Showing papers in "Psychopharmacology in 1978"

Intruder-evoked aggression in isolated and nonisolated mice: Effects of psychomotor stimulants and l -Dopa

Abstract: Adult male Swiss-Webster mice were housed either singly (isolated) or with a female (nonisolated). Aggressive behavior was evoked by introducing a group-housed male mouse (intruder) into the home cage of the isolated or nonisolated mouse (resident). d-Amphetamine, methamphetamine, methylphenidate, cocaine, and l-dopa decreased attack and threat behavior by resident mice, the isolates requiring 2–4 times higher drug doses for the antiaggressive effects than the nonisolates. d-Amphetamine, methamphetamine, and methylphenidate caused intruder mice to be more frequently attacked by their nontreated resident opponents, to escape more often, to assume the defensive upright posture less, and to move about more often. l-Dopa nonspecifically decreased all elements of agonistic and nonagonistic behavior, while the amphetamines and methylphenidate suppressed attacks, increased escapes, decreased upright postures, and increased nonagonistic locomotion. By contrast, cocaine's antiaggressive effects were remarkably specific, i.e., not accompanied by changes in other behavioral elements.

The effect of housing and gender on morphine self-administration in rats.

Abstract: To determine the effect of housing conditions on morphine self-administration, rats isolated in standard laboratory cages and rats living socially in a large open box (8.8 m2) were given morphine in solution (0.5 mg/ml) as their only source of fluid for 57 days. They were then exposed to a series of 3-day cycles previously shown by Nichols et al. (1956) to increase self-administration of morphine in caged rats. On morphine/water choice days late in the period of forced consumption, between the Nichols cycles, and during a subsequent period of abstinence, the isolated rats drank significantly more morphine solution than the social rats, and the females drank significantly more morphine solution than the males. During the four choice days in the Nichols Cycle Period the isolated rats increased their consumption, but the socially housed animals decreased theirs.

Dopaminergic supersensitivity after neuroleptics: time-course and specificity.

Abstract: It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months of years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease. Dopaminergic supersensitivity persists for a period proportional to the lenght of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments, but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.

Deprenyl administration in man: A selective monoamine oxidase B inhibitor without the ‘cheese effect’

Abstract: After pretreatment with the selective monoamine oxidase B inhibitor, (-)-deprenyl, in doses sufficient for complete inhibition of the platelet enzyme, 4 normal and 6 parkinsoniam volunteers (2 receiving levodopa and 2 levodopa plus carbidopa) suffered no adverse pressor reaction ('cheese effect') after challenge with oral tyramine in amounts considerably greater than those likely to be encountered in a normal diet. Nor did the levodopa-deprenyl combination itself result in a pressor response. Normal human intestinal mucosa was shown predominantly to contain the deprenyl-insensitive A form of the enzyme, which presumably degraded administered tyramine in the deprenyl-treated volunteers; even those receiving the drug for prolonged periods manifested no 'cheese effect', suggesting that the A form remained uninhibited. Intestinal monoamine oxidase A was able to oxidise dopamine, whereas in human platelet or striatum the amine is a monoamine oxidase B substrate. Like tyramine, oral phenylethylamine challenge with amounts greater than those known to be present in a normal diet similarly gave rise to no adverse reaction in (-)-deprenyl-treated subjects; the reasons for this remain to be determined.

The acquisition of responding with conditioned reinforcement: effects of pipradrol, methylphenidate, d-amphetamine, and nomifensine.

Abstract: The effects of pipradrol (5–15 mg/kg), methylphenidate (5–15 mg/kg), d-amphetamine (0.5–3.0 mg/kg), and nomifensine (5–15 mg/kg) on the acquisition of responding with conditioned reinforcement (CR) were examined. In preliminary training (phase 1), a panel-push was required for water-deprived rats to obtain access to a water-dipper. The presentation of the dipper occurred at variable intervals, independently of responding, and was preceded by a light stimulus. In phase 2, no water was available and presentation of light and empty dipper (CR) was contingent upon pressing one of two levers present (CR lever), according to a variable-ratio 2 schedule. Pressing the other lever had no effect (NCR lever). In Experiment I, pipradrol produced a dose-dependent increase in responding on the CR lever, but a dose-dependent decrease on the NCR lever. Methylphenidate and d-amphetamine produced inconsistent results, and nomifensine produced a general reduction in responding. The stimulation of responding by pipradrol transferred to the undrugged state, but previous experience with pipradrol outside the experimental setting did not increase responding during control sessions. Experiment II showed that the effects of repeated doses of pipradrol changed over sessions. Experiment III showed that 15 mg/kg pipradrol did not increase responding for the light and dipper stimuli when these had not previously been paired with water. The results suggest that pipradrol enhances the effects of conditioned reinforcers, and are discussed in terms of the other behavioral effects of ‘psychomotor stimulant’ drugs.

Classification of neuroleptic drugs according to their ability to inhibit apomorphine-induced locomotion and gnawing: evidence for two different mechanisms of action.

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.

Amphetamine-type reinforcement by dopaminergic agonists in the rat

Abstract: Intravenous self-administration of d-amphetamine (025 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil The dopaminergic agonists appear to suppress amphetamine intake in the same way as do ‘free’ amphetamine injections, by extending drug satiation in a given interresponse period Clonidine, an alpha noradrenergic agonist, did not have similar effects Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism Rats responding for amphetamine continued to respond for apomorphine or piribedil when the latter drugs were substituted for the former Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties

Progressive-ratio performance maintained by drug infusions: comparison of cocaine, diethylpropion, chlorphentermine, and fenfluramine.

Abstract: Cocaine, diethylpropion, chlorphentermine, and fenfluramine were compared on a drug-maintained progressive-ratio procedure in baboons. Intravenous infusions of drug were contingent on completion of a fixed-ratio response requirement (fixed number of lever-press responses) with a 3-h time-out period following each infusion. Prior to testing each dose of drug, stable self-infusion performance was first established with 0.4 mg/kg cocaine when the fixed-ratio requirement was 160. Subsequently, a test dose of drug was substituted for the standard dose of cocaine. If the dose of drug maintained a criterion level of self-infusion performance (six or more infusions per day for 2 days), the ratio requirement was systematically increased every day until the ‘breaking point’ at which the self-infusion performance fell below a criterion level (one or zero infusionsper day). Fenfluramine did not maintain criterion self-infusion performance at any dose tested (0.02–5.0 mg/kg). The dose ranges of the other drugs that maintained maximum breaking points were 1.0–5.6 mg/kg for chlorphentermine, 1.0–3.0 mg/kg for diethylpropion, and 0.1–0.4 mg/kg for cocaine. Within-animal comparison of the maximum breaking points indicated that cocaine maintained the highest breaking points, followed in order by diethylpropion, chlorphentermine, and fenfluramine. The rank ordering of these drugs with the breaking point measure corresponds well with both the results of other animal experiments on measurement of reinforcing efficacy of these drugs and with the clinical information about the human subjective effects and abuse of these drugs.

The relationship between changes in REM sleep and clinical improvement in depressed patients treated with amitriptyline

Abstract: EEG sleep recordings were obtained on consecutive nights from six hospitalized depressed patients before, during, and after treatment with amitriptyline for a total of 370 nights of data, about 85% of all nights of the study. Amitriptyline significantly reduced time spent in rapid eye movement (REM) sleep and prolonged the REM latency throughout the treatment period. Three patients who improved during treatment showed a REM rebound when amitriptyline was discontinued, whereas three patients who did not improve showed no REM rebound.

Effects of ethanol on pregnant rats and their offspring

Abstract: Pregnant rats were intubated with either 1.0 or 2.0 g/kg of ethanol daily throughout gestation. Pair-fed vehicle-treated, and nontreated rats fed ad libitum, served as control groups for ethanol-treated animals. Ethanol treatment reduced food and water consumption and attenuated the gain in body weight of pregnant animals relative to nontreated animals fed ad libitum. Litter size, litter weight, and the mean weight per pup were reduced in both the ethanol-treated and pair-fed control groups. There was no evidence of gross malformations in any of the offspring. Since the reduction in litter size and litter weights did not differ significantly between ethanol-treated and pair-fed controls, the effects of treatment with ethanol appeared to be related to a reduction in maternal intake of calories rather than to the direct effect of ethanol on the developing fetus. There were no significant differences between any of the groups of offspring on one-way shock avoidance learning, water maze escape learning, spontaneous alternation, or brightness discrimination learning in tests beginning at 75 days of age. Thus, at the doses of alcohol used in this study, there was no evidence of behavioral teratogenesis comparable to that reported for higher doses in animals or in man characterized by the fetal alcohol syndrome.

Experimental analysis of the 'happy hour": effects of purchase price on alcohol consumption

Abstract: An experimental analogue of a discount drink policy known as the "happy hour" was used to study the effects of purchase price on drinking behavior. Male volunteers with a prior history of either casual (N=20) or heavy (N=14) drinking were given free access to beverage alcohol during a 20-day period. Approximately half the subjects could purchase alcohol under a single-price condition (50 cents/drink), while a matched group was given a price reduction daily (25 cents/drink) during a three-hour period in the afternoon. The results demonstrated that the afternoon price reduction significantly increased alcohol consumption in both casual and heavy drinkers. Reinstatement of the standard purchase price effectively suppressed drinking in both groups. The findings are discussed in terms of the theoretical and research implications of environmental influences on drinking.

Clozapine in tardive dyskinesia

Abstract: Clozapine, which has had limited clinical testing in the U.S.A., was evaluated in 12 chronic schizophrenic patients with tardive dyskinesia. Its antipsychotic activity was again demonstrated and it suppressed the symptoms of tardive dyskinesia with a marked rebound occurring in these symptoms when it was withdrawn; there was no rigidity or other Parkinsonian symptoms. However, out of a total of 12 patients, neutropenia (800 and 1120) occurred in two patients, convulsion in one patient, marked withdrawal effects in three patients, and a hypotensive collapse with atrial fibrillation in one patient. If these adverse effects are confirmed in a larger sample size, then despite the novel desirable effects of clozapine it would seem unlikely that it will gain widespread or routine use.

Use of antianxiety agents in anxious outpatients

Abstract: The present paper reviews the role of antianxiety agents in the treatment of nonpsychotic anxious patients. Major emphasis is placed on findings from clinical trials conducted by this research group. Consideration is given to the relative efficacy of available antianxiety agents, to patients response in relation to patterns of symptomatology, and to the degree of symptom relief experienced by drug-treated anxious patients. Also discussed are some of the many nonspecific factors that affect improvement with drug treatment in general and with the benzodiazepines in particular. It is concluded that many anxious patients are not currently receiving adequate drug treatment, and may require longer periods of drug therapy or supplemental nondrug intervention.

A comparison of some pharmacological actions of morphine and delta9-tetrahydrocannabinol in the mouse.

Abstract: The effects of morphine and Δ9-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.

Situational factors contributing to the placebos effect.

Abstract: The influence of four variables (status of communicator of drug effects, attitude of dentist, attitude of dental technician, and message of drug effects) on the obtainment of placebo effects in an oral surgery clinic was investigated. Dependent variables were (1) rating of pain experienced from mandibular-block injection, (2) pre-post placebo state anxiety, and (3) pre-postplacebo fear of injection. Enthusiastic messages of drug effects produced statistically and clinically significant reductions in postplacebo fear of injection and state anxiety and markedly lower ratings of pain experienced during injection of local anesthetic. Although there was a strong tendency for positive placebo effects to occur when the dental staff was perceived as friendly and supportive, only the attitude factors obtained statistical significance. The status of the communicator accounted for very small portions of the variance.

Evidence for cell loss in corpus striatum after long-term treatment with a neuroleptic drug (flupenithixol) in rats.

Abstract: The number of nerve cells in two different areas of the corpus striatum (i.e., ventrolateral and dorsomedial) was estimated in rat brain after long-term (36 weeks) treatment with the neuroleptic flupenthixol. Nine rats were given weekly injections of 4 mg/kg flupenthixol dissolved in Viscoleo i.m., and seven rats received Viscoleo alone. Fourteen to 18 weeks after the last drug injection, the animals were decapitated and half of each brain was fixated with formalin for cell-count analysis and the remaining half used for a biochemical analysis (Nielsen, 1977). Separate cell counts in the ventrolateral and dorsomedial corpus striatum yielded a significant cell loss of approximately 10%, but only in the ventrolateral striatum of treated animals. These results suggest at least one concrete anatomical basis for the behavioral and biochemical deficits found in the same animals, as reported earlier. The results further suggest that persistent irreversible anatomical changes can follow long-term neuroleptic treatment. The inconsistencies of results regarding cell loss in the corpus striatum may be due to neglect of dorsal-ventral structural differences in corpus striatum.

The central antiserotonergic action of mianserin

Abstract: The central antiserotonergic action of mianserin (MS) was tested in mice, rats, and rabbits. MS, like cyproheptadine, to which it was compared, inhibits the head-twitch response to 5-hydroxytryptophan in mice and rats without affecting the pinna reflex. MS does not change the flexor reflex of the hind limb of the spinal rat; it antagonizes its stimulation induced by fenfluramine, LSD, and quipazine, but not that induced by clonidine. The hyperthermia in rabbits caused by the serotonergic stimulants cited above is also antagonized by pretreatment with MS. Unlike cyproheptadine, MS is not active in the oxotremorine test. The results indicate that at low doses MS is a central serotonergic-receptor blocker.

The attenuation of a specific cue-to-consequence association by antiemetic agents.

Abstract: Previous research has shown that rats develop a conditioned taste aversion after a single pairing of a distinct taste and subsequent toxicosis. The experiments reported here test the hypothesis that the expression of a taste aversion may reflect classically conditioned nausea mediated by activation of brainstem emetic centers by taste stimuli. Rats were allowed to drink a saccharin solution (1 g/l) and 10 min later were intubated with LiCl (180 mg/kg) to produce nausea. When control rats were posttested for saccharin preference they consumed less than 50% of their pretest intake. Experimental rats were injected with one of four pharmacologically distinct antiemetic drugs 30 min prior to their posttest with saccharin. Each drug significantly attenuated the aversion to saccharin at one dose level. The antiemetic drugs we used were scopolamine HBr, cyclizine, prochlorperazine dimaleate, and trimethobenzamide. These drugs had no effect on the conditioned fear of a noise that signaled foot shock or on a natural aversion to a bitter fluid (quinine monohydrochloride, 100 mg/l). Our data suggest that pharmacological suppression of the neural mechanisms of emesis selectively disrupts conditioned taste aversions, and that moderate dose levels are critical for obtaining this effect.

Effect of a specific 5-HT uptake inhibitor, citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro.

Abstract: The uptake of 3H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of 3H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of 3H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with 3H-5-HT is specific for 5-HT neurons. The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of 14C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain. When rats were treated orally with citalopram or chlorimipramine, the inhibition of 3H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.

Tardive dyskinesia during and following treatment with haloperidol, haloperidol + biperiden, thioridazine, and clozapine.

Abstract: In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.

Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, γ-acetylenic GABA (4-amino-hex-5-ynoic acid) and γ-vinyl GABA (4-amino-hex-5-enoic acid)

Abstract: The anticonvulsant potency and neurological toxicity of two new catalytic inhibitors of GABA-transaminase have been assessed in acute experiments in baboons with a natural syndrome of photic epilepsy. γ-Acetylenic GABA, 160–200 mg/kg, or γ-vinyl GABA, 450–950 mg/kg, intravenously, gave complete protection against generalised myoclonus or seizure responses induced by photic stimulation (in baboons without or with priming with subconvulsant doses of allyglycine). The protection became maximal 1–3 h after injection, and continued for 7–24 h. Signs characteristic of the acute toxicity of anticonvulsant drugs (nystagmus and ataxia) were not seen. The potential use of these compounds in human epilepsy deserves investigation.

Avoidance conditioning and Hebb-Williams maze performance in rats treated prenatally with alcohol

Abstract: Throughout gestation pregnant Wistar rats consumed a nutritious liquid diet containing 35% ethanol-derived calories. Control mothers were fed lab chow. Subsequently, the offspring of the ethanolfed mothers were found to be impaired on two-way avoidance conditioning when compared to control offspring, but did not differ from controls in their performance on the Hebb-Williams maze. Fostering and cross-fostering procedures indicated that the effect was due to prenatal influences arising from the drug treatment.

The activities of brain dopamine-beta-hydroxylase and catechol-O-methyl transferase in schizophrenics and controls.

Abstract: It has been suggested that deterioration of central noradrenergic pathways may be responsible for the production of certain schizophrenic symptoms, and that such a degeneration might be reflected in lowered dopamine-β-hydroxylase (DBH) activity in the brains of schizophrenics. The present study revealed that in rats lowered DBH activity was a sensitive index of noradrenergic degeneration. In the postmortem brains of 12 controls and 12 schizophrenics, however, no significant difference in DBH activity between controls and schizophrenics was found. DBH activity was relatively unstable postmortem and adversely affected by neuroleptic drugs, and these factors may have contributed to the previous finding of lowered DBH activity in the brains of schizophrenics. The activity of catechol-O-methyl transferase, which has also been previously reported as low in the brains of schizophrenics, was found to be no different in the controls of the present study.

The contribution of tryptamine to the behavioural effects of l-Tryptophan in tranylcypromine-treated rats.

Abstract: Rats pretreated with the monoamine oxidase inhibitor tranylcypromine and given l-tryptophan develop a characteristic behavioural syndrome. A comparison of the behavioural effects of tranylcypromine plus l-tryptophan (50 and 100 mg/kg) showed a small increase in locomotor activity and a greater increase in the behavioural score with the higher dose. This was associated with a proportionately smaller increase in brain 5-hydroxytryptamine (5-HT) than in brain tryptamine and no change in spinal cord 5-HT. Tryptamine (1–5 mg/kg) in the presence of tranylcypromine produced behavioural effects very similar to those occurring when l-tryptophan is given to tranylcypromine-pretreated rats. Increasing brain tryptamine, by the injection of tryptamine (0.75 mg/kg), enhanced the behavioural effects of tranylcypromine plus l-tryptophan (50 mg/kg) without altering brain 5-HT. Para-chlorophenylalanine pretreatment, which reduced brain 5-HT, prevented the behavioural effects of tryptamine. Inhibition of peripheral decarboxylase with R04-4602 (50 mg/kg) reduced brain tryptamine and did not alter brain 5-HT, but reduced the locomotor activity and the behavioural score of rats given tranylcypromine and l-tryptophan (100 mg/kg). The results suggest that brain tryptamine changes are partly responsible for the behavioural effects of tranylcypromine plus l-tryptophan and that some of this tryptamine is of extracerebral origin.

The reinforcing property of ethanol in the rhesus monkey - II. Some variables related to the maintenance of intravenous ethanol-reinforced responding

Abstract: Rhesus monkeys received intravenous injections of ethanol during daily sessions contingent on their presses on an available lever. Under the standard conditions, when each response on the lever during a 3-h period each day resulted in an i.v. injection of 0.1 g/kg ethanol, the monkeys made between 30 and 50 responses/session and developed blood ethanol levels of approximately 400 mg%. Under this and other conditions of response-contingent delivery of ethanol, a negatively accelerated pattern of self-injection within sessions was demonstrated. Variations in the dose per injection (0.05–0.2 g/kg/injection) resulted in changes in the rate of lever-pressing; the number of self-injections was inversely related to dose. Ethanol intake increased only slightly with increased dose per injection. Noncontingent administration of various doses of i.v. ethanol immediately prior to a daily session decreased the number of responses; the total amount of ethanol administered (contingent plus noncontingent), however, remained constant over a pretreatment dose range of 1 to 3 g/kg. When access time to ethanol was increased from 3 to 6 h/day, the total amount of ethanol taken increased slightly. However, the blood ethanol levels at the end of a 6-h session closely approximated those obtained following 3-h sessions, indicating that during the last 3–4 h of the 6-h sessions, the rate of ethanol intake closely matched the rate of ethanol elimination.

A comparison of the discriminative stimulus effects of ethanol, barbital, and phenobarbital in rats.

Abstract: Five different groups of rats were trained in a food-motivated, bar-pressing task to discriminate from the nondrug condition (physiologic saline, i.p.) the effects produced by i.p. injections of ethanol (330, 660, or 990 mg/kg), sodium barbital (80 mg/kg), or sodium phenobarbital (25 mg/kg). The establishment of highly effective discriminations required 20–40 training sessions for all drugs, with the exception that rats trained with 330 mg/kg of ethanol required 80–100 training sessions. After the drug-nondrug discriminations were well established, cross tests revealed that ethanol did not elicit drug-appropriate responding in the groups trained with sodium barbital or sodium in the groups trained with sodium barbital or sodium phenobarbital. However, both barbiturates elicited drug-approppriate responding to some extent in rats trained with ethanol as the discriminative stimulus. With barbital, the greatest generalization was observed in rats trained with the low dose of ethanol (330 mg/kg). The findings emphasize the need for the use of several training doses and for transfer tests in both directions when the stimulus effects of drugs are compared.

A twin study on three enzymes (DBH, COMT, MAO) of catecholamine metabolism

Abstract: In a sample of 48 healthy adult male twin pairs (24 MZ, 24 DZ) the activities of DBH (serum), COMT (red blood cells), and MAO (platelets) were determined. The twins had undergone a detailed psychodiagnostic test procedure before. Interindividual variability of enzyme activities is almost exclusively genetically determined. No correlation between enzyme activities within one subject is found. Correlations between enzyme activities and MMPI test scores were calculated. As in a comparable investigation by Murphy et al. (1977), negative correlations between MAO activity and MMPI scores prevailed.

Evidence for the role of serotonin in the inhibition of specific motor responses.

Abstract: Two behavioural paradigms were used to test the effects of serotonin depletion on a specific form of response inhibition. Treatment with both p-chlorophenylalanine (p-CPA) at 200 mg/kg and lesions of the medial raphe nucleus impaired the acquisition of a step-off passive-avoidance response. The experimental design allowed the elimination of alternative interpretations in terms of increased sensitivity to shock and increased responsiveness to stimuli. p-CPA also impaired response inhibition during an omission-training schedule. The results of the three studies support a general role of serotonin in withholding specific instrumental (reinforced) motor actions. The results contrast with those of studies supporting a role of noradrenaline in response inhibition. A tentative conclusion supports Konorski's (1967) suggestion for differentiation of various types of response inhibition that are mediated by different neurochemical systems.

Acute psychologic and neuroendocrine effects of dextroamphetamine and methylphenidate.

Abstract: These studies examine the interface between central neurochemical events, psychologic state, and neuroendocrine activity. Fifty-nine healthy young men received dextroamphetamine (10 or 20 mg), methylphenidate (10 or 20 mg), or placebo. Psychologic state and serum concentrations of growth hormone, cortisol, and amphetamine were monitored for 2 h following drug ingestion. There was considerable variance in both the endocrine and psychologic responses to these drugs. In general, both dextroamphetamine (20 mg) and methylphenidate (20 mg) stimulated growth hormone release, while only dextroamphetamine stimulated cortisol release. The variance in psychologic response precluded statistically significant differences among the drug groups; however, dextroamphetamine and methylphenidate appeared about equally effective in eliciting euphoria. Growth hormone response following these drugs correlated selectively with increases in euphoria, while cortisol response correlated somewhat selectively with increases in arousal. Serum amphetamine concentration correlated only with degree of growth hormone response and degree of elation. These findings suggest that a common or linked central mechanism underlies both the growth hormone response and euphoria elicited by these drugs, and that a different mechanism underlies the cortisol and arousal responses. More importantly, these findings suggest another way in which psychopharmacologic agents can be used to elucidate the neurophysiology of both pathologic and normative psychologic states.

Changes in Brain Catecholamine Turnover and Receptor Sensitivity Induced by Social Deprivation in Rats

Abstract: Catecholamine turnover was compared in two brain areas of rats housed under different social conditions. Rats reared in isolation for 6–8 weeks had a significantly lower noradrenaline turnover in the brainstem and lower noradrenaline and dopamine turnover in a brain segment comprising all other areas except the cerebellum, pineal gland, thalamus, and and subthalamus. In the open-field test, isolated rats were much more active than group-housed animals. Noradrenaline turnover increased in both brain areas of isolated rats but not in grouped animals after exposure to the open field. Hyperactivity was selectively reduced in isolated rats by chronic oral treatment with d-amphetamine, 5 mg/kg/24 h. It was also reduced 15 min after pretreatment with α-methyl-p-tyrosine 200 mg/kg. It is suggested that a prolonged period of reduced noradrenaline release may sensitise postsynaptic receptors in isolated rats. Hyperactivity appears to be associated with an increase in transmitter release onto sensitised receptors.