Intracranial self-stimulation in rats as a function of various stimulus parameters

The effects of different subcutaneous doses of cocaine (0.63, 1.25, 2.50, 5.00 and 10.0 mg/kg) on self-stimulation in rats were studied. Monopolar nichrome electrodes were implanted in the medial forebrain bundle at the level of the lateral hypothalamus. Six different stimulus parameter combinations (SPC's), inducing different predictable response rates were used. Cocaine showed a dose-related response stimulation, the highest at 10 mg/kg (49.7%); the response depression was very low at all doses and ranged from 3.20–8.23%.In the described experimental conditions apomorphine, amphetamine and cocaine have some properties in common but there are also important differences. With the three compounds response stimulation is related to the total control response rates at the different SPC's and is the highest at the two SPCs inducing the lowest control response rate. The differences in response stimulation associated with low intensity and low frequency SPC's could be related to a different mechanism of action.The response depression, the highest with apomorphine and the lowest with cocaine seems to be related to the stereotype inducing property of the compounds.The obtained effects of the three compounds are discussed in terms of their possible different influence on the dopaminergic system.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

Five separate but sequentially planned self-stimulation experiments were performed in rats with monopolar nichrome electrodes implanted in the medial forebrain bundle at the level of the lateral hypothalamus.A total of 272 sessions of 40 min were given and 44 different stimulus parameter combinations were used, i.e. pulse intensities from 0.100–0.250 mA, pulse frequencies from 20–80 pps, pulse widths from 2–10 ms, train durations from 200–800 ms and quantities of charge from 4–64 C.In all experiments the fixed ratio schedule was 21 (2 responses for 1 stimulus) and the 17 rats emitted a total of 508 365 responses. It was found that, besides the individual sensitivity of the rats, the response rate was not a simple function of quantity of charge, and that within each stimulus parameter combination a threshold value for each parameter had to be reached. Selective parameter combinations produced predictable response rates in spite of some contrast effects evoked, within each session, by randomisation of the stimulus parameter combinations according to a latin square design.     

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.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

The incidence, range, and severity of side effects in 65 children and young adolescents receiving imipramine treatment are compared with those occurring in 37 children and young adolescents receiving placebo. Minor side effects occurred in 83% of the imipramine group and in 70% of the placebo group. Just under 5% of the children in the imipramine group had significant side effects but none were serious enough to necessitate drug withdrawal. The majority of side effects in both groups occurred during the first three weeks of treatment. However, there may be serious individual idiosyncrasies to high dosage of imipramine, as possibly suggested by the sudden death of one six year old girl during imipramine treatment.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

The effects of different subcutaneous doses (0.08, 0.16, 0.31, 0.63 and 1.25 mg/kg) of apomorphine on self-stimulation in rats, with monopolar nichrome electrodes, implanted in the medial forebrain bundle at the level of the lateral hypothalamus were studied. Six different selected stimulus parameter combinations inducing different predictable response rates were used. Apomorphine was found to produce a dose-related response stimulation and a dose-related response depression. The highest stimulation was obtained at 0.63 mg/kg, the highest depression at 1.25 mg/kg. The response stimulation with apomorphine was 1. inversely related to the control response rate, i.e. the higher the control response rate, the lower the response stimulation after apomorphine and vice versa, 2. directly related to the control response rate of the individual rats, i.e. the highest response stimulation was obtained with the most sensitive rat and vice versa. The response inhibition with apomorphine was not related to the control response rates but was more pronounced during the first 1/2 h of the session. It is postulated that

1. increased self-stimulation with apomorphine could be the result of an increased motor response output;
2. decreased self-stimulation with apomorphine could be due to non-adaptive behaviour as a result of non-physiological overexcitation with interruption of integrated behaviour;
3. a complex behavioural pattern like intracranial self-stimulation depends on different interacting systems, mediated by different transmitters.

     

Intracranial self-stimulation in rats as a function of various stimulus parameters

Haloperidol, pimozide and pipamperone, three neuroleptics each with a different pharmacological and clinical profile were injected in rats with monopolar nichrome electrodes implanted in the medial forebrain bundle at the level of the lateral hypothalamus. Six different selected stimulus parameter combinations were used, two producing a predictable low response rate, two a predictable high response rate and two a response rate varying from low to high and less predictable. Each rat received four doses of the three compounds. A dose-related inhibition was found with all compounds in all rats and at all stimulus parameter combinations. The ED₅₀'s estimated graphically for the three compounds are: haloperidol: 0.055 mg/kg, pimozide: 0.220 mg/kg and pipamperone: 19.8 mg/kg. Overall drug effects indicate an inverse log-normal linear relationship between the quantitity of charge and the percentage of inhibition in response rate. This corresponds with a high inhibition at low response rates and vice versa, except that stimulus parameter combinations with lower frequencies are somewhat more sensitive to drug effects than those with higher frequencies. At the highest doses of the three compounds an almost equally high inhibition rate for all stimulus parameter combinations is obtained. The results obtained with neuroleptics in self-stimulation are compared to those obtained with different learned behavioural reactions and it is assumed that neuroleptics interfere with a general system involved in the output of stereotyped learned behaviour.     

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of rate-free psychophysical method. The acute administration of cocaine lowered the reinforcing thresholds independent of motor stimulatory effects. These results indicate that cocaine affects the sensitivity of the reward pathways in the brain, and further demonstrate the utility of rate-independent methods in the assessment of drug effects on self-stimulation behavior.     

Circling behaviour induced by electrical stimulation of the medial forebrain bundle, importance of stimulus parameters and dopaminergic processes

Unilateral electrical stimulation of the substantia nigra or the ventral tegmental area produced postural asymmetry and increased locomotor activity respectively. Concurrent stimulation of the efferent pathways of these two areas (medial forebrain bundle) resulted in contraversive circling behaviour that was dependent upon the current intensity and frequency of the stimuli. The application of biphasic electrical pulses minimised the damage to the brain site stimulated; no decrease in circling intensity over time, nor spontaneous circling after administration of amphetamine or apomorphine without stimulation was observed. The contraversive circling behaviour was induced by activation of the ascending dopaminergic pathways as revealed by the close correlation between the site of stimulation and the localisation of this pathway, its antagonism by haloperidol and its abolishment by pretreatment with reserpine and alpha-methyl-p-tyrosine. Apomorphine likewise inhibited the electrical stimulation-induced circling behaviour. These results are discussed with regard to the influence of the stimulation parameters and the dopaminergic processes involved.     

Intracranial alpha-methyl-P-tyrosine and response for electrical brain stimulation.

Chemitrodes, allowing electrical stimulation of the brain at the same site, were implanted in 18 rats aimed at the medial forebrain bundle of the lateral hypothalamus. After these animals were trained to bar-press for electrical brain stimulation, the crystalline form of alpha-methyl-paratyrosine (AMPT), an inhibitor of catecholamine synthesis, was administered intracranially, and change in response rate was noted. Intracranial tyrosine administration was also tested as a control study. It was found that AMPT depressed rate of response of intracranial self-stimulation, whereas tyrosine administered intracranially exhibited no such effects. This result lends support to data reported in the literature on the use of AMPT administered intraperitoneally or orally, and suggests a noradrenergic or dopaminergic system of reward in the lateral hypothalamus.     

The effects of ethanol upon threshold and response rate for self-stimulation

The hypothesis that ethanol would reduce the threshold for self-stimulation of the medial forebrain bundle was not supported. Ten rats, implanted with electrodes in the lateral hypothalamus, were shaped to bar press for electrical brain stimulation. The effects of 0.6, 0.9, and 1.2 g/kg ethanol injections upon threshold and response rate for self-stimulation were measured. The lowest dose had no effect upon self-stimulation threshold while 0.9 and 1.2 g/kg ethanol raised thresholds. Rate of bar pressing was increased by 0.6 g/kg ethanol but was not affected by higher dose. Results were discussed in terms of a postulated dual effect of ethanol upon a brain arousal system and upon a reward system.Offprints may be obtained from either author     

The effect of 6-aminodopamine on electrical self-stimulation in rats

The compound 6-aminodopamine is a powerful CNS catecholaminergic neurotoxin. Small dosages of 6-aminodopamine injected intraventricularly markedly depress electrical self-stimulation rates in rats. This 6-aminodopamine treatment produced whole brain lowering of norepinephrine to ca. 50% of normal while the dopamine content was unchanged The possible use of 6-aminodopamine treatment to elucidate the relative roles of norepinephrine and dopamine pathways is discussed.     

Comparison of the effects of morphine on hypothalamic and medial frontal cortex self-stimulation in the rat

The effect of morphine (3.75, 7.5, and 15.0 mg/kg. s.c.) on medial frontal cortex (MF) and hypothalamic self-stimulation (SS) was determined 1, 3, 5, and 7 h after injection for 5 consecutive days. Morphine suppressed or enhanced SS responding as a function of dose, time after injection, and the site stimulated. The MF SS groups were less sensitive to the toxic effects of morphine, and evidenced elevated rates of responding earlier after injection than the hypothalamic animals. The dose-response relationship of the MF rats, thus, clearly differed from that of the hypothalamic rats. With repeated administration, tolerance was rapidly (3–4 days) developed to the suppressive effect while the excitatory effect appeared earlier and tended to be enhanced, peaking 1 and 3 h after injection in the MF and hypothalamic groups, respectively.These data provide additional evidence against the hypothesis that the effect of morphine on SS behavior is non-specific. It it were, the time course and degree of effects should be similar, regardless of the electrode site tested. Furthermore, an inhibitory effect was not observed in the groups receiving 3.75 mg/kg although both showed a significant increase in responding 1 and/or 3 h after injection. This observation indicates that the excitatory effect is not dependent on the depressant effect and, therefore, probably is not a rebound phenomenon. It also suggests that the toxic effects of morphine can either mask or delay the appearance of its facilitatory action on SS responding.     

Effect of substance P on medial forebrain bundle self-stimulation in rats following intracerebral administration

The effect of Substance P infused intracerebrally via chronically implanted electrode-cannulae on self-stimulation induced from the same site was studied in rats. Substance P caused a significant depression of self-stimulation at 60 and 120 microgram/rat. Morphine infused into this site also caused significant depression of self-stimulation, but the doses were considerably lower than those of Substance P (5 and 10 microgram/rat). Pretreatment with naloxone, a narcotic antagonist, significantly antagonized the effects of Substance P on self-stimulation. It is proposed that Substance P modulates self-stimulation by the release of an endogenous morphine-like substance, but the possibility of a direct effect of Substance P was not ruled out.     

Differential antagonism by naloxone of inhibitory effects of haloperidol and morphine on brain self-stimulation

Haloperidol (0.16 mg/kg) or morphine sulfate (40 mg/kg), injected subcutaneously, completely suppressed bar-pressing for brain self-stimulation in rats implanted with electrodes in the lateral hypothalamus. Haloperidol also caused catalepsy and ptosis while morphine produced catatonia with exophthalmia. Naloxone in a dose (5 mg/kg) which was ineffective when given alone, differentially reversed the morphine-effects but was without any reversing influence on the actions of haloperidol.Visiting pharmacologist from Department of Pharmacology and Psychology, University of Rhode Island, Kingston, R. I., U.S.A.     

破坏前脑内侧束对精神分裂症大鼠神经递质的影响

目的研究精神分裂症动物模型大鼠前脑内侧束毁损后神经递质的变化。方法用苯环己哌啶（Phencyclidine,PCP）建立精神分裂症的动物模型。将动物分成模型组和毁损组。采用高效液相色谱分析的方法在体检测两组大鼠额叶皮层、杏仁核及海马中神经递质DA和5-HT的含量。结果显示模型组和毁损组大鼠DA和5-HT的含量有显著性差异。结论精神分裂症的动物模型与神经递质DA和5-HT密切相关,通过毁损前脑内侧束可以调节神经递质DA和5-HT的释放,缓解精神分裂症的症状。     

Facilitation of self-stimulation in rats by methadone

The effects of morphine and its derivatives on self-stimulation behavior have been widely studied. In those experiments which have used multiple injections (over days) and multiple post-injection tests (within days), the typical findings includes a depression of responding after the initial injections followed by a facilitation of responding on subsequent days. There have been only a few reports which have tested the effects of methadone in this paradigm. Some investigators have observed only depression of self-stimulation while others have reported both the transient depression and the subsequent facilitation generally obtained with morphine. In the present experiment we administered either 5 mg/kg or 10 mg/kg methadone IP over a five day period and tested MFB-LH self-stimulation at 2, 4, 6, 8, 10 and 23 hours post-injection. Compared to saline controls, the 10 mg/kg dose produced the typical opiate-induced changes in self-stimulation, i.e., an initial depression which lasted for two hours on the first two days but was replaced by significant facilitation by hour 4 of day 3. This facilitation persisted for at least 10 hours on all 5 days of the experiment. Except for a transient (days 2–3) depression of self-stimulation, 5 mg/kg was without effect. The present experiment demonstrates that methadone does facilitate self-stimulation but that its ability to do so is highly dose-dependent.     

Effects of parenteral morphine and oral methadone on self-stimulation in the rat

Facilitation of self-stimulation has been reported following the administration of various opiates. Methadone, a synthetic narcotic used in the treatment of narcotic addiction, has recently been demonstrated to facilitate self-stimulation when administered parenterally. The present study examined the effects of orally administered methadone (20 and 30 mg/kg), the route of administration used clinically, on MFB-LH self-stimulation at 2.5, 5, 8, 12, 17, and 24 hours post-administration. reliable facilitation was observed at 2.5 hours post-administration. However, the effect of methadone was less pronounced than that observed with a dose of parenteral morphine which was approximately equivalent in terms of analgesic potency.     

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.     

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.     

Brain site variations in effects of morphine on electrical self-stimulation

Pairs of bipolar electrodes were stereotaxically aimed at two of three sites: the locus coeruleus (LC), the substantia nigra, pars compacta (SNC), and the medial forebrain bundle (MFB). Rats were shaped to bar-press for trains of intracranial electrical stimulation presented as pairs of monophasic pulses. The first pulse of a pair (the C, conditioning pulse) was followed by a second pulse (the T. test pulse) after a parametrically varied interval. The effects of chronic morphine administration were tested in a paradigm of 7 days saline, 7 days morphine, 1 day morphine+naloxone, and 6 days post-drug saline. High doses of morphine (5 mg/kg) depressed response rates for intracranial selfstimulation (ICSS). LC placements and those just lateral or ventral to the LC showed large increases in ICSS rates under morphine (2.5 mg/kg). This area was delimited on either side by tips that showed response rate depressions under morphine. MFB placements yielded response rate facilitations under morphine. Sites medial to the MFB and ventral within the MFB showed rate depressions under morphine. Dorsal substantia nigra placements showed facilitated rates, whereas placements ventral within the SNC and substantia nigra, pars reticulata (SNR) produced more variable results, with rates tending to be depressed by morphine. The ICSS procedure may be a useful animal model for detecting the abuse potential of drugs.