Self-stimulation Behavior In Rats Research Articles

Facilitation of intracranial self-stimulation behavior in rats by environmental stimuli associated with nicotine

Environmental stimuli associated with nicotine act as a trigger for nicotine-seeking behavior and make it difficult to quit smoking. The trigger action might be related to the activity of the mesolimbic dopamine “reward” system. Thus, in the present study, we investigated the effects of nicotine-associated stimuli on reward seeking, assessed by current intensity thresholds of intracranial self-stimulation (ICSS) in rats. Rats were unilaterally implanted with an electrode into the lateral hypothalamus and trained to press a lever to obtain electrical brain stimulation. After stable responses had been established, the rats underwent six conditioning sessions with subcutaneous nicotine at 0.4mg/kg in particular visual and tactile contexts. The threshold for electrical stimulation was then tested in either the nicotine-conditioned environment or novel environment under saline or nicotine treatment. Nicotine enhanced the responding for ICSS and significantly lowered the threshold in both environments. Under saline treatment, the responding for ICSS was facilitated and the threshold was significantly lower in the nicotine-conditioned environment than in the novel environment. The present results demonstrate that nicotine-conditioned contextual stimuli may affect the mesolimbic dopamine system through ICSS threshold lowering effect.

Intracranial self-stimulation behaviour in rats elicited by STN-stimulation

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has emerged as a powerful therapeutic strategy in the treatment of levodopa-sensitive motor symptoms in late stage Parkinson's Disease (PD). Recently, there has been an increasing number of case reports indicating that STN-HFS also influences various non-motor aspects of behaviour, such as cognition, mood and motivation. These consequences of STN-HFS could be attributed to associative, limbic and motor cortical and subcortical loops involving the STN, suggesting STN-HFS to directly affect both motor as well as non-motor behavioural functions. The question arises as to whether psychotropic sensations experienced during STN-HFS could have reinforcing impact on the behaviour. This concern is considered relevant since it is known that commonly abused drugs eliciting similar hedonic effects can act as positive reinforcers contributing to the development of addictive behavior. It therefore is tempting to speculate that STN-HFS would also affect the reward systems, largely depending on dopamin(DA)ergic transmission in the Nucleus accumbens (NAc). Likewise, in a previous in-vivo microdialysis study we could demonstrate transient increase in levels in DA and its metabolites in the NAc induced by STN-HFS in anaesthetised rats. So far, no animal behavioral study has been done to confirm this notion.

Exposure to chronic mild stress alters thresholds for lateral hypothalamic stimulation reward and subsequent responsiveness to amphetamine

Chronic mild stress in rodents has been proposed to model some of the environmental factors that contribute to the induction of depressive disorders in humans. This model is based on the hypothesis that chronic mild stress induces a change in brain reward function that resembles the symptomatology of major depression, namely, a decrease in responsiveness to rewarding stimuli. The purpose of the first experiment was to investigate whether chronic mild stress affects brain reward function as measured by alterations in lateral hypothalamic self-stimulation behavior in rats. Exposure to chronic mild stress induces a reduction in body weight which might affect brain reward function on its own. Therefore, the potential contribution of a reduction in body weight to the chronic mild stress-induced alterations in brain reward function was examined in a separate group of food-restricted rats. Thresholds for lateral hypothalamic self-stimulation were slightly but significantly lowered in animals exposed to chronic mild stress, indicating an enhancement of stimulation reward efficacy. Food restriction had no effect on brain reward function. The second experiment examined the interaction between prior exposure to chronic mild stress or food restriction and responsiveness to a pharmacological challenge, amphetamine, that enhances brain reward function. Acute administration of amphetamine produced a greater enhancement of lateral hypothalamic self-stimulation reward in animals exposed to chronic stress relative to non-stressed and food-restricted animals. Taken together, the present findings indicate that chronic mild stress sensitizes the neural substrates that mediate both lateral hypothalamic stimulation and psychostimulant drug reward. These findings support the hypothesis that prior exposure to stress affects the vulnerability for drug-taking behavior by increasing the positive reinforcing properties of drug of abuse.

Differential effects of withdrawal from chronic amphetamine or fluoxetine administration on brain stimulation reward in the rat--interactions between the two drugs.

Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized. The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs. A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle. Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1-5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretreatment did not. Amphetamine-induced decreases in response latency, a measure of motor performance, were not affected by either chronic or acute fluoxetine pretreatment. The results of these experiments suggest that chronic fluoxetine treatment may induce adaptive changes in serotonergic transmission that, in themselves, do not alter the function of central reward processes, but may alter the ability of amphetamine to potentiate ICSS reward. In addition, the lack of change in ICSS thresholds during withdrawal from the chronic fluoxetine treatment regimen used suggests that withdrawal from all mood-altering drugs may not necessarily produce changes in central reward functions.

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concominant antidepressant treatment and may provide an heuristic animal model of depression.

The role of neurotransmitters in mediating the effect of somatostatin on self-stimulation behavior in rats

The role of neurotransmitters in mediating the effect of somatostatin on self-stimulation behavior in rats

Effects of cholecystokinin-related peptides on self-stimulation behaviour in rats

The effects of cholecystokinin octapeptide sulfate ester (CCK-8-SE), its N-terminal tripeptide (CCK-2-4-SE) and its C-terminal tetrapeptide (CCK-5-8) were investigated on hypothalamic self-stimulation in rats. CCK-8-SE and CCK-5-8 in 400 pmole doses inhibited self-stimulation behaviour, while CCK-2-4-SE was ineffective. In 80 pmole doses the peptides showed no effect. It is suggested that CCK-5-8 itself influences self-stimulation behaviour.

Effects of somatostatin on self-stimulation behaviour in rats pretreated with a receptor blocker

The effects of somatostatin on lateral hypothalamic self-stimulation were investigated in rats pretreated with haloperidol, bicuculline, phenoxybenzamine or propranolol. Somatostatin decreased the rate of self-stimulation. Halperidol, bicuculline and phenoxybenzamine potentiated the somatostatin-induced depression of self-stimulation behaviour. Propranolol had no effect. It is suggested that dopaminergic, GABAergic and noradrenergic systems are involved in the somatostatin-induced depression of self-stimulation.

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.

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Iminodibenzyl derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine and clocapramine have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, a new iminodibenzyl derivative, were compared with those of carpipramine, clocapramine, haloperidol and sulpiride. Y-516 inhibited apomorphine (0.5 mg/kg, s.c.)-induced hyperactivity in mice, apomorphine (10 mg/kg, s.c.)-induced hypothermia in mice, apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs, methamphetamine (2 mg/kg, s.c.)-induced hyperactivity in mice and methamphetamine (50 mg/kg, i.p.)-induced mortality in grouped mice. Y-516 also suppressed both lateral hypothalamic self-stimulation behavior in rats and circling behavior induced by methamphetamine (5 mg/kg, i.p.) in rats with unilateral 6-hydroxydopamine lesions of the striatum. In these tests, Y-516 was 2--3 times more potent than clocapramine, but less potent than haloperidol. The inhibitory effect of Y-516 on apomorphine (1.25 mg/kg, i.v.)-induced gnawing behavior in rats was slightly more potent than that of clocapramine. Y-516 in combination treatment with methamphetamine (5 mg/kg, i.p.) did not induce mortality in rats; however, carpipramine and sulpiride did. The cataleptogenic action of Y-516 was almost equipotent to that of clocapramine. From these results, Y-516 possesses a post-synaptic dopamine receptor blocking action similar to that of the iminodibenzyl antipsychotic drugs, suggesting its potential usefulness as an antipsychotic drug.

Effects of Chronic Haloperidol and Chlordiazepoxide Treatment on Lateral Hypothalamic Self-Stimulation Behavior in Rats

The effects of chronic administration of haloperidol and chlordiazepoxide for 14 days on self-stimulation behavior were investigated in rats with electrodes chronically implanted in the lateral hypothalamus. Haloperidol produced a prominent decrease in self-stimulation behavior during chronic treatment, followed by a significant increase in the lever-pressing rate during a 2 week withdrawal period, with a return to the control level about 5 weeks after drug withdrawal. Chlordiazepoxide produced a significant increase in self-stimulation behavior during chronic treatment. However, the lever-pressing rate was not significantly different from the control level during a 3 week observation period following drug withdrawal. These results indicate an increase in the sensitivity of central dopaminergic receptors following chronic haloperidol treatment, but not following chronic chlordiazepoxide treatment.

Effects of chronic haloperidol and chlordiazepoxide treatment on lateral hypothalamic self-stimulation behavior in rats.

The effects of chronic administration of haloperidol and chlordiazepoxide for 14 days on self-stimulation behavior were investigated in rats with electrodes chronically implanted in the lateral hypothalamus. Haloperidol produced a prominent decrease in self-stimulation behavior during chronic treatment, followed by a significant increase in the lever-pressing rate during a 2 week withdrawal period, with a return to the control level about 5 weeks after drug withdrawal. Chlordiazepoxide produced a significant increase in self-stimulation behavior during chronic treatment. However, the lever-pressing rate was not significantly different from the control level during a 3 week observation period following drug withdrawal. These results indicate an increase in the sensitivity of central dopaminergic receptors following chronic haloperidol treatment, but not following chronic chlordiazepoxide treatment.

Effect of cholecystokinin on self-stimulation behavior in rats

Experiments were performed to examine the effects of intracerebroventricularly administered cholecystokinin octapeptide sulfate ester (CCK-8-SE) and unsulfated cholecystokinin octapeptide (CCK-8-NS) on electrical self-stimulation behavior elicited from the medial forebrain bundle. CCK-8-SE and CCK-8-NS in 80 pmol doses reduced the response rate of self-stimulation behavior 22–30 min following injection, while 400 pmol doses of these peptides attenuated self-stimulation behavior between 13 and 36 min. It is suggested that CCK-8-SE and CCK-8-NS interact with central rather than peripheral nervous mechanisms.

Comparative effects of the ACTH 4–9 analogue (ORG 2766), ACTH 4–10 and [ d-Phe 7] ACTH 4ndash;10 on medial septal self-stimulation behaviour in rats

Experiments were performed to examine the effects of various analogues of ACTH on electrical self-stimulation behaviour elicited from the medial septal area using an ascending or descending sequence of stimulus intensities within a session. When an ascending sequence of threshold multiples was used ACTH 4–10 and the ACTH 4–9 analogue (ORG 2766) enhanced lever pressing for low intensity stimulation but attenuated self-stimulation at greater current intensities. The analogue ORG 2766 appeared to be a thousand times more potent than ACTH 4–10; [ d-Phe 7] ACTH 4–10 inhibited the response rate at threshold level but was inactive at greater current intensities. The same effect was found following administration of ORG 2766 in a dose which was 20 times greater (1 μg/rat) than that used in the first experiments. Lever pressing was not affected by treatment with ACTH 4–10 or ORG 2766 when a descending sequence of stimulus intensities was used within a session. Thus, ACTH-related peptides may affect motivational processes involved in self-stimulation rather than the reward of the stimulation per se. It is suggested that although ORG 2766 mimicked the action of ACTH 4–10 this synthetic peptide may have additional behavioural properties.

Post-amphetamine depression of self-stimulation behavior in rats: Prophylactic effects of lithium

Rats reliably interrupted a photobeam for electrical brain stimulation when electrodes were situated in the substantia nigra. The reinforcing value of electrical brain stimulation diminished, markedly, when animals were exposed to long-term amphetamine treatment and then tested in the absence of the drug. Chronic lithium treatment administered in conjunction with amphetamine protected against the development of the post-amphetamine depression of self-stimulation responding. These findings were not related to drug-induced changes in locomotor activity.

Enhancement of self-stimulation behavior in rats and monkeys after chronic neuroleptic treatment: Evidence for mesolimbic supersensitivity

The effect of chronic neuroleptic drug treatment on self-stimulation of the mesolimbic dopamine system was tested. Rats with electrodes implanted into the ventral tegmental nucleus (A10 cell body area) were treated with haloperidol for three weeks. Afterward, the rats showed a 35% increase in self-stimulation rate, as compared to pre-drug control rates. This increase persisted for three weeks after drug withdrawal before returning to baseline rates. Rats treated for three weeks with the atypical neuroleptic, clozapine, also showed an increase, the duration and magnitude of which was similar to that seen in the haloperidol group. In addition, four rhesus monkeys with electrodes in the nucleus accumbens (one of the terminal projection areas of the A10 mesolimbic dopamine system) were given a three week treatment with haloperidol, after which all animals showed a significant, long-lasting decrease in self-stimulation threshold, as measured by a rate-independent reward paradigm. Taken together, these results suggest the induction of receptor supersensitivity in the mesolimbic dopamine system by long-term treatment with neuroleptic drugs.

Actions and interactions of cocaine on self-stimulation behavior in rats

The effect of cocaine, over a dose range of 2--60 mg/kg, i.p., on self-stimulation (SS) behavior was studied in rats with electrodes either in the posterior hypothalamus (PH, monoaminergic) or the area ventralis tegmentum (A10, dopaminergic). The drug increased SS behavior with peak effects at 30 mg/kg in PH rats and 20 mg/kg in A10 rats. Azaperone (an alpha-adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) given at doses that did not affect baseline SS responses reduced cocaine-induced enhancement of SS in both PH and A10 rats, showing the involvement of both noradrenergic and dopaminergic mechanisms in SS behavior. A scopolamine dose that itself facilitated SS responding enhanced the effect of cocaine on this behavior, thus suggesting an additional involvement of cholinergic mechanisms in cocaine effect.

26 - Effects of psychotropic drugs on DRL-schedule based on self-stimulation behavior in rats

26 - Effects of psychotropic drugs on DRL-schedule based on self-stimulation behavior in rats

Effects of L-DOPA on self-stimulation and brain biogenic amines in rats

Effects of various doses of L-DOPA were tested on self-stimulation behaviour in rats with electrodes implanted in the posterior hypothalamus (PH) or area ventralis tegmentum (A10 area) as well as on the concentration of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the caudate nucleus (CN), diencephalon-midbrain (DM) and pons-medulla (PM). L-DOPA (50, 100 and 150 mg/kg. i.p.) showed a biphasic action on self-stimulation responding with an initial decrease for 40–60 min, followed by an increase for about an hour or more in rats with both PH and A10 electrodes. Both effects were more marked in rats with A10 electrodes. The effects of these doses on spontaneous motor activity were not significant. L-DOPA markedly increased DA levels in the CN and DM, and moderately decreased 5-HT, without significantly altering NE levels in the DM and PM. It appears that L-DOPA-induced changes in self-stimulation responding cannot be correlated with the increase of DA levels in the CN and DM. It is possible that this behaviour involves a system of several neurotransmitters, including biogenic amines and acetylcholine, and a sudden increase of one, such as DA, causes an imbalance in the multitransmitter system and disrupts the behaviour.

15) - Effects of various psychotropic drugs on intracranial self-stimulation behavior in rats

15) - Effects of various psychotropic drugs on intracranial self-stimulation behavior in rats