Psychopharmacology

Conn, P.; Sanders-Bush, E.

doi: 10.1007/BF00210830pmid: 2819915

213 92 92 3 3 P. J. Conn E. Sanders-Bush Departments of Pharmacology and Psychiatry Vanderbilt University School of Medicine, A5321 Medical Center North 37232 Nashville TN USA Department of Pharmacology Yale University School of Medicine Sterling Hall of Medicine P.O. Box 3333 New Haven CT USA Abstract Radioligand binding studies have revealed four distinct serotonin (5HT) binding sites in rat brain that are thought to function as 5HT receptors. These include the 5HT-1a, 5HT-1b, 5HT-1c, and 5HT-2 binding sites. Studies have shown that the 5HT-2 binding site mediates a number of effects of 5HT agonists and serves as a 5HT receptor in neuronal and non-neuronal tissues. The 5HT-2 site employs phosphoinositide hydrolysis for signal transduction. The 5HT-1c binding site is also a functional receptor that is linked to phosphoinositide hydrolysis. However, the physiological role of the 5HT-1c receptor is not yet known. Lack of appropriate pharmacological tools for probing the 5HT-1a and 5HT-1b binding sites has made it difficult to definitively determine whether these binding sites are coupled to biochemical effector systems or mediate any of the physiological responses to 5HT agonists. However, there is some evidence that the 5HT-1a site is coupled to adenylate cyclase, and a number of functional roles for the 5HT-1a and 5HT-1b sites have been proposed.

Farde, L.; Halldin, C.; Stone-Elander, S.; Sedvall, G.

doi: 10.1007/BF00210831pmid: 2957716

213 92 92 3 3 L. Farde C. Halldin S. Stone-Elander G. Sedvall Department of Psychiatry and Psychology, Karolinska Institute, and the Karolinska Pharmacy Karolinska Hospital PO Box 60500 S-10401 Stockholm Sweden Abstract Tracer doses of 11 C-SCH 23390 and 11 C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11 C-SCH 23390, but not 11 C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11 C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis (Z)-flupentixol decanoate. 11 C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis (Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis (Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.

Winkler, J.; Thermos, K.; Weiss, B.

doi: 10.1007/BF00210832pmid: 2957717

213 92 92 3 3 J. D. Winkler K. Thermos B. Weiss Division of Neuropsychopharmacology, Department of Pharmacology, Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute 3200 Henry Avenue 19129 Philadelphia PA USA Abstract Fluphenazine-N-mustard (FNM) has been shown to irreversibly block dopaminergic receptor sites and inhibit certain dopaminergically-mediated behaviors. In this study we measured whether FNM has any differential effects on D 1 and D 2 dopaminergic events. Accordingly, we examined the relative effects of FNM on rotational behavior induced by SKF 38393 (D 1 agonist) and Ly 171555 (D 2 agonist) in mice with unilateral, 6-hydroxydopamine-induced lesions of the striatum and the effects of FNM on the binding of ( 3 H)Sch 23390 (D 1 ligand) and ( 3 H)spiroperidol (D 2 ligand) to mouse striatal membranes. FNM inhibited rotational behavior induced by Ly 171555 at doses 10-fold lower than those required to block rotations induced by SKF 38393 (ID 50 values: Ly 171555=1.8 μmole/kg, IP; SKF 38393=16 μmole/kg, IP). The inhibitory effect of high doses of FNM (20 μmole/kg) on rotational behavior was overcome by increasing the dose of SKF 38393 and apomorphine, a nonselective dopaminergic agonist. By contrast, the inhibitory effect of FNM was not overcome by Ly 171555, even when given in doses more than 100 times its ED 50 . Using striatal homogenates in vitro, FNM inhibited the specific binding of ( 3 H)spiroperidol at concentrations about 10-fold lower than those required to inhibit the binding of ( 3 H)Sch 23390 (IC 50 values: ( 3 H)spiroperidol=90 nM; ( 3 H)Sch 23390=840 nM). Considerably higher concentrations of FNM were needed to irreversibly inhibit calmodulin activity in striatal homogenates (IC 50 =10 μM). In vivo, FNM inhibited the binding of ( 3 H)spiroperidol measured ex vivo (ID 50 =4 μmole/kg), but did not inhibit the binding of ( 3 H)Sch 23390, even when given in doses as high as 100 μmole/kg. These studies indicate that FNM was approximately 10 times more potent at inhibiting D 2 -than D 1 -mediated behavior and at displacing D 2 versus D 1 ligands and suggest that FNM may be useful for studying and differentiating D 2 - and D 1 -mediated events.

Aigner, T.; Mitchell, S.; Aggleton, J.; DeLong, M.; Struble, R.; Price, D.; Wenk, G.; Mishkin, M.

doi: 10.1007/BF00210833pmid: 3114781

213 92 92 3 3 T. G. Aigner S. J. Mitchell J. P. Aggleton M. R. DeLong R. G. Struble D. L. Price G. L. Wenk M. Mishkin Laboratory of Neuropsychology National Institute of Mental Health 9000 Rockville Pike 20892 Bethesda MD USA Departments of Neurology and Neuroscience John Hopkins University, School of Medicine 21205 Baltimore MD USA Department of Pathology John Hopkins University, School of Medicine 21205 Baltimore MD USA Departments of Pathology, Neurology, and Neuroscience, Neuropathology Laboratory John Hopkins University, School of Medicine 21205 Baltimore MD USA Department of Psychology Johns Hopkins University 21218 Baltimore MD USA Department of Psychology, Science Laboratories University of Durham South Road DH1 3LE Durham England Abstract Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.

Bejanian, M.; Finn, D.; Syapin, P.; Alkana, R.

doi: 10.1007/BF00210834pmid: 3114782

213 92 92 3 3 M. Bejanian D. A. Finn P. J. Syapin R. L. Alkana Alcohol and Brain Research Laboratory, Institute for Toxicology, School of Pharmacy University of Southern California 1985 Zonal Avenue 90033 Los Angeles CA USA Abstract The present study tested the assumption that deep rectal temperature reflects brain temperature in ethanol-intoxicated mice exposed to a range of ambient temperatures. Adult C57BL/6J mice were injected IP with one of three hypnotic doses of ethanol (3.2, 3.6, or 4.0 g/kg, 20% w/v) or with normal saline and were exposed to ambient temperatures of 15, 22, 32, or 34° C. Thirty minutes post-injection, the mice were killed by cervical dislocation, decapitated and their rectal and brain temperatures were recorded simultaneously. Rectal and brain temperatures in the intoxicated mice increased significantly as the ambient temperature increased and were highly correlated and linearly related with each other. Although correlated, brain and rectal temperatures in these mice did not change in parallel, with brain temperatures increasing less rapidly than rectal temperatures. Additional studies indicated that similar relationships (correlated, but non-parallel) exist between the brain and rectal temperatures at 60, 120, and 180 min after injection of 3.6 g/kg ethanol. These findings suggest that rectal temperature can be used to quantify brain temperature in intoxicated mice, and extend to intoxicated animals evidence that brain temperature is controlled independently from rectal temperature.

Lieberman, H.; Wurtman, R.; Emde, G.; Roberts, C.; Coviella, I.

doi: 10.1007/BF00210835pmid: 3114783

213 92 92 3 3 H. R. Lieberman R. J. Wurtman G. G. Emde C. Roberts I. L. G. Coviella Department of Brain and Cognitive Sciences and the Clinical Research Center E20-138 Massachusetts Institute of Technology 02139 Cambridge MA USA Department of Applied Biological Sciences Massachusetts Institute of Technology 02139 Cambridge MA USA Abstract Caffeine is thought to have stimulant-like behavioral effects on mood and performance. However few behavioral studies have examined this substance's acute effects when administered in a range of doses that include the low doses typically found in foods and over-the-counter drugs. We therefore gave single doses of caffeine (32, 64, 128 and 256 mg) to 20 healthy male subjects and assessed various aspects of performance and self-reported mood states, as well as plasma caffeine concentration. As little as 32 mg (which elevated plasma caffeine concentration to less than 1 μg/ml), typical of the dose found in a single serving of a cola beverage, and less than that found in a single cup of coffee or a single dose of over-the-counter drugs, significantly improved auditory vigilance and visual reaction time. All other caffeine doses administered also significantly improved performance on these tests. No adverse behavioral effects, such as increased anxiety or impaired motor performance, were noted even at the highest dose administered.

Emmett-Oglesby, M.; Herz, A.

doi: 10.1007/BF00210836pmid: 2819916

213 92 92 3 3 M. W. Emmett-Oglesby A. Herz Department of Neuropharmacology Max-Planck-Institute for Psychiatry Am Klopferspitz 18a 8033 Martinsried Federal Republic of Germany Abstract Rats were trained to detect the stimulus properties of pentylenetetrazol (PTZ), 16 mg/kg, and prototypic drugs for mu, kappa and sigma opioid receptors were tested for their ability to block or substitute for PTZ. Only the sigma agonist, phencyclidine, showed any capacity for blocking the PTZ stimulus. Drugs with selective kappa or sigma actions did not substitute for PTZ. However, morphine, fentanyl and Mr 2034 did substitute for the PTZ stimulus. This substitution was found to be centrally mediated in that quaternary morphine did not produce a PTZ-like stimulus. In contrast to the substitution of these drugs for PTZ, in rats trained to detect the stimulus properties of fentanyl, no substitution of PTZ for the fentanyl stimulus occurred. In tests of the capacity of various drugs to block the PTZ-like stimulus of mu agonists, the stimulus produced by morphine or fentanyl was blocked by naloxone, diazepam and haloperidol, but not by scopolamine. These results demonstrate that drugs with mu agonist properties show a one-way substitution for the discriminative stimulus produced by PTZ. The observation that haloperidol blocked the PTZ-like stimulus of mu agonists suggests the possible involvement of dopaminergic mechanisms in the mediation of the effect.

García-Sevilla, J.; Ulibarri, I.; Ugedo, L.; Gutierrez, M.

doi: 10.1007/BF00210837pmid: 2819917

213 92 92 3 3 J. A. García-Sevilla I. Ulibarri L. Ugedo M. Gutierrez Department of Pharmacology, Faculty of Medicine University of the Basque Country Leioa, Vizcaya Spain Drug Addiction Unit Santiago Hospital Vitoria Spain Abstract The inhibition of basal and forskolin-stimulated platelet adenylate cyclase activity by (-)adrenaline was studied in ten heroin addicts during spontaneous withdrawal. Both basal and forskolin-stimulated enzyme activities were increased during heroin withdrawal and the inhibitory effect induced by (-)adrenaline was potentiated with parallel shifts to the left of the concentration-effect curves. The number of binding sites for ( 3 H)(-)adrenaline in platelet membranes was also increased during withdrawal. Treatment with clonidine markedly attenuated the inhibitory effect induced by (-)adrenaline on platelet adenylate cyclase activity. The results indicate that the heroin withdrawal syndrome induces supersensitivity of the platelet α 2 -adrenoceptor-adenylate cyclase system.

Quock, R.; Wojcechowskyj, J.; Emmanouil, D.

doi: 10.1007/BF00210838pmid: 3114784

213 92 92 3 3 R. M. Quock J. A. Wojcechowskyj D. E. Emmanouil Departments of Basic Sciences and Pediatric Dentistry Marquette University School of Dentistry 53233 Milwaukee Wisconsin USA Abstract Mice were exposed for 10–20 min to room air, 100% oxygen (O 2 ) or increasing concentrations of nitrous oxide (N 2 O) in O 2 , then tested for 3 min in a staircase inside a glovebag. N 2 O produced a concentration-dependent increase in the number of steps ascended (NSA) but no change in the number of rears (NR). Pretreatment with naloxone reversed the increase in NSA and also unmasked N 2 O reduction in NR. By comparison, increasing doses of the narcotic standard morphine reduced NSA and NR; these changes in NSA and NR were sensitive to antagonism by naloxone. The benzodiazepine standard diazepam produced a dose-related reduction in NR while reducing NSA only at higher doses. These data indicate that N 2 O influences on NSA and NR resemble neither morphine nor diazepam. In addition, it appears that the opioid activity of N 2 O might mask its antianxiety activity in this particular paradigm.

Solomon, R.; Wasserman, E.; Gebhart, G.

doi: 10.1007/BF00210839pmid: 3114785

213 92 92 3 3 R. E. Solomon E. A. Wasserman G. F. Gebhart Department of Pharmacology, College of Medicine University of Iowa 52242 Iowa City IA USA Department of Psychology University of Iowa 52242 Iowa City IA USA Abstract The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio ( mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0–8.0 mg/kg) or chlordiazepoxide (CDP; 4.0–32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0–8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0–16.0 mg/kg) produced increases in response rates. Finally, the effects of cumulative doses of morphine did not differ significantly from the effects of noncumulative doses of the drug.