Irving Geller

The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in the rat

SummaryConflict behavior was induced in rats by simultaneously rewarding with liquid food and punishing with pain shock every lever response made in the presence of a tone. Meprobamate, phenobarbital and pentobarbital increased the number of shocks a rat would accept in order to obtain the food reward; in contrast, promazine and d-amphetamine decreased the number of shocks taken. The technique thus permits a separation on a behavioral basis of meprobamate, pentobarbital and phenobarbital from promazine and d-amphetamine.

The effects of chlordiazepoxide and chlorpromazine on a punishment discrimination.

SummaryA punishment discrimination was conditioned in laboratory rats by simultaneously rewarding with food and punishing with shock all lever responses made in the presence of a discriminative stimulus (tone). Appropriate setting of the shock intensity resulted in either high or low but stable output of responses during the tone periods. Rats working on a high-shock control baseline were administered CDAP at 7.5, 15.0, and 30 mg/kg. These rats worked during the tone periods and tolerated more shocks in order to obtain food rewards. Rats working on a lowshock control baseline were administered CPZ at 0.25, 0.5, 1.0, 2.0, and 3.0 mg/kg. These rats accepted less shocks during the tone periods. The decrease in shocks taken bears a direct relationship to the increase in dose of the drug. Some preliminary data for a monkey show the reproducibility of the behavior as well as the CDAP effects in another species.

ALTERATIONS IN ETHANOL PREFERENCE IN THE RAT: THE ROLE OF BRAIN BIOGENIC AMINES*

The in vitro formation of tetrahydroisoquinoline alkaloids from condensation reactions between monoamines and aldehydes has been Cohen and Collins have speculated that the formation of such compounds in vivo could account for “the process of physical dependence and addiction in alcoholism.”’ In 1961, MsIsaac3 reported on the in vitro formation of a similar compound by a condensation reaction of 5-methoxytryptamine and acetaldehyde. The compound, l-methyl-6-methoxy-l,2,3,4-tetrahydro-2-carboline(MMTC) also was detected in the urine of rats treated with 5-methoxytryptamine and acetaldehyde in conjunction with their respective metabolic inhibitors, iproniazid and disulfiram. The possible in vivo formation of MMTC from an alcohol metabolite led to the speculation that alcohol drinking on the part of the rat might in some way be related to the in vivo formation of the compound. Therefore we decided to determine the effects of MMTC on ethanol preference in the rat. The experimental method and equipment have been described in part p rev i~us ly .~ Male Sprague-Dawley rats were housed individually in cages 9 X 15 X 18 inches (Wahman LC-28). They were kept in a laboratory with ambient temperatures of 21’ to 24OC and were maintained on an unrestricted diet of Wayne Lab Blox. Water and an ethanol solution were available at all times in lOO-ml, Kimax drinking tubes mounted on the back and either side of the cages so that the drinking spouts protruded into the cages approximately 1% inches above the cage floor level. The two-fluid, three-bottle choice method, as previously de~cr ibed ,~ was used to prevent rats from selecting a fluid based on a position preference. The cages contained a tube of water, a tube of ethanol, and an empty tube. Each day at 10 A.M. the experimenter recorded the amounts of fluids consumed during the preceding 24 hours. The drinking tubes were washed, refilled, and put back on the cages, and their positions were rotated randomly from day to day. Ethanol preference curves for two rats are shown in FIGURE 1. The arrows indicate the beginning and termination of drug or saline injections, which were given each day at 10 A.M. and 4 P.M. For rat V-21, ethanol intake was reduced and water intake increased by MMTC at 50 mg/kg. For rat V-22, saline had no observable efTect. On the day following the last drug administration, the animals were sacrificed and their brains were subjected to biochemical analyses. Whole-brain serotonin for the MMTC-treated rat was 0.94 pg/g tissue, almost twice that of the rat given saline, while the obtained value of 0.63 for 5-HIAA was more than twice that of the salin-injected rat. Values obtained for the latter animal approximated those obtained for other nondrinking control animals. The effects of 3 dose levels of MMTC on ethanol preference of a single rat are

Effects of nicotine, nicotine monomethiodide, lobeline, chlordiazepoxide., meprobamate and caffeine on a discrimination task in laboratory rats

Hungry rats were trained on a discrimination task in order to obtain food rewards. During each experimental session, discrete stimuli of 1 min duration were delivered through a small speaker in the experimental chamber at random intervals on the average of once every 2 min. Lever responses in the presence of a light and tone were correct and produced food rewards. Lever responses in the presence of the light stimulus were incorrect and were punished by total inactivation of the experimental chamber. Rats were selected for this experiment based on their inability to acquire the discrimination task even after six months of training. Administration of nicotine, lobeline, chlordiazepoxide and meprobamate produced an improvement in discrimination performance through a reduction of responses to incorrect stimuli. Caffeine and nicotine monomethiodide, the quaternary salt of nicotine, were without effect on the discrimination.

Soporific action of ethanol in mice: possible role of biogenic amines.

Abstract Ethanol-induced sleep time was measured in mice after administration of L-3,4-dihydroxyphenylalanine (L-DOPA), L-tryptophan (L-TP), DL-5-hydroxytryptophan (5-HTP), serotonin (5HT), DL-5-hydroxyindole-3-acetic acid (5HIAA), and DL-parachlorophenylalanine (pCPA), a serotonin depletor. The pCPA administration, with concomitant reduction of brain serotonin, had no effect on ethanol-induced sleep; TP, 5-HTP and 5HIAA failed also to significantly enhance ethanol sleep in mice. However, serotonin significantly enhanced sleeping time of mice administered an ineffective dose of ethanol. Pretreatment with L-DOPA produced a marked prolongation of ethanol narcosis with a concomitant large increase in whole brain dopamine (DA). Administration of L-DOPA and pCPA, together, produced a smaller augmentation of ethanol effects.

Blockade of 5-HTP reduction of ethanol drinking with the decarboxylase inhibitor, Ro 4-4602

5-Hydroxytryptophan (5-HTP) reduced ethanol intake in laboratory rats. The reduction of ethanol intake was blocked when Ro 4-4602, the decarboxylase inhibitor, was given in combination with the 5-hydroxytryptophan. These observations provide further support for the involvement of brain serotonin in voluntary ethanol drinking by the rat.

Synergy of Ethanol and Putative Neurotransmitters: Glycine and Serine

The putative neurotransmitters, glycine and serine, significantly enhanced the sleeping time (loss of the righting reflex) that was induced by ethanol in mice. The observed synergistic effect between ethanol and the amino acids is probably not related to an alteration of ethanol metabolism, but rather to an interaction of these compounds in the central nervous system.

Effects of 1,1,1‐trichloroethane on a match‐to‐sample discrimination task in the baboon

1,1,1-trichloroethane was evaluated for its effects on the delayed match-to-sample discrimination task in juvenile baboons. Acute 4-h exposures to 700, 1400, 1800, and 2100 ppm were conducted no more frequently than once a week. Three months later a subchronic exposure to 1200 ppm was conducted over a 7-d period in the same animals. The effects on accuracy of responding were minimal; however, 1,1,1-trichloroethane reduced the number of trials attempted by the animals, reduced the number of extra inconsequential responses during the delay intervals, and increased reaction times. The findings of these experiments illustrate the usefulness of the young baboon as a primate human surrogate model for testing this type of central nervous system depressant.

Alteration of ethanol preference in hamsters: effects of photoperiod and 5-hydroxytryptophan.

Relatively few investigators have made use of the golden hamster as an experimental animal for ethanol studies. This is somewhat surprising insofar as hamsters show a marked preference for ethanol solutions in free-choice experiments. Given a choice of water or a 10% ethanol solution, hamsters will drink 88% of their total fluid as ethanol solution (Arvola and Forsander, 1961). Furthermore, the most preferred concentration of ethanol for the male hamster is 15% (Arvola and Forsander, 1963) in contrast to the rat that shows a preference only for much lower ethanol concentrations.

Phenobarbital and d-amphetamine effects on discrimination performance of rats and juvenile baboons☆

Hungry rats in Skinner boxes were trained to select the right or left lever as correct as a function of the presence of a tone or light stimulus, respectively. Correct responses produced liquid food rewards. Acute intraperitoneal administration of d-amphetamine or phenobarbital did not affect accuracy of performance, but decreased the percent trials attempted and lengthened response times as a function of increasing doses. The mean extra responses during the delay intervals generally decreased under phenobarbital and increased under d-amphetamine. Juvenile baboons were trained to respond on a delayed match-to-sample task in order to obtain banana pellet rewards. Acute intramuscular administration of phenobarbital produced a dose-related increase in errors, a decrease in mean extra responses and an increase in response times. A slight reduction in the percent trials attempted occurred only at the highest dose of the drug. Acute intramuscular d-amphetamine did not increase errors even at dose levels that increased reaction times, decreased extra responses and reduced the percent trials attempted.