Alterations by centrally acting drugs of the suppression of self-stimulation behavior in the rat by tetrabenazine,physostigmine, chlorpromazine and pentobarbital

The effects of pre-treatment (32 min) with d-amphetamine (2 mg/kg), scopolamine (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) were studied on the suppression of self-stimulation behavior in the male albino rat by central depressants. The antagonism of each compound was determined against the suppressant action of tetrabenazine (2 mg/kg), physostigmine (0.1 mg/kg), chlorpromazine (2.5 mg/kg) and pentobarbital sodium (10 mg/kg).Against the suppression produced by tetrabenazine, only d-amphetamine gave partial protection throughout the test. Scopolamine and chlordiazepoxide had a transient delaying action. Against the suppressant effect of chlorpromazine, protection was given by d-amphetamine, scopolamine and chlordiazepoxide.Against physostigmine, scopolamine gave full protection, d-amphetamine partial protection, and chlordiazepoxide was without effect.Against the effect of pentobarbital on self-stimulation behavior, there was no protection by d-amphetamine and scopolamine when the animal showed motor deficits, and a stimulant action when these had worn off, but the rates of responding were still depressed. Chlordiazepoxide potentiated the action of pentobarbital.These results are interpreted in terms of a short-run stimulant action on depressed rates of responding, and a longer-run protective action against changes produced by the compounds suppressing self-stimulation behavior in levels of transmitter-like substances.Supported by grant MH-16978, U. S. Public Health Service.The author is indebted to Mrs. S. Foster and Mrs. H. Cevallos for technical assistance.     

Interactions of naloxone with morphine,amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.     

Psychotropic drug influences on brain acetylcholine utilization

The cholinergic antisynthesis agent HC-3 was given intraventricularly to young male rats 20–30 days old to deplete brain acetylcholine (ACh). The rate of HC-3 induced depletion of ACh was used as an index of ACh utilization. Total brain ACh was determined following various doses of chlordiazepoxide, pentobarbital, chlorpromazine, methotrimeprazine, imipramine, morphine, d-amphetamine, scopolamine, LSD-25, and phencyclidine given i.p. alone and after intraventricular administration of HC-3. It was found that psychotropic drugs have marked differential effects on the rate of HC-3 induced ACh depletion.Supported in part by grant MH-11846, USPHS.     

The effects of stimulants and depressants on cocaine self-administration behavior in the Rhesus monkey

The effects of acute intramuscular pretreatment with several dosages of a variety of centrally acting compounds on intravenous cocaine self-administration behavior were ascertained. Pretreatment with morphine and pentobarbital produced no change in this behavior until dosages (2.0 mg/kg and 15.0 mg/kg respectively) were administered which grossly depressed grooming, exploratory, and locomotor activity behaviors, d-amphetamine (0.5–4.0 mg/kg) and phenmetrazine (2.0–12.0 mg/kg) pretreatment produced a dose-related decrease in cocaine self-administration. Trifluoperazine in dosages of 0.01–0.1 mg/kg increased the frequency of this behavior; whereas, higher dosages (0.2, 0.4 mg/kg) grossly depressed behavior. Imipramine (10–50 mg/kg) produced a dose-related decrease in cocaine self-administration. Potential mechanisms of these drug—behavior and drug—drug interactions are discussed.This study was supported by NIMH Grant No. MH-12084 and by NIMH Grant No. MH-18245.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Effects of chlordiazepoxide,oxazepam, chlorpromazine,andd-Amphetamine on sexual responses in male and female hamsters

The acute effects on sexual behavior of oxazepam (16–64 mg/kg), chlordiazepoxide (8–64 mg/kg), chlorpromazine (2–8 mg/kg), andd-amphetamine (0.8–3.2 mg/kg) were examined in intact male and female golden hamsters (Mesocricetus auratus). Intraperitoneal injections were given 45 min before the first behavioral test. In 10-min tests lordosis was observed in estrous females both before and after copulation, and mounts, intromissions, and ejaculations were observed in males. Dose-response related decrements in male sexual behavior were observed following chlorpromazine and chlordiazepoxide. All dose levels of oxazepam depressed male sexual behavior. The highest dose of chlordiazepoxide and oxazepam attenuated the onset of female sexual behavior, and all dose levels reduced postcopulatory lordosis durations. Amphetamine did not interrupt either male or female sexual behavior, and chlorpromazine disrupted male but not female behavior.     

Shifting of the d-amphetamine dose-response curve in rats with frontal cortical ablations

Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of d-amphetamine (0.25–4.0 mg/kg) both before and 6–8 weeks after bilateral ablation of frontal cortex. Preoperatively, low doses (e.g. 0.25–0.5 mg/kg) of (d-amphetamine increased responding and high doses (e.g. 2.0–4.0 mg/kg) of d-amphetamine depressed responding. Postoperatively, frontal rats showed larger facilitatory effects in response to low doses of d-amphet-amine but lesser depressant effects in response to high doses of d-amphetamine; the whole dose-response curve was generally shifted higher by the frontal lesions. These results indicate that frontal lesions differentially influence mechanisms mediating two different actions of d-amphetamine.This research was supported by NIMH grant MH21156 and NIMH Research Scientist Development Award (Type 2) DA70082 to S. D. Glick.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Drug effects on discrimination performance at two levels of stimulus control

The effects of several doses of d-amphetamine, chlordiazepoxide (CDP), chlorpromazine (CPZ), LSD, pentobarbital, and scopolamine were examined in rats trained to respond to the brighter of two keys. On each of the 100 trials during a daily session, the rat pressed the key that was brighter (correct key) and received a food pellet, or pressed the incorrect key and terminated the trial without food, or pressed neither key for 10 s, allowing the trial to terminate. Within a session, trials were mixed randomly such that on 50 trials the incorrect key was not lit (easy trials,) and on 50 trials the incorrect key was dimly lit (difficult trials). Amphetamine (0.5–2.0 mg/kg) reduced percent correct responses, with a greater effect of difficult than on easy trials. CDP (4.0–16.0 mg/kh) and pentobarbital (2.0–16.0 mg/kg) reduced percent correct responses on the difficult trials at the highest doses tested. Scopolamine (0.12–1.0 mg/kg) reduced both percent correct (more so on the difficult trials) and percent of trials on which a response was made, in a dose-related fashion. CPZ (1.0–4.0 mg/kg) reduced trial responding at 2.0 and 4.0 mg/kg and reduced percent correct on the difficult trials at 4.0 mg/kg. LSD (0.08–0.32 mg/kh) did not significantly alter behavior in this study.A preliminary report of these data was presented at the Rocky Mountain Psychological Association Annual Convention, Denver, Colorado, April, 1978     

Chlordiazepoxide and diazepam induced mouse killing by rats

Chlordiazepoxide HCl, at dose levels from 2.5 mg/kg to 80 mg/kg, significantly increased the low base rates of mouse killing (3–9%) observed in large samples (N=100/ dose) of Holtzman strain albino male rats. Maximal killing rates were obtained at doses from 7.5 mg/kg to 20 mg/kg. Diazepam was equally effective, and several times more potent than chlordiazepoxide. Pentobarbital did not increase killing. Killing induced by chlordiazepoxide was blocked by d-amphetamine SO₄, but not by l-amphetamine, at dose levels similar to those that block undrugged killing in this strain (ED₅₀=1.5 mg/kg). Unlike pilocarpine-induced killing, the effects of chlordiazepoxide were not increased or decreased significantly by either peripherally or centrally active anticholinergic drugs, over wide dose ranges of these agents; nor were the effects of chlordiazepoxide increased by repeated daily administration.A preliminary report of the findings described here was made at the Spring 1974 meeting of the American Society for Pharmacology and Experimental Therapeutics (Wnek, Gay, and Leaf, 1974).     

The effects of d-amphetamine,chlordiazepoxide and alpha-flupenthixol on food-reinforced tracking of a visual stimulus by rats

Rats were trained to respond to one of two levers under a random ratio schedule of food reinforcement. Which of the levers was correct was redetermined before each response and signalled by a light. The effects of d-amphetamine (0.2–3.2 mg/kg), chlordiazepoxide (1–8 mg/kg), and the neuroleptic alpha-flupenthixol (0.03–0.33 mg/kg) on the efficiency of rats tracking this visual cue were examined. d-Amphetamine increased the proportion of responses made on the correct lever at low and intermediate doses, but reduced the proportion at 3.2 mg/kg. At the highest dose, chlordiazepoxide produced a small increase in this measure, together with a reduction in response rate, but alpha-flupenthixol had no effect, even at a dose reducing response rate. Low doses of amphetamine also increased switching between the levers, producing a proportionately greater increase in switching from the correct lever to the incorrect lever than vice versa. The results are interpreted as showing that d-amphetamine facilitates tracking performance as a result of its action of enhancing response switching, and supporting the hypothesis that facilitation of performance by amphetamine-like drugs depends on the effect of the drug on response output coinciding with task requirements.     

Amphetamine and the reward system: Evidence for tolerance and post-drug depression

Existing reports of tolerance to the behavioral effects of d-amphetamine are most parsimoniously interpreted as reflecting behavioral adaptation to the disruptive effects of the drug rather than physiological tolerance. The present study shows that physiological tolerance does develop to the facilitation of self-stimulation behavior which the drug produces. Rats were trained to bar-press for electrical stimulation of the medial forebrain bundle and tested for facilitation of responding following the administration of 0.25 or 0.50 mg/kg d-amphetamine. Testing was terminated for 4 days during which increasing doses (1.0–12.0 mg/kg) of the drug were given. 16 h after the last injection, the test doses (0.25 or 0.50 mg/kg) no longer produced facilitation of self-stimulation. In addition, testing on the following day with no further drug administration showed a depression of responding indicating depression of the sensitivity of the reward system of the brain.     

Interactions of chlordiazepoxide and anorectic agents on rate and duration parameters of feeding in the rat

d-Amphetamine (0.5 and 1.0 mg/kg) and dl-fenfluramine (2.0 and 4.0 mg/kg) reduced food intake in a short exposure feeding test, and their effects were counteracted by chlordiazepoxide, particularly at 5.0 mg/kg. Chlordiazepoxide reduced latency to eat, extended the duration of feeding and depressed the rate of feeding. Antagonism occurred in combination with d-amphetamine in relation to latency and duration, but in this experiment d-amphetamine did not affect feeding rate. Antagonism also occurred in combination with fenfluramine, with latency and duration measures, but only at the lower chlordiazepoxide dose. Instead, chlordiazepoxide (10.0 mg/kg) enhanced fenfluramine's effects to reduce feeding duration and feeding rate.     

The effects of scopolamine on performance on a geometric progressive ratio schedule

Rats were trained to respond on a geometric progressive ratio schedule until performance was stable. They were then injected with the anticholinergic drug scopolamine at doses of 0.05, 0.1, 0.25, 1.0 and 2.0 mg/kg. Control animals were administered atropine methyl nitrate (1–20 mg/kg). Increasing doses of scopolamine typically produced first an increase, then a decrease in behavior compared with baseline levels, measured by total number of responses, total number of reinforcements, and final completed ratio, per session. Atropine methyl nitrate had no effect on the behaviour of the control animals.This indicates that the effects of scopolamine are due to its central action. The inverted-U dose-response curve found for scopolamine resembles that found for chlordiazepoxide, phenobarbital, and d-amphetamine on progressive schedules.Research supported by grants C70/20, 70/44, and 72/24 to N.M.B. Preparation of the paper was aided by a grant to W.J.S. from the Canterbury Branch, N.Z. Psychological Society. An early version of this paper was presented to the Annual Conference, N.Z. Ps. S., Auckland, 1973. Research reported was performed in partial fulfilment of the requirements of the M. Sc. degree by W. J. S.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

Effects of d-amphetamine and naloxone on brain stimulation reward

Self-stimulation thresholds were determined in rats by means of a modification of the psychophysical method of limits. Reinforcement values were determined after the administration of d-amphetamine alone, naloxone alone, and naloxone administered concurrently with d-amphetamine. d-Amphetamine yielded dose-related decreases in the threshold (0.25–2.00 mg/kg IP), while naloxone alone (2.0–16 mg/kg IP) caused no consistent changes. For each animal, a dose of d-amphetamine that substantially lowered the threshold was then selected to be administered with varying doses of naloxone. The threshold-lowering effect of d-amphetamine was blocked by naloxone at doses as low as 2.0 or 4.0 mg/kg. This finding suggests the possible involvement of an opiate receptor in the mediation of the enhancement by d-amphetamine of brain stimulation reward.     

Can the DRL 72s schedule selectively reveal antidepressant drug activity?

The effects of three antidepressants, desipramine (2.5–20 mg/kg) tranylcypromine (0.63–2.5 mg/kg) mianserin (1.25–10 mg/kg) and three non-antidepressants, chlordiazepoxide (CDP; 1.25–10 mg/kg) haloperidol (0.02–0.16 mg/kg)d-amphetamine (0.31–1.25 mg/kg) were evaluated in rats responding for water reinforcement under a DRL 72s schedule. The antidepressants all produced dose-related decreases in overall response rates, but no significant changes in reinforcement frequency. In contrast, the anxiolytic CDP did increase the number of reinforcers obtained. Haloperidol decreased both reinforcers and responses whilstd-amphetamine stimulated responding, thereby decreasing reinforcement frequency. An analysis of the modes of inter-response times (IRTs) revealed no significant shifts in the peaks of the IRT distributions for most of the drugs tested. Amphetamine, however, (0.31 and 0.63 mg/kg) decreased the modal values in correspondence with the shift to the left of the peak of responding caused by this compound. These results are discussed in the context of the use of the DRL 72s procedure as a screening test for antidepressant drugs.     

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0–30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1–3.0 mg/kg), meperidine (1.0–30 mg/kg), oxymorphone (0.03–1.0 mg/kg), and d-amphetamine (0.1–3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0–30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for self-stimulation responding were: oxymorphone > levorphanol > methadone > morphine > meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for self-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors

The effects of four indirect dopamine agonists,d-amphetamine (0.25–4.0 mg/kg), cocaine (2.5–40.0 mg/kg), GBR 12909 (10.0–30.0 mg/kg), and nomifensine (5.0–20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated withd-amphetamine (<2.0 mg/kg), cocaine (<20.0 mg/kg), GBR 12909 (<20.0 mg/kg), or nomifensine (<10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy,h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kgd-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses ofd-amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy,h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems.