Showing papers in "Psychopharmacology in 1983"
TL;DR: It is concluded that amphetamine self-injected into the accumbens is a positive reinforcer, and this localization of ‘amphetamine reward’ suggests that the nucleus accUMens contains a synaptic mechanism underlying amphetamine abuse and, perhaps, also natural reinforcement of behavior.
Abstract: Rats learned to self-administer d-amphetamine (10 micrograms/microliter) through a cannula implanted in the nucleus accumbens. They responded more frequently for 65 +/- 15 nl of amphetamine than for equal amounts of saline. When presented with two levers (one amphetamine, one blank) they responded more on the correct lever for amphetamine. They would also switch levers, when necessary, to maintain access to the drug. When half the usual drug intake was given automatically, animals reduced their response rate by half, thus self-regulating the total amount of amphetamine they received. In tests for leakage into the ventricles, eight rats that self-injected with an accumbens cannula showed response extinction when switched to a ventricular cannula. We conclude that amphetamine self-injected into the accumbens is a positive reinforcer. This localization of 'amphetamine reward' suggests that the nucleus accumbens contains a synaptic mechanism underlying amphetamine abuse and, perhaps, also natural reinforcement of behavior.
368 citations
TL;DR: Data suggest an important role for the mesolimbic DA system in mediating the reinforcing effects of heroin and that depletion of central and peripheral noradrenaline induced by 6-OHDA had no significant effect on heroin-induced place preference.
Abstract: The rewarding propertics of systemically administered heroin were investigated with a conditioned place-preference paradigm. Reinforcing effects were observed with all doses of heroin tested (0.5, 1.0, 2.0 mg/kg) as indicated by a significant increase in preference for the place paired with drug injections. No similar change in preference was observed following saline injections. The rewarding effect of heroin (2 mg/kg) was attenuated by pretreatment with haloperidol (0.2 mg/kg), but haloperidol alone did not produce a place aversion. Lesions induced by 6-hydroxydopamine (6-OHDA) of the mesolimbic dopaminergic pathway at the level of the nucleus accumbens also attenuated the heroin-induced place preference. In contrast, depletion of central and peripheral noradrenaline induced by 6-OHDA had no significant effect on heroin-induced place preference. These data suggest an important role for the mesolimbic DA system in mediating the reinforcing effects of heroin.
308 citations
TL;DR: Since methamphetamine releases several catecholamines, including dopamine, and haloperidol blocks dopamine receptors, it is plausible that the horizontal location of the psychometric function (the speed of the clock) is related to the effective level of dopamine.
Abstract: Forty rats were trained to make a left lever response if a signal (white noise) was 2.5s and to make a right lever response if the signal was 6.3s. When seven intermediate signal durations, to which responses were not reinforced, were randomly interspersed the probability of a right-lever (‘long’) response increased as a function of signal duration. Methamphetamine shifted this psychometric function leftward and decreased its slope: haloperidol also decreased the slope but shifted the function rightward. A combination of haloperidol and methamphetamine led to a function similar to the saline control function. The leftward shift probably reflects an increase in the speed of an internal clock, and the rightward shift probably reflects a decrease in its speed. Since methamphetamine releases several catecholamines, including dopamine, and haloperidol blocks dopamine receptors, it is plausible that the horizontal location of the psychometric function (the speed of the clock) is related to the effective level of dopamine.
278 citations
TL;DR: Non-contingent, ‘priming’ IV drug injections led to reinstatement of heroin-reinforced responding after a period of extinction and these results may help the understanding of ‘relapse of drug-taking’ behavior.
Abstract: Non-contingent, ‘priming’ IV drug injections led to reinstatement of heroin-reinforced responding after a period of extinction. Rats implanted with IV catheters were trained to self-administer heroin (100 μg/kg/infusion diacetylmorphine HCl) and were given test sessions consisting of a period of self-administration followed by extinction conditions. ‘Priming’ infusions of heroin and other drugs were presented during extinction and lever pressing following the injection was observed. Priming injections of 50, 100 and 200 μg/kg heroin effectively restored responding after a period of extinction. Morphine and, to a lesser extent, amphetamine and apomorphine also reinstated heroin-reinforced responding whereas cocaine and clonidine did not. These results may help our understanding of ‘relapse of drug-taking’ behavior.
259 citations
TL;DR: A total of 31 psychoactive drugs were offered to groups of naive rats for IV self-administration and an injection rate greater than that for rats offered only saline indicated reinforcement, and nalorphine and ethylketazocine were reinforcers only in rats, and ethanol was a reinforcer only in monkeys.
Abstract: A total 31 psychoactive drugs were offered to groups of naive rats for IV self-administration and an injection rate greater than that for rats offered only saline indicated reinforcement. Two protocols were used: in the first, rats were offered drug at a selected dose for 5 days, then the dose was reduced by 1 log unit (to 0.1 the original dose) for an additional 4 days; in the second, rats were offered saline for 3 days as a ‘prescreen’ to eliminate rats with high or low operant-injection rates. Drug was offered to acceptable rats for 5 days, then the dose was reduced 0.5 log unit (to 0.32 the original dose) for 5 more days. A scoring system, based upon the injection rates during the last 3 days of each period, describes the reinforcing action. Scores were dose-related. Tests on both protocols gave similar results. Data from monkey studies have been reported for 27 of the drugs tested. Of these drugs, 18 were reinforcers and six were nonreinforcers in both species, nalorphine and ethylketazocine were reinforcers only in rats, and ethanol was a reinforcer only in monkeys.
227 citations
TL;DR: It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.
Abstract: The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.
193 citations
TL;DR: Psychomotor stimulant drugs and drugs outside this class were examined on the efficacy of stimuli previously paired with reinforcement or reward (conditioned reinforcers, CR) in controlling responding to show that d-amphetamine was generally more potent than pipradrol in its effects on in vitro monoamine uptake and release.
Abstract: The effects of various psychomotor stimulant drugs and drugs outside this class were examined on the efficacy of stimuli previously paired with reinforcement or reward (conditioned reinforcers, CR) in controlling responding. Pipradrol (5-45 mumol/kg), d-amphetamine (1.25-15.0 mumol/kg), and the cocaine analogues WIN 35,428 (0.1-30.0 mumol/kg) and in one of two determinations WIN 35,065-2 (0.1-29.0 mumol/kg) all generally increased responding on a lever providing CR, but did not change or decreased responding on a lever providing no CR (NCR). Cocaine (5-125 mumol/kg) and chlordiazepoxide (3.75-60.0 mumol/kg) had no significant effects. Morphine (3.2-32.0 mumol/kg) and alpha-flupenthixol (0.02-2.0 mumol/kg) generally reduced responding on both levers. Apomorphine (0.1-1.0 mumol/kg) generally increased responding on both levers. Neurochemical data showed that d-amphetamine was generally more potent than pipradrol in its effects on in vitro monoamine uptake and release.
189 citations
TL;DR: Examination of the effects of d-amphetamine on response switching and perseveration in apparatus allowing a choice of response location showed that increased switching and increased perseveration occurred in the same situation at the same doses, although perseveration generally occurred at higher doses than increased switching.
Abstract: Four experiments examined the effects of d-amphetamine on response switching and perseveration in apparatus allowing a choice of response location. The relative ‘cost’ of a switch between two response locations and repetitive responding at a single location by rats was manipulated in the various test settings to provide baseline probabilities of switching. d-Amphetamine (0.2–2.3 mg/kg) increased response switching. This effect did not depend on switching being necessary to produce reinforcement and was not explained by increases in locomotor activity, motivational change or randomisation of responding. Further evidence was provided in support of a ‘probability-dependency’ hypothesis, that the effect of the drug depends in part upon the baseline probability of a response. A measure of perseveration independent of response switching (extra responses made prior to the collection of food) showed that increased switching and increased perseveration occurred in the same situation at the same doses, although perseveration generally occurred at higher doses than increased switching. Therefore the effect of amphetamine on response switching or repetition depends on the dose of drug, the context of the response and its probability of occurrence under control conditions.
157 citations
TL;DR: It was found that scopolamine impaired performance of delayed alternation to a greater extent than performance of visual discrimination, and performance of a workingmemory task is significantly more sensitive to disruption of cholinergic mechanisms in the hippocampus thanperformance of a reference-memory task.
Abstract: This study examined the effects of intrahippocampal injections of scopolamine (a muscarinic antagonist drug) on performance of a working-memory task (contingently) reinforced T-maze alternation) and a reference-memory task (visual discrimination) by the same rats in the same maze. Rats in the first shipment were trained in delayed alternation, received bilateral implantation of cannulae aimed at the CA3 field of the dorsal hippocampus, and were tested for retention with 1 μl microinjections of scopolamine (35 μg) and saline on alternate days. These rats were then trained on visual discrimination and tested alternately under scopolamine or saline as described above. It was found that scopolamine impaired performance of delayed alternation to a greater extent than performance of visual discrimination. Data from rats in the second shipment replicated this finding, with the order of the tasks reversed, and, additionally, showed that delayed alternation, but not visual discrimination, was impaired at a dose of 12 μg/μl. A dose of 4 μg/μl had no effect on either task. It is concluded that performance of a workingmemory task is significantly more sensitive to disruption of cholinergic mechanisms in the hippocampus than performance of a reference-memory task.
155 citations
TL;DR: The hypothesis that nicotine-stimulated neuropeptide release provides positive reinforcement for smoking is strengthened by strengthening the functional relationship between plasma nicotine and β-endorphin.
Abstract: The present study explored neuropeptide responses to nicotine from smoking. Habitual smokers smoked research cigarettes of known strength under controlled laboratory conditions while blood samples were withdrawn unobtrusively for subsequent biochemical analysis. To provide a metric that reflected total nicotine intake and total neurohormonal output, data were integrated over time. Subjects were relatively unresponsive in the low-nicotine (0.48 mg) condition. In the high-nicotine (2.87 mg) condition, there were significant positive correlations between integrated plasma nicotine and plasma arginine vasopressin (r=+0.985), its carrier protein neurophysin I (r=+0.944), and β-endorphin-β-lipotropin (r=+0.977), but not adrenocorticotropic hormone. Data from an experiment that used an extraction step to remove β-lipotropin corroborated the functional relationship between plasma nicotine and β-endorphin implied by the original findings. Taking into account recent research on the role of neuropeptides in the modulation of affective states and cognitive function as well as of other CNS activity, the present findings were interpreted as strengthening the hypothesis that nicotine-stimulated neuropeptide release provides positive reinforcement for smoking.
151 citations
TL;DR: Sulpiride, metoclopramide and thioridazine produced a dose-dependent increase in cocaine intake similar to that found for chlorpromazine, haloperidol, pimozide and flupenthixol; Clozapine, however, produced adose-dependent decrease in cocaine Intake.
Abstract: Several drugs have been shown to exert antipsychotic effects, yet they display an atypical profile with respect to standard neuroleptic drug screens. Low doses of traditional neuroleptics are known to increase self-administration of psychomotor stimulants; we sought to determine whether these atypical drugs would cause a comparable effect. Sulpiride, metoclopramide and thioridazine produced a dose-dependent increase in cocaine intake similar to that found for chlorpromazine, haloperidol, pimozide and flupenthixol. This effect was found to correlate (r=0.94) with daily clinical dose. Clozapine, however, produced a dose-dependent decrease in cocaine intake. The advantages and disadvantages of using this measure as a screening procedure for neuroleptic drugs are discussed.
TL;DR: Following eight monthly haloperidol decanoate injections rats showed an increased rate of vacuous chewing movements (VCM's), which gradually disappeared within 4 drug-free months, and there was a significant negative correlation between individual VCM rates and nigral GAD activity.
Abstract: Following eight monthly haloperidol decanoate injections rats showed an increased rate of vacuous chewing movements (VCM's), which gradually disappeared within 4 drug-free months. Another single dose of non-decanoate haloperidol reinstated a second increase in VCM rate which was still significant after 2 months. The glutamic acid decarboxylase (GAD) activity in the substantia nigra of these chronically haloperidol-treated rats was lower than untreated controls. Furthermore, there was a significant negative correlation between individual VCM rates and nigral GAD activity. No corresponding changes occurred in other brain regions. The depression of nigral GAD may reflect a reduced tissue density of GABA-ergic axon terminals within the descending striato-nigral pathway.
TL;DR: The perception of cognitive disorientation may mediate the effects of alcohol on those behaviors normally suppressed by various controlling influences, and the disinhibition of certain types of verbal behavior is related neither to affective state or to direction of the BAL curve.
Abstract: A study was conducted to investigate the effects of acute alcohol administration on affective states and verbal behavior during the ascending and descending limbs of the blood alcohol curve Sixteen male social drinkers were given alcohol (10 g/kg) or placebo in a double-blind crossover research design Subjects tested while blood alcohol levels (BAL) were ascending close to peak concentration (011 g%) described themselves as more elated, friendly, and vigorous than when tested under placebo conditions As BAL declined, subjects described themselves as more angry, depressed, and fatigued Cognitive confusion, hostile verbal interaction, and aggressive thematic content were also greater during alcohol intoxication, but these measures were unrelated to direction of change in the BAL curve It was concluded that (1) the effects of alcohol on affect are biphasic and are closely related to direction of change in the BAL curve, (2) the disinhibition of certain types of verbal behavior is related neither to affective state or to direction of the BAL curve, and (3) the perception of cognitive disorientation may mediate the effects of alcohol on those behaviors normally suppressed by various controlling influences
TL;DR: The finding that there is some correlation between the behavioural effects of these compounds and their actions at the nicotine binding site may indicate that the nicotine cue is mediated throuth a cholinergic receptor.
Abstract: Rats were trained to discriminate nicotine (0.4 mg/kg SC) from saline in a standard two-bar operant conditioning procedure with food reinforcement. The response to nicotine was dose-related and at the ED50 of 0.14 mg/kg, plasma nicotine concentrations were similar to those reported previously for cigarette smokers who inhale. The nicotine analogues anabasine and cytisine increased nicotine-appropriate responding in a dose-related manner. Animals predominantly responded on the saline-associated lever when administered drugs from a range of pharmacological classes, even at doses that were sufficiently large to reduce the overall numbers of responses. The results confirm that the nicotine discriminative stimulus is highly specific. Previous work has shown anabasine and cytisine to be active at nicotinic-cholinergic binding sites in rat brain. The finding that there is some correlation between the behavioural effects of these compounds and their actions at the nicotine binding site may indicate that the nicotine cue is mediated throuth a cholinergic receptor.
TL;DR: In this article, the effects of metergoline, amitriptyline, chlorimipramine, fluoxetine, and imiprindole on [3H]-5HT binding were investigated in vitro and ex vivo.
Abstract: Changes in [3H]-5HT and [3H]-spiperone binding in vitro and ex vivo following withdrawal from chronic administration of certain antidepressants and the 5HT antagonist metergoline were compared with changes in 5-methoxy-N′,N′-dimethyltryptamine (5MEODMT, 2.5 mg/kg) induced behaviour following acute, chronic and withdrawal from chronic treatment with the same drugs. In vitro metergoline, amitriptyline, imipramine and chlorimipramine displaced [3H]-5HT and [3H]-spiperone binding in that order of potency. Iprindole weakly blocked only [3H]-spiperone binding while fluoxetine had no effect on either ligand at concentrations up to 100 μm. Following 72h withdrawal from 14 days chronic treatment ex vivo [3H]-5HT binding was unaffected by any of the drugs, while fluoxetine (15 mg/kg), chlorimipramine (15 mg/kg) and iprindole (15 mg/kg) significantly reduced [3H]-spiperone binding. The 5MEODMT behavioural response was attenuated by metergoline (2 mg/kg) and amitriptyline (15 mg/kg) (Stolz and Marsden 1982) and by iprindole (15 mg/kg) and imipramine (15 mg/kg). Neither fluoxetine (2 mg/kg) nor chlorimiprmaine (15 mg/kg) altered the behavioural response. After 14 days chronic treatment metergoline, amitriptyline, chlorimipramine, fluoxetine and imipramine significantly reduced the 5MEODMT response while the reduction with iprindole did not reach significance. When further tested after 72h withdrawal from chronic treatment fluoxetine-and chlorimipramine-treated rats showed a significantly reduced response, imipramine-treated rats an increased response, while those given iprindole showed no significant change. The results suggest that decreased functional responsiveness observed following treatment with 5HT uptake blockers corresponds with changes in [3H]-spiperone but not [3H]-5HT binding. In contrast the enhanced functional response on withdrawal from metergoline, amitriptyline (Stolz and Marsden 1982) or imipramine does not correlate with changes in the binding of either ligand.
TL;DR: It is suggested that attempts to explain tolerance in terms of changes in synaptic functioning are subject to very considerable problems of interpretation and that an analysis of behavioural mechanisms may be of greater value in understanding the process of behavioural tolerance.
Abstract: An hypothesis is presented about the nature of behavioural tolerance in animals to stimulant drugs. It is suggested that, in many behavioural procedures, tolerance is due to behavioural adaptation to those drug effects which cause disruption of ongoing rewarded behaviour. This unitary hypothesis accounts for the available data on tolerance and cross-tolerance to stimulants more effectively than all of the other more conventional explanations which are based upon dispositional or functional concepts, the most common of which are described, evaluated, and found to be inadequate. Furthermore, it is suggested that attempts to explain tolerance in terms of changes in synaptic functioning are subject to very considerable problems of interpretation and that an analysis of behavioural mechanisms may be of greater value in understanding the process of behavioural tolerance. Evidence for the basic behavioural hypothesis is outlined in some detail, and a theoretical justification presented for its major assumptions. Operant studies of chronic stimulant effects on behaviour have often produced very complex patterns of data, considerable differences being reported both between subjects and between studies. A speculative model is presented which attempts to account for this pattern of data in tolerance studies.
TL;DR: The effects of these cholinergic manipulations suggest that neuroleptic-induced perioral responses in rats do not resemble tardive dyskinesia in man.
Abstract: Rats treated continuously for 4 months with haloperidol (1.4–1.6 mg/kg/day), trifluoperazine (4.5–5.1 mg/kg/day), or sulpiride (102–110 mg/kg/day), but not clozapine (23–26 mg/kg/day), exhibited an increased frequency of chewing jaw movements. Chewing in both control and haloperidol-treated rats was increased by acute administration of the cholinergic agents pilocarpine or physostigmine. Physostigmine or pilocarpine also induced abnormal gaping jaw movements; physostigmine-induced gaping was more prevalent in haloperidol-treated rats than control rats receiving physostigmine alone. Acute administration of the anticholinergic agents scopolamine and atropine decreased chewing in control animals and reduced haloperidol-induced chewing to control values or below. The effects of these cholinergic manipulations suggest that neuroleptic-induced perioral responses in rats do not resemble tardive dyskinesia in man.
TL;DR: It is suggested that clonidine may be useful in the management of alcohol withdrawal states, and that the underlying pathophysiology of at least some of these manifestations may be sympathetic nervous system hyperactivity.
Abstract: Clonidine hydrochloride 5 μg/kg and placebo were given orally to 11 patients experiencing well-developed alcohol withdrawal states. Active drug and placebo were given in a randomised, cross-over double blind fashion 2 h apart. Clonidine significantly suppressed heart rate (P=0.002), arterial blood pressure (P=0.006), and an accumulated score of withdrawal symptoms and signs (P=0.004). These data suggest that clonidine may be useful in the management of alcohol withdrawal states, and that the underlying pathophysiology of at least some of these manifestations may be sympathetic nervous system hyperactivity.
TL;DR: Within- and between-group analyses of results suggest that the effect of ethanol on cigarette smoking may be related to prior history of alcoholic beverage consumption.
Abstract: The effects of ethanol on cigarette smoking were assessed in volunteer research subjects who had histories of light to moderate social drinking. Five subjects participated individually in daily 90-min sessions that were conducted in rooms equipped to permit automatic monitoring of cigarette smoking behavior. Each subject was tested at four dose levels of ethanol and placebo, which were given orally on a double-blind basis, 30 min prior to sessions. Dose order was according to a random block sequence in which each dose was given in each of five blocks of five sessions. Data from five alcoholic subjects who were similarly tested at only one ethanol dose level were used for comparison. For the nonalcoholic group, ethanol doses that produced reliable changes in group scores on various psychometric instruments produced no significant change in smoking behavior. there were differences among the nonalcoholic subjects, however, in that smoking was significantly decreased by ethanol in two subjects, was increased by ethanol in two subjects, and was unchanged in the fifth subject. For the alcoholic group, ethanol produced reliable changes in psychometric measures and significant increases in cigarette smoking. Within- and between-group analyses of results suggest that the effect of ethanol on cigarette smoking may be related to prior history of alcoholic beverage consumption.
TL;DR: Naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrex one in reversing ethanol-induced hypnosis and ethanol- induced changes in locomotor activity.
Abstract: The effects of naltrexone on the increase in locomotor activity induced by a low dose (135 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (35 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice Naltrexone, at a dose of 01 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice The duration of loss of ringting reflex was, however, differentially affected in all three strains by naltrexone The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity
TL;DR: It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (-)-3-PPP with weak antagonistic activity in some test models and (+-3- PPP with agonistic and antagonistic effect.
Abstract: The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Improvement of obsessional symptoms was significant on clinical ratings and was correlated with improved performance on an attention task, and changes were also significant for self-rated measures of activation and altered reality in patients with severe chronic obsessive-compulsive disorder.
Abstract: In a double-blind rossover study, single doses of d-amphetamine and placebo were administered to 12 patients with severe chronic obsessive-compulsive disorder (OCD). Improvement of obsessional symptoms was significant on clinical ratings and was correlated with improved performance on an attention task. Changes were also significant for self-rated measures of activation and altered reality. The behavioral response to amphetamine was not statistically correlated with subsequent improvement during a 6-week clomipramine trial, although the direction of change was the same during both treatments for every patient studied.
TL;DR: The pharmacological data suggest that the loss of tactile placing after motor cortex injury is due to a depression of catecholaminergic function, which is temporarily reversible by catechlaminergic stimulation.
Abstract: Unilateral motor cortex injury in the cat results in a prolonged loss of tactile placing in the forelimb contralateral to the injury. Amphetamine (5 mg/kg) temporarily reverses this tactile placing deficit as early as 4 days following the injury. Racemic amphetamine was found to produce a significantly more prolonged restoration of placing than the d isomer, which was significantly more effective than the l isomer. Haloperidol (0.4 mg/kg) blocked the amphetamineinduced recovery of placing responses and also blocked placing in nondrugged cats showing partial spontaneous recovery. This dosage of haloperidol had no effect on tactile placing in normal cats. Apomorphine at moderate dosages (0.25 and 0.5 mg/kg) produced a weak restoration of tactile placing in motor cortex-injured animals. These pharmacological data suggest that the loss of tactile placing after motor cortex injury is due to a depression of catecholaminergic function, which is temporarily reversible by catecholaminergic stimulation.
TL;DR: A therapeutic window was suggested by the present study, with optimum patient response associated with plasma haloperidol levels of 4.2–11.0 ng/ml for the first 2 weeks of treatment.
Abstract: Plasma haloperidol levels were compared to clinical response during the first 14 days of drug treatment in 14 DSM III-diagnosed inpatient schizophrenic patients using an improved methodology, which utilized predetermined constant dosages and derived a therapeutic range of plasma haloperidol levels from a curvilinear regression analysis. An inverted U-shaped relationship was found which reflected a significant curvilinear correlation (r=0.66, P<0.02) between plasma levels (as assayed by gas chromatography) and improvement on the Serial New Haven Schizophrenia Index. A therapeutic window was suggested by the present study, with optimum patient response associated with plasma haloperidol levels of 4.2–11.0 ng/ml for the first 2 weeks of treatment.
TL;DR: The role of reinforcers in influencing choice was studied by use of a schedule that included a random intermixing of reinforced and explicitly non-reinforced components to derive a choice measure of reinforcement which was independent of alterations in average response rate.
Abstract: The role of reinforcers in influencing choice was studied by use of a schedule that included a random intermixing of reinforced and explicitly non-reinforced components The just-reinforced response had a high likelihood of being repeated (win-stay), although there was no differential reinforcement for doing so, whereas responses just followed by explicit non-reinforcement had a very low probability of repetition (lose-stay) Non-parametric indices based on the theory of signal detection were used to derive a choice measure of reinforcement which was independent of alterations in average response rate Treatments with d-amphetamine (02–45 mg/kg), chlordiazepoxide (025–16 mg/kg) and α-flupenthixol (003–06 mg/kg) showed that changes in the choice measure could be dissociated from changes in the response rate These findings were supported by extinction and satiation tests
TL;DR: At all doses up to 600 mg, Ro 15-1788 demonstrated none of the classical behavioural effects of the benzodiazepines, except at very high doses.
Abstract: The benzodiazepines are typified by a profile of side effects which includes drowsiness, ataxia and incoordination. Ro 15-1788, an imidazodiazepine derivative, exhibits marked antagonism of the behavioural and biochemical effects of the benzodiazepines in animals and man. It is devoid of any behavioural activity in animals, except at very high doses. In the present study the effects of single rising oral doses of Ro 15-1788 on cognitive, psychomotor and subjective function in man have been assessed using a battery of psychometric tests designed to identify the sedative action of the benzodiazepines. At all doses up to 600 mg, Ro 15-1788 demonstrated none of the classical behavioural effects of the benzodiazepines.
TL;DR: The DSP-4-treated rat may constitute a new model of functional supersensitivity to adrenergic agonists, and is discussed in terms of the selective action of D SP-4 and the responsiveness of Dsp-4 rats to adren allergic agonists.
Abstract: Rats treated with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenergic neurotoxin, showed no differences compared to control rats in the number of head dips, a measure of exploratory behavior. Since a previous neurochemical investigation had demonstrated that DSP-4 rats have supersensitive α2 and β-adrenergic receptors in certain regions of the central nervous system, the behavior of these animals was also examined after the injection of clonidine, an α2 agonist, and clenbuterol, a β agonist. These drugs reduced, in a dose-dependent manner, the head-dipping of both control and DSP-4 rats. However, this effect was of greater magnitude in DSP-4 animals. Control experiments suggested that the response to clonidine and clenbuterol was mediated centrally by α2 and β receptors, respectively. Other behavioral experiments with agonists of the dopaminergic and serotoninergic systems indicated that these neurotransmitter systems were unchanged in DSP-4 animals. The results are discussed in terms of the selective action of DSP-4 and the responsiveness of DSP-4 rats to adrenergic agonists. The DSP-4-treated rat may constitute a new model of functional supersensitivity to adrenergic agonists.
TL;DR: The results provide evidence for nicotine withdrawal and its alleviation by nicotine gum and a significant treatment-x-time of day interaction was observed.
Abstract: Subjects (N=32) provided morning, afternoon, and evening data for week-1 withdrawal from smoking. Withdrawal symptoms were measured using Schneider's Smoker Complaint Scale. Twenty subjects received nicotine gum and 12 subjects received placebo gum. Carbon monoxide levels verified smoking abstinence. Results showed significantly less withdrawal for nicotine gum subjects compared to the placebo group. A significant treatment-x-time of day interaction was also observed: Placebo subjects reported increased withdrawal in the evenings compared to their morning and afternoon scores, and in contrast to nicotine-group responses. The results provide evidence for nicotine withdrawal and its alleviation by nicotine gum.
TL;DR: The selective changes in agonistic behavior by dominant monkeys when challenged with amphetamine may reflect a status-related functional alteration of catecholaminergic processes upon which the drug acts.
Abstract: The influences of social status on amphetamine-induced behavioral effects in squirrel monkeys were investigated. Social status was determined by constructing a sociogram. d-Amphetamine (0.3--1.0 mg/kg orally, 0.3 and 0.6 mg/kg IM) increased stereotyped head movements and reduced the time spent in the sitting posture in all monkeys (N = 25) regardless of sex, age, or social status. The high levels of locomotor activity in dominant and juvenile monkeys were decreased at higher amphetamine doses (0.6 mg/kg IM, 0.6 and 1.0 mg/kg orally), whereas the same doses increased locomotion in otherwise less active subdominant and submissive animals. Low doses of amphetamine (0.1, 0.3 mg/kg) decreased the incidence of agonistic behavior initiated by dominant monkeys, and higher doses (0.6, 1.0 mg/kg) caused these monkeys to change from predominant initiators of agonistic behavior into recipients. At 2 h after amphetamine administration (0.3 mg/kg IM), the high levels of locomotor behavior had returned to baseline, the social isolation began to disappear, and the disrupted agonistic behavior of dominant monkeys returned to control levels, yet the stereotyped head movements continued to occur with high frequency. In half of the monkeys, amphetamine produced a large increase in distress-like vocalizations. Amphetamine-mediated motor stereotypies may be mediated by mechanisms different than those responsible for agonistic behavior. The selective changes in agonistic behavior by dominant monkeys when challenged with amphetamine may reflect a status-related functional alteration of catecholaminergic processes upon which the drug acts.
TL;DR: Bupropion, in contrast to amphetamine, had no peripheral sympathomimetic effects and did not reduce appetite or caloric intake, and was compared with dextroamphetamine and placebo in a randomized double-blind crossover study.
Abstract: The subjective, behavioral, and physiological effects of bupropion, a nontricyclic antidepressant, were compared with those of dextroamphetamine and placebo in a randomized double-blind crossover study. The volunteers who participated were multiple-drug abusers. Six acute drug treatments, three doses of bupropion (100, 200, 400 mg), two doses of dextroamphetamine (15, 30 mg), and placebo were administered orally at intervals of not less than 72 h. Results indicated that the subjective effects of amphetamine as measured by the Addiction Research Center Inventory (ARCI) differed markedly from bupropion and placebo. Bupropion, in contrast to amphetamine, had no peripheral sympathomimetic effects and did not reduce appetite or caloric intake.