours France Istituto di Psicobiologia e Psicofarmacologia Via Renos I-00198 Rome Italy Dipartimento di Genetica e Biologia Molecolare Università di Roma, “La Sapienza” Rome Italy Abstract Injections of glutamatergic NMDA as well as dopaminergic antagonists produce selective place- but not cue-learning deficits in associative spatial tasks. The present work was aimed at examining if the blockade of NMDA and dopaminergic receptors interferes with the encoding of spatial information in a non-associative task specifically designed for rodents. CD1 mice injected with MK-801 (0.1 and 0.25 mg/kg), haloperidol (0.04 and 0.08 mg/kg), a combination of the lower doses of each drug (haloperidol: 0.04 mg/kg and MK-801: 0.1 mg/kg) or saline were placed in an open field containing five objects and their reactivity to the displacement (spatial change) or the substitution (non-spatial change) of some of these objects was examined. The results show that saline-injected mice reacted to spatial as to non-spatial change by increasing the time spent exploring the displaced objects or the substituted one. Both doses of MK-801 prevented mice from detecting spatial change but did not affect their reactivity to the novel object. Both doses of haloperidol abolished the reactivity of mice to spatial change but the higher dose of the drug also altered the reaction to non-spatial change. Taken together, the present results indicate that the blockade of dopaminergic or glutamatergic NMDA receptors abolishes the detection of spatial novelty. The well-documented impairing effects of haloperidol and MK-801 on spatial learning may, therefore, be the consequence of a drug-induced inability in forming and/or updating spatial representions. The effect of haloperidol was, however, less specific than that of MK-801, since haloperidol always modified activity together with the response to spatial change and, at the higher dose, abolished the detection of both spatial and non-spatial change. Finally, haloperidol pretreatment was found to enhance the effect of MK-801 thus suggesting a possible interaction between the two systems in modulating these behavioral responses.

Fletcher, P.

doi: 10.1007/BF02246412pmid: 8853218

213 126 126 1 1 P. J. Fletcher Section of Biopsychology Clarke Institute of Psychiatry 250 College Street M5T 1R8 Toronto Ontario Canada Departments of Psychiatry and Psychology University of Toronto Toronto Ontario Canada Abstract Injection of d -amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect of d -amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injected d -fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection of d -amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR. d -Amphetamine (10 μg) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 μg) into the nucleus accumbens abolished the response-potentiating effect of d -amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect of d -amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effects of d -amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.

Levy, F.; Hobbes, G.

doi: 10.1007/BF02246413pmid: 8853219

213 126 126 1 1 F. Levy G. Hobbes Avoca Clinic, Department of Child and Adolescent Psychiatry Prince of Wales Hospital High Street 2031 Randwick NSW Australia Macquarrie University Sydney NSW Australia Abstract The effect of methylphenidate preceded by a moderate dose of haloperidol on reaction times over the duration of a continuous performance test (CPT) was investigated in ten male children, with a DSM-III diagnosis of attention deficit disorder with hyperactivity disorder (ADDH). Using a within-subject double-blind design, the effects of methylphenidate preceded by haloperidol on reaction time during the first and second blocks of CPT test were compared. Methylphenidate maintained a significantly improved reaction time in the second block of the CPT test. When methylphenidate, preceded by placebo, was preceded by haloperidol this effect was not observed, suggesting opposing effects on attentional systems by methylphenidate versus haloperidol. The study is the first to examine the “blocking” effect of haloperidol over the course of a CPT. The results suggest that dopamine systems are involved in the maintenance of the CPT response, and support an “incentive motivation” theory of sustained attention.

Matthews, K.; Hall, F.; Wilkinson, L.; Robbins, T.

doi: 10.1007/BF02246414pmid: 8853220

213 126 126 1 1 K. Matthews F. S. Hall L. S. Wilkinson T. W. Robbins Department of Experimental Psychology University of Cambridge Downing Street CB2 3EB Cambridge UK National Institute on Alcohol Abuse and Alcoholism Bethesda MD USA Abstract Adult hooded rats exposed to a repeated maternal separation procedure during the neonatal period showed a blunted expression of locomotor hyperactivity conditioned to the presentation of the daily food ration. We have demonstrated that the expression of food-conditioned anticipatory hyperactivity is sensitive to the response-enhancing effects of systemic d -amphetamine (0.5; 1.0 mg/kg) and to the response-attenuating effects of the selective dopamine D 2 antagonist sulpiride (8; 20 mg/kg), the selective dopamine D 1 antagonist SCH 23390 (0.01; 0.022 mg/kg) and the mixed α 1 /α 2 adrenoceptor agonist clonidine (5; 15 μg/kg) in a dose dependent manner. Animals from the early separation groups showed a reduced enhancement of activity in response to 0.5 mg/kg d -amphetamine and a greater attenuation of activity in response to 8 mg/kg sulpiride and 5 μg/kg clonidine. Female separated rats also exhibited an attenuated locomotor response to the unconditioned stimulant effects of 0.5 mg/kg systemic d -amphetamine. The experiments confirm that early maternal separation attenuates the response to conditioned appetitive cues in adult rats and implicate altered dopaminergic and noradrenergic function in the changes. It is possible that early maternal separation in the rat may offer a useful preparation for investigation of the neural substrates mediating affective development and affective psychopathology.