Evaluation of Motivational Effects Induced by Intracranial Self-Stimulation Behavior

In the runway model of intracranial self-stimulation (ICSS) experimentation, the experimental animal is timed in running a fixed distance to depress a lever that releases electrical stimulation to an electrode implanted along its medial forebrain bundle. This ICSS has both a reward and a motivational component. Using the runway method and priming stimulation, we designed an experimental method for directly measuring motivation. An assessment of pharmacological agents that are known to influence motivational states was also undertaken. Using the experimental methods that we created, we observed prominent changes in running speed when animals were exposed to methamphetamine and nicotine. According to these data, the runway method employing intracranial self-stimulation behavior may be useful for the evaluation of substances that act on motivation. We review the underlying neuropharmacological and anatomical functions associated with our experimental methods. We hope that this technique will be used to scientifically evaluate the impact of drugs and/or therapeutic interventions on human motivation

Influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats.

We studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing effect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened significantly. From the viewpoint of imipramine's effect, these findings suggest that chronic forced-swim stress testing in rats may be an effective animal model for depression.</p

Motivational Effects of Nicotine as Measured by the Runway Method Using Priming Stimulation of Intracranial Self-stimulation Behavior

It is well known that priming stimulation promotes the motivational effects of intracranial self-stimulation(ICSS) behavior. An experimental methodology using the runway method could separately study the reward and motivational effects of ICSS behavior. In the present study, we examined the motivational effect of nicotine as measured by the runway method using priming stimulation of ICSS behavior. Electrodes were implanted chronically into the medial forebrain bundle (MFB) in rats. A lever for stimulation of the MFB was set on the opposite side of the start box in the apparatus, and rats were trained to get a reward stimulation (50-200 microA, 0.2 ms, 60 Hz) of MFB when the goal lever was pressed. After the rats were trained to press the lever, a priming stimulation of the MFB was performed. After receiving the priming stimulation, rats were placed at the start box of the runway apparatus, and the running time duration until the goal lever was pressed was measured. Subcutaneous injection of nicotine at a dose of 0.2mg/kg produced an increase in running speed to obtain the reward stimulation, and priming stimulation facilitated the motivational effect to obtain the electrical brain stimulation reward in the rats. These results suggest that nicotine significantly enhanced the motivational effect on ICSS behavior as determined using the runway method. The runway method using priming stimulation of ICSS behavior may become the new experimental methodology with which to measure the motivational effect of some drugs.</p

The Influence of Hyperactivity of the Hypothalamic-pituitary-adrenal Axis and Hyperglycemia on the 5-HT2A Receptor-mediated Wet-dog Shake Responses in Rats

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induces hyperglycemia and serotonin (5-HT)2A receptor supersensitivity. In the present study, to investigate the effect of hyperglycemia on the function of 5-HT2A receptors, we compared the 5-HT2A receptor-mediated wet-dog shake responses in rats treated with adrenocorticotropic hormone (ACTH), dexamethasone and streptozotocin. ACTH (100 &#956;g/rat per day, s.c.), dexamethasone (1 mg/kg per day, s.c.) and streptozotocin (60 mg/kg, i.p.) produced significant hyperglycemia at 14 days after the start of these treatments, and the hyperglycemia was most pronounced in the streptozotocin-treated rats. The wet-dog shake responses induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, were significantly enhanced at 14 days after repeated treatment with ACTH and dexamethasone. However, streptozotocin-induced diabetes had no effect on the wet-dog shake responses. The results of the present study suggest that hyperglycemia is not strongly associated with the enhanced susceptibility of 5-HT2A receptors under the condition of hyperactivity of the HPA axis.</p

Effects of anxiolytic drugs on rewarding and aversive behaviors induced by intracranial stimulation.

In considering the characteristics of the action of anxiolytic drugs and their mechanism in the brain, it may be necessary not only to study the behavioral pharmacology but also to perform brain site research. In the present study, the action of anxiolytic drugs was examined with respect to various behaviors that were induced by stimulating the brain areas related to emotions such as reward (pleasure) or aversion in rats. First, the low rate of response in lateral hypothalamic self-stimulation behavior was induced by schedules of low current brain stimulation, variable interval (VI) and differential reinforcement of low rate (DRL). Anxiolytic drugs such as benzodiazepines facilitated these low-rate responses. The drug susceptibility was highest in the low current stimulation, lower in the VI stimulation, and lowest in the DRL stimulation schedules. Furthermore, it was found by the auto-titration method in intracranial self-stimulation behavior that anxiolytic drugs decreased the threshold of stimulation reward. Second, it was recognized using the decremental lever pressing (DLP) paradigm that anxiolytic drugs increased the threshold of aversive stimulation of mesencephalic dorsal central gray (DCG), and this increasing effect of the drug was antagonized by GABA receptor blockers such as biccuculline. Finally, it was examined whether or not the conflict situation is established by combining brain stimulation reward and aversion, such as foot-shock or DCG stimulation. As a result, the conflict behavior was established by combining not only the brain stimulation reward and foot-shock aversion, but also the brain stimulation reward and DCG stimulation aversion. Further anxiolytic drugs exhibited anti-conflict action in both situations. The susceptibility of anxiolytic drugs was higher with respect to the conflict behavior induced by intracranial reward and aversion than to that induced by the conventional method based on milk reward and foot-shock aversion. These results suggest that behavioral methods using brain stimulation can examine the mechanisms of direct drug action at the brain stimulation site. Indeed, in the present brain stimulation behavioral study, anxiolytic drugs such as benzodiazepines increased the stimulation threshold in lateral hypothalamic self-stimulation and inhibited the DCG aversive stimulation, thus resulting in an anticonflict action of the drugs.</p

Characteristics of the Runway Model of Intracranial Self-stimulation Behavior and Comparison with Other Motivated Behaviors

Motivation incorporates several psychological aspects that produce reward-related and learning behaviors. Although reward-related behavior is reported to be mediated by the dopaminergic reward pathway, the involvement of dopaminergic systems in motivated behavior has not been fully clarified. Several experimental methodologies for motivational behavior have been reported, but pharmacological characteristics seem to vary among these methodologies. In this review, we attempt to summarize three main concepts:(1) the relationship of dopamine neuron physiology with motivated behavior, (2) the pharmacological characteristics of the runway intracranial self-stimulation model, and (3) the behavioral distinction of disparate motivated behaviors

Influence of emotional stress on pharmacokinetics of isosorbide dinitrate intraperitoneally administered to rats.

The plasma level of isosorbide dinitrate intraperitoneally administered to rats stressed by foot-shock was almost the same as that in non-stressed control rats. However, levels of its metabolites, 5-isosorbide mononitrate and 2-isosorbide mononitrate, were lower in stressed rats than in non-stressed rats, suggesting that stress may influence the metabolism and/or excretion of the metabolites.</p

Effect of high dose alpha-tocopherol acetate on the toxicity and tissue distribution of adriamycin (doxorubicin).

The effect of alpha-tocopherol acetate (VE) on the toxicity and tissue distribution of adriamycin (ADM) in mice was studied. After the administration of ADM in 2 doses of 15 mg/kg, mice pretreated with olive oil survived 7.1 +/- 1.0 days, while mice pretreated with VE in ten doses of 500 mg/kg/day (subcutaneously) survived 5.5 +/- 1.7 days (p less than 0.01). The total concentration of ADM and its major metabolite, aglycone I in the liver (1, 3, 5 h), kidneys (1, 3 h), and heart (3 h), as determined by high performance liquid chromatography was significantly higher in the VE-pretreated group (four doses of 500 mg/kg/day) than in the olive oil-pretreated group. The aglycone levels of the VE-pretreated group were significantly higher than those of the olive oil-pretreated group in the liver, kidney and heart, but there was no significant difference between the groups in the levels of the unmetabolized form. Considering these results, the administration of VE concomitant with anti-tumor drugs, including ADM, requires great caution.</p

Protection against adriamycin (doxorubicin)-induced toxicity in mice by several clinically used drugs.

Protective effects of clinically used drugs against adriamycin (ADM)-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.). The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg), 402.2% for dextran sulfate (MDS, 300 mg/kg), 121.6% for flavin adenine dinucleotide (20 mg/kg), 236.3% for adenosine triphosphate disodium (50 mg/kg), 213.7% for reduced glutathione (100 mg/kg), 121.6% for phytonadione (50 mg/kg), 155.2% for inositol nicotinate (Ino-N, 500 mg/kg), 335.5% for nicomol (1000 mg/kg), 157.5% for nicardipine (10 mg/kg) and 123.3% for dipyridamol (50 mg/kg). Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.</p

Influence of exposure to new circumstances on pharmacokinetics of plasma drugs concentrations in rats.

The influences of emotional changes induced by being exposed to a new environment on the pharmacokinetics of plasma drug concentration were studied in male Wistar rats. Transfer from a familiar home cage to a new home cage was considered to induce psychological (non-physical) emotional changes. First, nicorandil and zonisamide, drugs that act on the peripheral system and central nervous systems, were used, respectively. Immediately after oral administration of nicorandil (10 mg/kg) or zonisamide (50 mg/kg), the animals were transferred to new home cages. Plasma nicorandil and zonisamide concentrations were determined by high-performance liquid chromatography at 1 and 4 h after administration. Plasma nicorandil concentration in the group transferred to new home cages was significantly decreased relative to levels in the non-transferred control group. However, zonisamide concentrations were unchanged. These findings suggest that the pharmacokinetics of nicorandil, but not those of zonisamide, tend to be influenced by non-physically induced emotional changes.</p