Effect of centrally administered neurotensin on multiple feeding paradigms

Recent studies have suggested that the tridecapeptide, neurotensin, may be an endogenous satiety factor. The present study was undertaken to examine the effects of neurotensin on multiple paradigms known to stimulate feeding. Following a 30 hour starvation period, neurotensin suppressed feeding at the 20 microgram and 10 microgram dose, but not at the 1 microgram dose when compared to saline controls. Norepinephrine (20 micrograms ICV) induced feeding was suppressed at the 20 microgram neurotensin dose but not at the 10 microgram or 1 microgram dose. In contrast, neurotensin did not suppress muscimol induced feeding at any of the doses. Insulin induced feeding (10 units SC) also was not suppressed by neurotensin. Neurotensin suppressed dynorphin induced feeding at the 20 microgram and 10 microgram but not at the 1 microgram dose. Neurotensin suppressed spontaneous feeding (p less than 0.01) in vagotomized rats (2.5 +/- 0.3 g/2 hr) when compared with saline controls (4.2 +/- 0.5 g/2 hr) suggesting that an intact vagus is not necessary for neurotensin's anorectic effect. We conclude that neurotensin may play a role in short-term appetite regulation by a complex interaction with monoamines and neuropeptides, particularly norepinephrine and the kappa opiate agonist, dynorphin.     

Electroencephalographic and autonomic effects of centrally administered neurotensin in the rabbit

Neurotensin perfusion into the third ventricle of the unanesthetized rabbit induces an increase of the total power density spectrum of the cortex, without modifying the electrical activity of the cornu Ammonis dorsale. This evidence suggests a direct action of the peptide on the cortical neurons and seems to exclude the involvement of the brainstem reticular formation in inducing the electroencephalographic pattern. Simultaneously Neurotensin produces an evident behavioural excitation and a moderate thermolytic effect. The electroneurophysiologic, autonomic and behavioural changes are independent from one another and seem to depend on an action exerted by Neurotensin at various levels in the CNS.     

The effect of centrally administered naloxone on deprivation and drug-induced feeding

In the present study we evaluated the effect of intracerebroventricular (ICV) administration of naloxone on feeding induced by food deprivation, norepinephrine (NE), muscimol and neuropeptide Y (NPY). Naloxone (200, 100 and 50 micrograms ICV) decreased deprivation-induced feeding. In contrast, only the 200 micrograms dose of naloxone decreased NE-induced feeding and the 200 and 100 micrograms doses decreased muscimol-induced feeding. Eating stimulated by central administration of NPY was potently decreased by doses of naloxone ranging from 10-200 micrograms.     

Enhancement of ethanol-induced sedation and hypothermia by centrally administered neurotensin, β-endorphin and bombesin

Intracisternal administration of three endogenous neuropeptides (neurotensin, β-endorphin, or bombesin) potentiated the duration of sedation induced by a fixed dose of ethanol (5.2 g/kg) in mice. The minimally effective dose of each peptide that enhanced ethanol-induced sedation was: neurotensin, 0.18 nmoles; β-endorphin, 1.79 nmoles; and bombesin, 0.06 nmoles. The enhancement of ethanol-induced sedation was correlated with the potentiation of ethanol-induced hypothermia for all three peptides. None of the neuropeptides studied significantly altered blood or brain ethanol concentrations, suggesting that the observed effects were not due to differences in ethanol metabolism.     

Behavioral effects of urotensin-II centrally administered in mice

Urotensin-II (U-II) receptors are widely distributed in the central nervous system. Intracerebroventricular (i.c.v.) injection of U-II causes hypertension and bradycardia and stimulates prolactin and thyrotropin secretion. However, the behavioral effects of centrally administered U-II have received little attention. In the present study, we tested the effects of i.c.v. injections of U-II on behavioral, metabolic, and endocrine responses in mice. Administration of graded doses of U-II (1–10,000 ng/mouse) provoked: (1) a dose-dependent reduction in the number of head dips in the hole-board test; (2) a dose-dependent reduction in the number of entries in the white chamber in the black-and-white compartment test, and in the number of entries in the central platform and open arms in the plus-maze test; and (3) a dose-dependent increase in the duration of immobility in the forced-swimming test and tail suspension test. Intracerebroventricular injection of U-II also caused an increase in: food intake at doses of 100 and 1,000 ng/mouse, water intake at doses of 100–10,000 ng/mouse, and horizontal locomotion activity at a dose of 10,000 ng/mouse. Whatever was the dose, the central administration of U-II had no effect on body temperature, nociception, apomorphine-induced penile erection and climbing behavior, and stress-induced plasma corticosterone level. Taken together, the present study demonstrates that the central injection of U-II at doses of 1–10,000 ng/mouse induces anxiogenic- and depressant-like effects in mouse. These data suggest that U-II may be involved in some aspects of psychiatric disorders.     

Modification of the anti-nociceptive activity of morphine by centrally administered ouabain and dopamine

Measurements of the anti-nociceptive activity of morphine were made in mice which had received intracerebroventricular injections of small doses of ouabain or dopamine, which were themselves devoid of anti-nociceptive activity. Both agents produced an immediate potentiation of the anti-nociceptive activity of morphine. Since centrally administered ouabain can increase whole-brain dopamine levels, it is possible that the observed potentiating effects of ouabain may involve a dopaminergic component.     

Naltrexone-sensitizing effects of centrally administered morphine and opioid peptides.

Rats were trained to lever-press on a multiple-trial, fixed-interval, 3-min schedule of food-reinforcement; each trial consisted of a 10-min time-out and a 9.5-min response period. Naltrexone, injected s.c. prior to each trial, reduced response rates in a dose-related fashion, with an ED50 of 21 mg/kg. Four-hour pretreatment with i.c.v. morphine (3.0-30 micrograms) produced leftward shifts of the naltrexone dose-effect curve of up to 3 orders of magnitude. The selective mu agonist, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO; 0.1-0.3 microgram i.c.v.), sensitized animals to the rate-decreasing effects of naltrexone by more than 2 orders of magnitude. Pretreatment with the selective kappa agonist, dynorphin A-(1-17) (30 micrograms i.c.v.) or the selective delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE; 30-100 micrograms i.c.v.) induced moderate sensitization with leftward shifts of 1.0-1.5 log units. Thus, the naltrexone-sensitizing effect of acute opioid pretreatment is centrally mediated, consistent with the hypothesis that the phenomenon is related to the initiation of opioid physical dependence. Further, the effect appears to be mediated predominantly by mu-opioid receptors, because mu agonists consistently produced the largest sensitization to naltrexone.     

Autonomic effects of centrally administered dermorphin in conscious rabbits

The administration of 1 microgram dermorphin into the mesencephalic ventricle of conscious rabbits modifies some autonomic functions, heart rate, respiratory rate and temperature decreasing in a statistically significant way. Naloxone completely reverses such effects. Pretreatment with drugs which inhibit serotoninergic, catecholaminergic, Gabaergic and cholinergic systems does not affect these central dermorphin actions.     

Behavioral and pharmacological effects of centrally administered aminooxyacetic acid in rats

In the present experiment unilateral intrastriatal injections of aminooxyacetic acid (1, 2.5, 5 μmol) to freely moving animals and pentobarbital-anesthetized rats produced contralateral jerks and dose-dependent mortality, but no barrel rotation. At 10–12 days there were no significant differences in exploratory activity, passive avoidance behavior, and elevated plus-maze test in aminooxyacetic acid-treated animals as compared with controls. However freely moving animals microinjcctcd with aminooxyacetic acid (but not the pentobarbital-pretreated group) had impaired learning activity in an active avoidance conditioning test, and showed reduced striatal concentrations of substance P and GABA. Intrastriatal injections of aminooxyacetic acid therefore result in both acute and chronic behavioral changes which are attenuated by pentobarbital anesthesia.     

Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat

A series of experiments was conducted to examine the effects of dopamine D₁ receptor agonists on food intake in rats. In the first experiment, the D₁ agonist SKF 38393 (3.0–30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D₁ agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED₅₀ values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D₁ antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1–10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D₁ antagonist. The effects of SKF 82958 were also antagonized by the D₂ receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D₁ receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D₁ receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D₁ agonist. The results also demonstrate the need for comparisons among several compounds in studies of D₁ mediated behavioral effects.     

Differential effects on conditioned taste aversion learning with peripherally and centrally administered acetaldehyde

Acetaldehyde, the primary metabolite of ethanol, produces a variety of aversive symptoms when present in the body in high concentrations. Laboratory rats were able to learn to associate a novel tasting saccharin solution with the toxic effects of an intraperitoneal injection of acetaldehyde. However, when the acetaldehyde was administered intracerebroventricularly, there was no manifestation of a conditioned avoidance of the saccharin taste. It is suggested that the aversive effects of acetaldehyde are mediated by peripheral toxicosis rather than by the pharmacological actions of acetaldehyde in the brain.     

Synergistic behavioural effects of dopamine D1 and D2 receptor agonists are determined by circadian rhythms.

The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine D1 receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D2 receptor agonist) or both D1 and D2 receptor agonists, on locomotor activity were investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark:dark) or continuous light (light:light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D2 receptor agonist initially increased locomotion in rats kept under dark:dark during both subjective night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D2 receptor agonist on rats kept in dark:dark increase during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D1 receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D1 receptor agonist interacted synergistically with the D2 receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats under dark:dark but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occurred as a function of treatment duration, but only during subjective day. The D1 receptor agonist blocked the effects of the D2 receptor agonist during the rats' subjective night after 100 h of treatment, but not after 25 or 325 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiovascular effects of centrally and peripherally administered indoramin in conscious rats

Indoramin has centrally mediated hypotensive effects in anesthetized animals. In the present study, the cardiovascular effect of central and peripheral indoramin was determined in conscious, freely moving rats. Animals were instrumented with femoral arterial and venous catheters and miniaturized pulsed-Doppler flow probes were placed on the superior mesenteric and renal arteries and lower abdominal aorta. Injection of indoramin (25-100 micrograms) in the lateral cerebroventricle produced an immediate (1.5 min) increase in arterial pressure which was accompanied by vasoconstriction in all three vascular beds. By 10 min all values had returned to control except for heart rate which was decreased. Vehicle alone or intravenous indoramin (100 micrograms) had no effect. In baroreceptor-denervated rats smaller effects were seen. Intravenous indoramin (3.0-13.5 mg/kg) produced dose-related decreases in arterial pressure, heart rate, and hindquarter vascular resistance. The 13.5 mg/kg dose blocked to a similar degree the cardiovascular effect produced by intravenous norepinephrine or stimulation of the paraventricular nucleus. These data suggest that indoramin is an effective peripheral alpha-adrenergic receptor antagonist but does not appear to be centrally active as a hypotensive agent.     

Respiratory and circulatory effects of centrally administered phencyclidine in anesthetized dogs.

1. Anesthetized dogs were given phencyclidine HCl (PCP) by intracerebroventricular (i.c.v.) injection. 2. Physiological parameters were monitored after consecutive doses of 0.5, 1.0 and 2.0 mg of PCP. 3. Dose-related changes seen, including bradycardia, hypotension and bradypnea, were opposite to those produced by i.v. doses. 4. Single doses of 1.0 or 2.0 mg of PCP confirmed the prior observations, and the latter provided the baseline for further observations on dogs receiving PCP before various i.c.v. pretreatments--atropine, haloperidol, phentolamine or propranolol--in efforts to characterize the central neurotransmitter system(s) involved in the PCP effects.     

The cardiovascular effects of centrally administered taurine in anaesthetised and conscious rats

The effects of pentobarbitone anaesthesia on the cardiovascular changes induced by centrally administered taurine have been investigated in spontaneously hypertensive (SHR) and normotensive rats. Administration of taurine (100-400 micrograms) into the lateral cerebral ventricle (i.c.v.) of anaesthetised SHR and normotensive rats induced a dose-related fall in systemic blood pressure and heart rate, which tended to be of a greater magnitude in the SHR. In anaesthetised rats attached to a ventilator, taurine was not as potent at inducing a fall in systemic blood pressure, approximately double the dose being required to produce the same cardiovascular changes as that which occurred in anaesthetised rats without a ventilator. In conscious normotensive rats taurine had no effect on blood pressure until a dose of 800 micrograms was administered i.c.v., whereas in conscious SHR, a small, but significant depressor response was evident with 400 micrograms. These findings demonstrate that pentobarbitone anaesthesia sensitises the rats to the cardiovascular effects of taurine, partially through a mechanism which involves respiratory depression. Conversely in conscious rats a much higher dose of taurine is required to induce a fall in arterial pressure and heart rate per se.     

6-Hydroxydopamine inhibits some effects of mescaline centrally administered to rabbits

The narcotic antagonist naloxone does not antagnonize antinociception elicited in the rabbit by 100 g/kg of mescaline centrally administered, whereas pretreatment with 6-hydroxydopamine (6-OHDA) inhibits this mescaline effect. Stereotyped behavior of rabbits following central mescaline administration is also prevented by 6-OHDA pretreatment. Since 6-OHDA in known to produce a degeneration of catecholamine containing nerve terminals, a crucial role of catecholamines is suggested in the complex of effects seen in the rabbit after central administration of the hallucinogen.     

The effects of glutamate receptor agonists on neurotensin release using in vivo microdialysis

In the present study, extracellular concentrations of neurotensin were measured from the striatum, nucleus accumbens and the medial prefrontal cortex in the awake, freely moving rat. Using a highly sensitive solid phase radioimmunoassay, basal concentrations of neurotensin were 2-5 pg/sample. In each region, glutamate receptor agonists, N-methyl-D-aspartate (NMDA) and kainic acid, increased neurotensin release 2-3-fold. Preincubation with the Na(+) channel blocker tetrodotoxin abolished the glutamate receptor agonist-induced increases except in the striatum following kainic acid infusion. These findings indicate that activation of glutamate receptors may indirectly stimulate neurotensin release.     

The biphasic effects of centrally and peripherally administered caffeine on ethanol-induced motor incoordination in mice

The possible biphasic effect of caffeine on acute ethanol-induced motor incoordination by rotorod evaluation was investigated in mice. Caffeine in various doses was administered intracerebroventricularly (i.c.v.) to mice implanted with permanent indwelling stainless steel guide cannulae and intraperitoneally (i.p.) to non-cannulated animals. A motor incoordinating test dose of ethanol, 2 g kg-1, was given i.p. in both cases. Caffeine less than 25 micrograms administered i.c.v., dose-dependently attenuated while 75 micrograms i.c.v. potentiated ethanol (i.p.)-induced motor incoordination. Similarly, caffeine less than 20 mg kg-1 given i.p., dose-dependently attenuated while 62.5 mg kg-1 potentiated ethanol (i.p.)-induced motor incoordination. The data obtained demonstrated that caffeine given either i.c.v. or i.p. exerted biphasic effects on ethanol-induced motor incoordination. The data also suggested that caffeine antagonized ethanol-induced motor micrograms i.c.v.; less than 20 mg kg-1 i.p.) caffeine is well known to display high affinity for adenosine binding sites. Therefore, the present investigation lends further support to our earlier suggestion that adenosine may be involved in the motor impairing effect of ethanol.