Motivational effect of nomifensine in the intracranial self-stimulation behavior using a runway method

Intracranial self-stimulation (ICSS) behavior is an experimental methodology to study reward and motivational effects. We have established a new paradigm to evaluate enhancing motivation by drugs in the runway method using the priming stimulation of ICSS. In the present study, we investigated the effects of nomifensine on the experimental extinction process of non-reinforcing reward and pre-trial electric priming stimulations in lateral hypothalamic self-stimulation. In this study, the experimental extinction process of the non-reinforcing reward means the experimental method of excluding reward effect in ICSS behavior. The extinction process in the runway method consisted of these 15 trials. Nomifensine, an antidepressant drug, delayed the running speed of the extinction process at doses of 5 and 10 mg/kg (i.p.) compared with the vehicle alone. This result suggests that the delay in the running speed of the extinction process promotes a motivational effect in rats. Previously, priming stimulation in the runway method was found to affect motivational function of ICSS. Therefore, our findings suggest the possible application of nomifensine for improving motivation.     

Effect of diazepam on the runway method using priming stimulation of intracranial self stimulation behavior

Intracranial self-stimulation (ICSS) behavior is an experimental methodology to study reward and motivational effects. We have established a paradigm to evaluate enhancing motivation by drugs in the runway method using the priming stimulation of ICSS. In the present study, we investigated the effects of diazepam on the experimental extinction process of non-reinforcing reward and pre-trial electric priming stimulations in lateral hypothalamic self-stimulation. The extinction process in the runway method consisted of these 15 trials. Diazepam, an anti-anxiety drug, at doses of 0.5 and 1 mg/kg (i.p.) delayed the extinction of running behavior when priming stimulation was given. The GABAergic antagonist flumazenil at doses of 5 and 10 mg/kg (i.p.) totally prevented the effect of diazepam. These results demonstrate that diazepam delays the extinction of running behavior on ICSS in the runway method and flumazenil, a GABAergic antagonist, eliminates the delayed effect of diazepam, that is, indicating that the delayed extinction effect of diazepam may be related to facilitation of motivation, which was promoted via the GABAergic system in the ICSS behavior.     

Motivational effects of nicotine as measured in a runway model of drug self-administration

Traditional operant self-administration and conditioned place preference methods have yielded inconsistent results in studies of nicotine reinforcement thereby hindering efforts to identify the neurobiological systems underlying the drug's motivation and reinforcement. This study was designed to assess the motivation of subjects to seek nicotine using a runway self-administration procedure. Male Sprague-Dawley rats (N=67) were trained to run a straight alley for a single daily intravenous injection of nicotine (0.01-0.09 mg/kg/injection) on each of 21 consecutive trials. Run Speed (1/Run Time) served as the dependent measure for the animals' motivation to traverse the alley and enter a goal-box associated with intravenous nicotine administration. Nicotine induced an inverted U-shaped dose-response curve with the 0.03 mg/kg dose producing optimal runway performance over trials. Subjects running for doses larger or smaller than the optimal dose exhibited slower running and took longer to enter the goal-box. Thus, the runway procedure proved to be an effective methodology for reliably assessing the motivation of trained but nondrugged animals to seek intravenous nicotine.     

Auto-titration technique using intracranial self-stimulation and effects of antianxiety drugs

In order to study effects of antianxiety drugs on the threshold of intracranial self-stimulation (ICSS), the auto-titration technique was used in the two lever Skinner box. This procedure consisted of conventional ICSS except the brain stimulation current intensity was decreased after every 20 lever press for ICSS, and the animal could press the another reset lever (at any time) to reset the stimulation current intensity to the preseted level. The current intensity at which the animal pressed the reset lever (reset current) was defined as the threshold of ICSS. Since reset currents that the animals showed were very stable during this experiment, the effects of chlordiazepoxide, diazepam and meprobamate were studied. The reset current was significantly lowered by 5.0 mg/kg chlordiazepoxide, p.o., at 1 hr after administration accompanied by the significant increase of ICSS, and the reset current was significantly lowered by 20.0 mg/kg of chlordiazepoxide. On the other hand, diazepam did not lower the reset current, although a significant increase of ICSS was observed at 1.0 mg/kg, p.o. The reset current was lowered by meprobamate at 100 mg/kg, p.o., accompanied by the increase of ICSS, and a significant increase of ICSS was observed at 200 mg/kg but not accompanied by lowered reset current. From these results, increased susceptibility to the brain stimulation current may be involved in the facilitating effects of chlordiazepoxide and meprobamate on ICSS.     

Excitatory effects of hydergine on intracranial self-stimulation

The effect of Hydergine on intracranial self-stimulation was tested in male albino Holtzman rats. The rats had monopolar electrodes implanted in the medial forebrain bundle of the posterior hypothalamus. Hydergine was given orally at 40 and 80 mg/kg. A dose-dependent excitatory effect occurred which was rapid in onset, large, long-lasting, and evidenced in acute trials of the drug. The results suggest that a major portion of Hydergine's action in aged patients is stimulatory and antidepressant in nature.     

Cocaine's effects on rate of intracranial self-stimulation.

While some investigators have reported that cocaine increases response rates for brain stimulation reward, others have failed to demonstrate this effect. The present study was designed to evaluate the influence of stimulation parameters, dose of cocaine and operant-dependent response requirements on cocaine's ability to alter self-stimulation rates. Self-stimulation rates were collected on a minute by minute basis for 45 min following IP injections of 0, 5, 15 or 30 mg/kg cocaine HCI. All doses were tested using both nose-poking and lever-pressing operants. It was found that mean lever-pressing rates were significantly increased by 5 mg/kg cocaine, while nose-poking rates were significantly increased by 15 and 30 mg/kg cocaine. Further examination of the pattern of results indicated that the cocaine-induced increases in lever-pressing rate were mainly due to an increase in the time spent self-stimulating, whereas increases in nose-poking were mainly due to increases in nose-poking rate/min within self-stimulation bouts. It was hypothesized that 5 mg/kg cocaine increased lever-pressing by producing response perseveration, while the higher doses increased nose-poking mainly due to the compatibility of the nose-poking response topography with cocaine-induced stereotypies.     

Effect of inhalation of xylene on intracranial self-stimulation behavior in rat

The effect of the inhalation of xylene on intracranial self-stimulation behavior was studied in rats in a flow-through (dynamic) inhalational behavioral chamber. Rats were exposed successively to four graded concentrations (102, 192, 419 and 623 ppm) of xylene vapor during 2-hr sessions on different days. The rate of lever-pressing showed a dose-dependent decrease during exposure to 192, 419 and 623 ppm of xylene. The 4-hr exposure to the smallest concentration (106 ppm) of xylene failed to show any effect on self-stimulation behavior. During a 5-day 2 hr/day exposure, the decrease in response observed on the 1st day was further accentuated with a nadir on the 3rd day; from the 4th day onwards, the depressant effect was attenuated showing the development of tolerance.     

Enhancing effects of Ro 15-1788 on straw-climbing behavior as measured with the straw-suspension method: reversal by diazepam

Ro 15-1788 (0.5, 1, 5, or 20 mg/kg), a pure benzodiazepine receptor antagonist, was studied for its effect on the duration of immobility and the number of straw-climbing attempts in a modified forced-swim test with straw-suspension of rats. A single dose of 20 mg/kg of Ro 15-1788 injected IP prolonged only the duration of immobility with no effect on straw-climbing behavior, whereas both doses of 1 and 5 mg/kg of this compound significantly enhanced the number of straw-climbing attempts in an inverted U-shaped manner. Ro 15-1788 at 1 mg/kg significantly reversed the inhibitory effect of 1 mg/kg of diazepam on the number of straw-climbing attempts. It is suggested that the enhancing effect of low doses of Ro 15-1788 on straw-climbing behavior can be regarded as an index of its anxiogenic effect, by acting via central benzodiazepine receptors.     

"Conflict" situation based on intracranial self-stimulation behavior and the effect of benzodiazepines

Based on lateral hypothalamic self-stimulation behavior of the rat in a Skinner box, a "conflict" situation was established by combining foot shock punishment with brain stimulation. Diazepam (10-20 mg/kg, PO) caused a marked increase in the lever pressing response in the punished period without affecting the unpunished response. Bromazepam (10--20 mg/kg PO) also caused an increase in the lever pressing response in the punished period and a decrease of the punished response. These results indicate that a "conflict" situation based on self-stimulation behavior is useful for the evaluation of antianxiety action.     

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 amphetamine and nomifensine on intracranial self-stimulation discrimination behavior in rats.

Rats implanted with electrodes in the medial forebrain bundle-lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation [intracranial self-stimulation (ICSS)]. When animals reached a high level of accuracy (95% correct) in the discrimination task, testing was begun. In the first experiment, we compared the effects of saline and 0.3 mg/kg d-amphetamine when the intertrial interval (ITI) was 1, 5, 10, and 15 s. In the second experiment, animals were tested either with saline, 0.3 mg/kg d-amphetamine, or 1, 3, or 10 mg/kg nomifensine and the ITI was held constant at 5 s. Increasing the ITI from 1-15 s did not produce a drug-induced change in the discriminative stimulus properties of ICSS, although it did produce changes in total numbers of lever presses and numbers of intertrial lever presses. In the second experiment, neither d-amphetamine nor nomifensine altered the discriminative stimulus properties of ICSS, but a dose-response increase occurred in the time to complete the test session and in total number of lever presses and in presses on the initiating lever. Under conditions known to increase extracellular dopamine (DA) levels in brain, both amphetamine and nomifensine produced large increases in locomotor activity, but neither drug produced changes in the detection threshold for ICSS. Results indicated that the internal cues produced by ICSS are different from those produced by these psychomotor stimulant drugs.     

The effects of the beta-carboline FG 7142, on intracranial self-stimulation in the rat

The effects of FG 7142 were examined, alone and in combination with chlordiazepoxide, on self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable-interval schedule of reinforcement. FG 7142 (1-20 mg/kg) produced a dose-related depression in responding, and chlordiazepoxide (5 mg/kg) enhanced it. When these two drugs were given together, response rates did not differ significantly from control rates.     

Xanthines alter behavior maintained by intracranial electrical stimulation and an operant schedule

Caffeine and related alkylxanthines are widely used for recreation and therapeutic effects. In behavioral studies, both response rate-enhancing and attenuating effects have been described, depending upon the dose and behavioral measure used. Intracranial self-stimulation (ICSS) and differential reinforcement of low rates of responding (DRL) were assessed after rats were administered one of a range of doses of caffeine or aminophylline. These measures were chosen because of their demonstrated sensitivity to psychotropic drugs and the potential for comparing the alkylxanthine data to the extensive literature of amphetamine effects on ICSS and DRL behavior. Caffeine and aminophylline elicited dose-and drug-dependent changes in ICSS responding, and increased response rates and decreased reinforcements on the DRL schedule. These behavioral results are discussed with reference to alkylxanthine interactions with adenosine receptors.     

A new method for studying working memory by using the three-panel runway apparatus in rats

We designed a new method for studying working memory, by using a repeated acquisition procedure in the three-panel runway apparatus. This apparatus is composed of a start box, a goal box and four consecutive choice points; each choice point consists of three panel gates. Male Wistar rats were trained with 6 consecutive trials (one session) per day. Each trial was performed every two minutes. In this apparatus, rats could pass through only one gate (correct gate) among three panel gates in the direction of the goal box and were given 100 mg food pellets as the positive reinforcement. The sequence of correct gate position in each rat was changed everyday, but not in each session. Error responses (pushing the incorrect gate) were gradually reduced as training was repeated, and the learning was established within 16 training sessions to achieve criterion performance. Intraperitoneal scopolamine and intrahippocampal ethylcholine aziridinium ion (AF64A) produced increases in both the number of errors and the latency in a dose-dependent manner. The increase in errors induced by AF64A did not return to the control level, though the prolonged latency returned to normal. As a conclusion, this experimental procedure using the three-panel runway apparatus would be a useful method for studying working memory, and its memory deficit is involved at least in the dysfunction of the cholinergic system in the hippocampus.     

Opiate modification of intracranial self-stimulation in the rat.

Studies were conducted to confirm the involvement of central opiate receptors in the expression of opiate modulation of intracranial self-stimulation (ICSS). Biphasic, dose-related changes in ICSS responding are described following IP administration of morphine sulfate (1-25 mg/kg) and levorphanol tartrate (LEV, 0.5-5 mg/kg). Similar patterns of response modification are reported following intraventricular (IVt) administration of LEV (0.01-0.2 muMoles) LEV's enantiomorph, dextrorphan, was not found to elicit comparable effects after either IP or IVt administration. Both the facilitatory and the depressant phases of LEV's action were antagonized by naltrexone (10 microgram, IVt), which had no apparent effect on ICSS by itself. Complete tolerance developed to the suppression of responding by 2.5 mg/kg LEV (IP) but not to the facilitatory effect of 0.5 mg/kg (IP), during a 5-day course of administration. The implications of these results for opiate reinforcement theory are discussed and possible mechanisms are advanced.     

Assessment of reinforcement enhancing effects of toluene vapor and nitrous oxide in intracranial self-stimulation

Rationale

Despite widespread abuse, there are few validated methods to study the rewarding effects of inhalants. One model that may have utility for this purpose is intracranial self-stimulation (ICSS).

Objectives

This study aims to compare and contrast the ICSS reward-facilitating effects of abused inhalants to other classes of abused drugs. Compounds were examined using two different ICSS procedures in mice to determine the generality of each drug’s effects on ICSS and the sensitivity of the procedures.

Methods

Male C57BL/6J mice with electrodes implanted in the medial forebrain bundle were trained under a three-component rate-frequency as well as a progressive ratio (PR) ICSS procedure. The effects of nitrous oxide, toluene vapor, cocaine, and diazepam on ICSS were then examined.

Results

Concentrations of 1,360–2,900 parts per million (ppm) inhaled toluene vapor significantly facilitated ICSS in the rate-frequency procedure and 1,360 ppm increased PR breakpoint. A concentration of 40 % nitrous oxide facilitated ICSS in the rate-frequency procedure but reduced PR breakpoint. Doses of 3–18 mg/kg cocaine facilitated ICSS in the rate-frequency procedure, and 10 and 18 mg/kg increased PR breakpoint. Doses of 1 and 3 mg/kg diazepam facilitated ICSS in the rate-frequency procedure, and 3 mg/kg increased PR breakpoint.

Conclusions

The reinforcement-facilitating effect of toluene in ICSS is at least as great as diazepam. By contrast, nitrous oxide weakly enhances ICSS in only the rate-frequency procedure. The data suggest that the rate-frequency procedure may be more sensitive than the PR schedule to the reward-facilitating effects of abused inhalants.     

The effects of long-term administration of antidepressant drugs on intracranial self-stimulation responding in rats

A discrimination procedure employing a two hole nose-poke technique was used to evaluate the effects of chronic administration of desipramine, amitriptyline, bupropion, nomifensine and zimelidine on intracranial self-stimulation (ICSS). Analysis of ICSS as a function of descending and ascending current presentation revealed that long-term exposure to desipramine significantly facilitated rates of responding from the medial forebrain bundle, and resulted in a shift to the left of the rate-intensity functions. The use of a discrimination paradigm allowed for the assessment of incorrect responses which proved to be a sensitive measure of the motor activating properties associated with electrical brain stimulation. These data indicated that the positive reinforcing effects of desipramine were not accompanied by concomitant increases in motor arousal. No changes in ICSS responding were evident after long-term treatment with amitriptyline, or the atypical antidepressants, bupropion, nomifensine and zimelidine. The implications of these findings were discussed in terms of the effects of these drugs on reward processes and the role of dopamine in the therapeutic efficacy of antidepressant drugs.     

Facilitation of electrical brain self-stimulation behavior by abused solvents

Animal models are needed to study the abuse-related behavioral and pharmacological effects of inhaled solvents. Previous studies have suggested that intracranial self-stimulation techniques may be successfully adapted for testing the effects of solvent exposure. The present study aimed to assess the effects of toluene, cyclohexane, acetone, and petroleum benzine (a widely used mixture of hexanes and heptanes) in rats trained to lever press or nose-poke for electrical stimulation delivered through electrodes implanted into the medial forebrain bundle. It was found that toluene, cyclohexane, and benzine but not acetone, increased rates of responding, particularly at the lower stimulation intensities. In another set of experiments utilizing an auto-titration procedure, all tested solvents significantly reduced self-stimulation thresholds. However, only for toluene and benzine were these effects observed at the exposure levels that did not impair rates of operant performance. There may not be such a clear separation of effects for acetone and cyclohexane. Thus, toluene and benzine appear to selectively affect brain reward systems in a manner similar to that for most other abused drugs. Data from intracranial self-stimulation studies of solvents may be useful in abuse potential assessment of individual compounds and for examining neural and behavioral processes involved in inhalant abuse.     

Tolerance and sensitization to stimulant and depressant effects of nicotine in intracranial self-stimulation in the rat

Nicotine is thought to be an important factor in addiction to tobacco but its psychopharmacological properties are still uncertain. In the present study, rats were trained to operate a pedal to obtain threshold-current, variable-interval hypothalmic stimulation. Response rates were printed out at 10min intervals to provide a continuous record of facilitatory or depressant effects by injected nicotine. Responding was enhanced in all rats but this depended on dose, time after injection, and previous exposure to the drug. In the first 10min after injection, responding by drug-naive rats was either unaffected (40-130mg/kg s.c., as base) or strongly depressed (400μg/kg). This phase was followed by prolonged (>50min) dose-dependent facilitation. Higher doses (1.3mg/kg) caused prostration. Chronic exposure to nicotine (400μg/kg x 10 at 2-5 day intervals) reduced the initial depressant effect; it also augmented subsequent responding, but only in the early minutes after injection; the latter finding indicates that apparent sensitization to chronic nicotine may depend primarily on tolerance to its depressant effects, rather than on receptor upregulation. Stimulant and depressant effects of nicotine were prevented by pretreatment with the centrally acting antagonist, mecamylamine (2.0mg/kg s.c.), but not by the peripheral antagonist, hexamethonium (1.0mg/kg s.c.) or by the muscarinic receptor antagonist, hyoscine (scopolamine; 100-300μg/kg s.c.). Self-stimulation was unaffected by mecamylamine alone. Thus the inhibitory action of nicotine is unlikely to be due to depolarization block, peripheral activity or muscarinic activity. Its facilitatory and depressant effects appear to be narrowly time- and dose-specific, thus accounting for divergent findings in many studies.     

Effect of nimodipine on drinking behavior measured in the runway: comparison and interaction with (+/-)-amphetamine

The aim of the present study was to evaluate the ability of the calcium channel blocker (CCE), nimodipine (NIM), to interact with (+/-)-amphetamine (AMPH) in modifying ingestive behavior. Rats performed in a water-reinforced runway paradigm with multiple trials. Water was available in sufficient quantity to produce satiety under control conditions as measured by a decline in response rate over the session. NIM and AMPH, given alone, did not produce significant effects on performance but produced behavioral changes when administered in combination. In particular, the combination of the highest doses (13 mg/kg i.p. NIM plus 0.56 mg/kg i.p. AMPH) initially depressed both running and drinking, whereas in later trials it increased running rate, without producing a parallel increase in water intake. These results suggest that NIM enhances AMPH-produced inhibition of drinking, whereas it first depresses and then enhances the AMPH-mediated runway performance, suggesting the rate dependency of this latter effect.