Glucocorticoids modulate behavioral effects induced by dopaminergic agonists in rats

Studies showing the presence of glucocorticoids, and their binding sites in the central nervous system indicate that these hormones may affect central neurotransmission. Both, dopaminergic brain system and glucocorticoids are considered to be involved in certain psychopathological conditions in humans, including depression, addiction or schizophrenia. The present study aimed to investigate the influence of glucocorticoids on dopamine agonists-induced stereotyped behavior and locomotor hyperactivity in rats. The results of the experiment demonstrate that prior to administration of prednisolone (4, 6, 10 or 20 mg/kg) or dexamethasone (4 or 8 mg/kg) intensified and prolonged the stereotypy induced by apomorphine (1 mg/kg sc) or amphetamine (2 mg/kg ip). The effect of dexamethasone was more potent. Amphetamine (0.4 mg/kg)- or amantadine (50 mg/kg)-induced locomotor hyperactivity was significantly reduced in rats pretreated with dexamethasone at a dose of 8 mg/kg or 4 mg/kg. Our observations suggest that exogenous glucocorticoids may enhance the activity of the dopaminergic agonists in the striatum but reduce it in the mesolimbic system of rats.     

Modifications of nutrient selection induced by naloxone in rats

Total caloric intake and dietary self-selection of the three macronutrients protein, fat, and carbohydrate were examined in male rats maintained on a 6-h feeding schedule following the administration of the opioid antagonist naloxone HCl (0.1, 1.0, and 10.0 mg/kg IP). Total caloric intake (calculated as the sum of caloric intakes from each of the macronutrients) was decreased for up to 2 h following naloxone administration. By the end of the 6-h feeding period, however, no differences in total caloric intakes were observed as a function of naloxone injections. Examination of intakes of the individual macronutrients revealed that naloxone differentially affected fat, carbohydrate, and protein consumption. Across the 6-h feeding period, animals consumed less calories from the fat ration following all three doses of naloxone than after saline injections. Carbohydrate intake was decreased for up to 2 h following naloxone injections, but returned to control values by the end of the 6-h feeding period. Protein intake, in contrast to fat and carbohydrate intakes, did not vary as a function of naloxone administration. Results of the present experiment are contrasted with patterns of dietary self-selection observed following morphine administration.     

Diprenorphine and naloxone in squirrel monkeys with enhanced sensitivity to opioid antagonists

The effects of diprenorphine and naloxone were examined in squirrel monkeys responding under a multiple fixed-ratio 30, fixed-interval 5-min schedule of food presentation. Dose-response curves for diprenorphine and naloxone were determined prior to and following chronic administration of 10.0 mg/kg naloxone once daily for at least 21 days. Prior to the chronic regimen, naloxone (0.1–10.0 mg/kg) had little effect on performance. At the highest dose examined, rates of responding were decreased only slightly. Diprenorphine (0.003–0.1 mg/kg) produced dose-dependent decreases in rates of responding under both components of the multiple schedule. Subsequent to the chronic naloxone regimen, doses of both naloxone and diprenorphine produced greater decreases in rates of responding. This suggests that frequent exposure to naloxone enhances its own rate-decreasing effects as well as those of diprenorphine.     

Effect of naloxone on the sensitivity of the vas deferens to various agonists

The effect of naloxone in vitro, on noradrenaline (NA)-induced responses in guinea-pig isolated vas deferens was studied. The responses of NA were potentiated by naloxone (3 μm). It potentiated the responses to methoxamine which has least affinity for uptake sites. Responses induced by acetylcholine and potassium chloride were also potentiated by naloxone. Low calcium (0.8 mM) in the medium antagonized the potentiating action of naloxone. It is suggested that naloxone produces non-specific potentiation, by promoting calcium influx at the post-synaptic site.     

The role of naloxone infusions in the treatment of overdoses of long half-life narcotic agonists: application to nor-methadone

This report describes the use of a naloxone infusion at a rate of 300 micrograms/h to provide constant antagonism of the respiratory depressant effects of a near fatal nor-methadone dose in a 2 year old boy. The terminal half-life for nor-methadone was calculated to be 13.5 h. The results indicate that a single dose of a narcotic antagonist with a short half-life (e.g. naloxone) will probably be inadequate to provide long lasting reversal of the effects of overdoses of long half-life narcotic agonists, and that continuous infusion may be the preferable to repeated bolus doses.     

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating

BACKGROUND: Compared to outbred Sprague Dawley (SD) rats, inbred Brown Norway (BN) rats exhibit less prepulse inhibition of startle (PPI) at long prepulse intervals, and more PPI at short intervals. Sensitivity to dopaminergic drug effects on PPI differs substantially across strains, and is heritable within SD and other outbred strains. To further understand the heritability of PPI and its sensitivity to dopamine agonists, we assessed PPI and apomorphine sensitivity in SD, BN and F1 (SD x BN) rats. METHODS: PPI was measured in BN, SD and F1 rats under a variety of stimulus conditions, and after treatment with apomorphine. RESULTS: Findings confirmed significantly more PPI in BN compared to SD rats at short prepulse intervals, and significantly more PPI in SD compared to BN rats at long intervals. F1s were "supersensitive" to both the PPI-disruptive effects of apomorphine at longer intervals, and the PPI-enhancing effects of apomorphine at shorter intervals, compared to either parental strain. CONCLUSION: Differences in sensorimotor gating between SD and BN rats are robust, time-locked and consistent across studies. Unlike patterns in other strains, heritability of PPI apomorphine sensitivity phenotypes in SD x BN F1s cannot be easily explained by simple additive effects.     

Effect of naloxone on the sensitivity of the vas deferens to various agonists.

The effect of naloxone in vitro, on noradrenaline (NA)-induced responses in guinea-pig isolated vas deferens was studied. The responses of NA were potentiated by naloxone (3 microM). It potentiated the responses to methoxamine which has least affinity for uptake sites. Responses induced by acetylcholine and potassium chloride were also potentiated by naloxone. Low calcium (0.8 mM) in the medium antagonized the potentiating action of naloxone. It is suggested that naloxone produces non-specific potentiation, by promoting calcium influx at the post-synaptic site.     

Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone

  Rationale: Non-dependent and dependent opiate users appear to be driven by two distinct motivational factors: the primary reinforcing properties of the drug, and the negative reinforcing effects associated with relieving the negative affective component of opiate withdrawal in the dependent state. Objective: To investigate the motivational significance of opioid dependence on heroin self-administration (HSA) in rodents. Methods: Rats were trained to self-administer heroin intravenously (0.06 mg/kg per infusion; FR1), and opiate dependence was induced by subcutaneous implantation of two morphine (75 mg base) pellets.Rats in a non-dependent control group received placebo pellets. Three days after pellet implantation, HSA was resumed in daily 3-h sessions until baseline criteria were met and testing was conducted with subcutaneous injections of vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session. Results: Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet-implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a second experiment, the HSA session was shortened to 1 h and the training dose reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo pellet-implanted rats was increased only following the highest dose of the antagonist, while dependent rats were still affected by naloxone doses of 0.003–0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3), breaking point values in dependent animals were 198% above baseline. Conclusions: The present study supports the hypothesis that dependence-induction by morphine-pellet implant in rats resulted in increased sensitivity to very small naloxone doses, as measured by changes in HSA. Taken together, these data suggest that opiate dependence, as measured by changes in sensitivity to naloxone, is a continuum which can contribute to the motivational state of drug-seeking. Received: 5 June 1998 / Final version: 21 December 1998     

Pharmacological specificity of enhanced sensitivity to naltrexone in rats

Rats treated weekly with cumulative doses (1–100 mg/kg, IP) of naltrexone develop an enhanced sensitivity to the operant response-rate decreasing effect of naltrexone. In the present experiment the pharmacological specificity of that enhanced sensitivity was determined by testing a variety of drugs for cross-sensitivity to naltrexone. Cross-sensitivity was evaluated with two procedures. In one, dose-effect functions were determined for each of the test compounds before and after the development of enhanced sensitivity to naltrexone in a single group of rats. In the second procedure, one group of rats was made sensitive to naltrexone, while a second was not. Test compounds were then evaluated in both groups. For both procedures, a shift to the left in the dose-effect functions similar to naltrexone was considered evidence of cross-sensitivity. Of the opioid antagonists tested, only naloxone showed clear cross-sensitivity to naltrexone, although MR 2266 and diprenorphine also showed evidence of cross-sensitivity. The opioid antagonist quadazocine did not show cross-sensitivity to naltrexone on the day of testing, although some evidence of cross-sensitivity was evident 24 h later. In addition, the dose-effect function ford-amphetamine was significantly changed following naltrexone treatment. No evidence of cross-sensitivity was observed for the optical isomer of naloxone,d-naloxone, or for naloxone's quaternary derivative, naloxone methiodide. None of the opioid agonists or agonist-antagonists tested showed cross-sensitivity to naltrexone (i.e. morphine, U-50, 488H, ethylketocyclazocine,N-allylnormetazocine and pentazocine). The non-opioid drugs chlordiazepoxide and phencyclidine also failed to show evidence of cross-sensitivity. However, the dose-effect curves for chlordiazepoxide were shifted significantly to the right following naltrexone treatment. The results of the present experiment indicate that the enhanced sensitivity which develops to naltrexone in rats is stereospecific and centrally mediated. The effect is specific, in that it does not appear to confer changes in the behavioral effects of non-opioids or even opioid agonists.     

The role of dopaminergic receptors in the behavioral effects induced by lisuride in male rats

Lisuride increased the incidence of stretching and yawning (SY) as well as of penile erection (PE) and elicited stereotyped behavior (SB), aggressive behavior and mounting in male rats, depending on the dose used. SY was prevented by two dopaminergic antagonists, haloperidol and sulpiride, but not by methysergide, a serotoninergic antagonist, while PE was antagonized by all three drugs. With regard to SB, aggressive behavior and mounting, all three were suppressed by haloperidol; sulpiride, while partially antagonizing aggressiveness, failed to affect SB and mounting; methysergide did not significantly influence any of the three. This suggests that lisuride principally affects the dopaminergic system. Although further detailed studies are required to elucidate which type of the complex population of DA-receptors is involved in each kind of behavior, we suggest that SY at least is due to the activation by lisuride of presynaptic DA-receptors.     

Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats

Repeated administration of amphetamine to adult rats results in enhanced behavioral responses to subsequent amphetamine exposure. These experiments were designed to determine the earliest age at which behavioral sensitization to amphetamine could be detected. Rats from both sexes (n=6–8/group) at ages of 1, 7, 21 or 49 postnatal days (PNDs) were injected with eitherd-amphetamine sulfate (5 mg/kg) or saline, SC, twice daily for 5 consecutive days. Stereotyped behavior and locomotor activity responses to a challenge dose ofd-amphetamine (2.5 mg/kg), or saline, IP, were assessed for a total of 90 min, 15 days after the last dose of pretreatment. Amphetamine-induced stereotyped behavior was significantly enhanced only when amphetamine pretreatment was initiated at PND 49, but not at the earlier ages of PND 1, 7 or 21. There was no apparent sex difference in this effect. Correspondingly, amphetamine-induced locomotor activity was reduced in both sexes of the same age group (PND 49), but not in gropus pretreated earlier, when compared to the saline-pretreated rats. These results sugges that amphetamine sensitization may be a late-developing effect, one which occurs sometime after the 3rd week of postnatal life.     

Tolerance to behavioral effects of caffeine in rats

Tolerance develops to three behavioral effects of caffeine in rats treated daily with the drug: stimulation of locomotor activity, rate-decreasing effect on food-reinforced operant responding, and discriminative stimulus effects. Tolerance induced by caffeine to stimulation of locomotor activity: (1) develops rapidly, being nearly maximal 24 hr after the start of daily treatment with 35-40 mg/kg in four divided oral doses; (2) is insurmountable (i.e., complete) so that rats are unresponsive, even to high doses of caffeine, and dose-response curves are displaced downward and flattened; (3) is pharmacologically specific, extending to other methylxanthines but not to nonxanthine psychomotor stimulants. Tolerance to the other two behavioral effects of caffeine: (1) appears to develop gradually; (2) is surmountable so that dose-response curves are displaced to the right; (3) extends to nonxanthine psychomotor stimulants, methylphenidate, in the case of discriminative effects. Thus, at least two distinct types of tolerance to behavioral effects of caffeine in the rat can be identified. The potency of an adenosine analog, R(-)-PIA, in depressing locomotor activity does not increase during or 24 hr after termination of chronic daily treatment with caffeine when rats are completely tolerant to caffeine-induced stimulation of locomotor activity. These results do not support the view that enhanced functional sensitivity of central adenosine systems (e.g., up-regulation of receptors) is the mechanism of tolerance to the stimulant effect of caffeine on locomotor activity.     

Barbital-induced changes in sensitivity to the behavioral effects of narcotics

Twelve male (Sprague-Dawley) rats were trained to respond under a variable-interval 15 sec schedule of sweetened-milk reinforcement. Rats were tested with doses of morphine and methadone, both before and after the development of tolerance to barbital (100 mg/kg, IP). Barbital-tolerant rats were tolerant to the effects of methadone on VI responding but were not tolerant to the effects of morphine. These data demonstrate that tolerance to some narcotics can develop after chronic exposure to drugs other than those of the same pharmacologic class. Furthermore, this investigation demonstrates the necessity of considering changes in the pharmacokinetics of a narcotic as a possible explanation for the development of tolerance to the behavioral effects of the drug.     

Increased sensitivity to serotonergic agonists after repeated electroconvulsive shock in rats

The effect of single and repeated electroconvulsive shock (ECS) (once daily for 7 days) on head twitches produced by 5-HT agonists (LiCl, 5-hydroxytryptophan; 5-HTP and 5-methoxytryptamine; 5-MT) was investigated 1 hr, 24 hr, 5 days and 10 days after the last ECS, while locomotor activity induced by serotonergic agonists (fenfluramine, 3-chlorophenylpiperazine; m-CPP) and antagonists (metergoline, cyproheptadine) was only investigated after 24 hr. 5HT and 5-HIAA concentrations were measured 0.5, 1 and 24 hr after a single ECS and up to 10 days after repeated ECS. Head twitches induced by LiCl were significantly depressed 1 hr after both single and repeated ECS. The number of head twitches produced by LiCl, 5-HTP or 5-MT given 24 hr after single or repeated ECS did not change but it rose significantly 5 and 10 days after the last shock. Repeated ECS increased locomotor activity 24 hr after the last shock. This increase was significantly enhanced by serotonergic antagonists. Biochemical assays showed that a single ECS did not significantly change brain 5-HT and 5-HIAA concentrations 0.5, 1 or 24 hr after the ECS. On the other hand, repeated ECS raised brain 5-HIAA 0.5, 1 and 24 hr or 5 and 10 days and 5-HT 0.5 hr after the final ECS. It is concluded that a single or repeated ECS both depress the serotonergic system response to LiCl but repeated ECS facilitates the response to serotoninomimetics.     

Tandem regulation of phosphoinositide signaling and acute behavioral effects induced by antidepressant agents in rats

Rationale Antidepressants increase synaptic monoamine concentrations, but the subsequent signaling events that produce the beneficial clinical effects remain unclear. Diverse antidepressants increase CDP-diacylglycerol, a crucial step in phosphoinositide signaling. Serotonin 5HT₂ receptors, implicated in depression or the actions of some antidepressants, signal through phosphoinositide hydrolysis. Thus, cross talk between antidepressant-induced CDP-diacylglycerol and 5HT₂ signaling could contribute to the antidepressant mechanism. Objective The objective of the study was to test the hypotheses that antidepressants enhance net signaling via 5HT₂ receptors by augmenting the supply of phosphoinositide substrates and that this action contributes to the behavioral effects of the drugs. Materials and methods Brain slices pre-labeled with [³H]inositol in the presence of various antidepressant concentrations were washed and incubated with the 5HT₂ agonist, α-methylserotonin, followed by measuring phosphoinositide synthesis and inositol phosphate accumulation. Further, rats administered antidepressants after pretreatment with neomycin to inhibit metabolic utilization of phosphoinositides were behaviorally evaluated in the forced swim test. Results Diverse antidepressants significantly enhanced phosphoinositide synthesis. While α-methylserotonin increased inositol phosphate accumulation, this effect was significantly accentuated in hippocampal or cortical tissues pre-incubated in the presence of imipramine, desipramine, fluoxetine, paroxetine, or maprotiline. Drug-induced behavioral antidepressant effects were reversed by neomycin pretreatment, whereas neomycin alone did not alter basal immobility times. Conclusions Antidepressants probably exert tandem neurochemical effects by increasing synaptic monoamine concentrations and by producing phosphoinositides used in 5HT₂ receptor signaling. This combination of actions may constitute the mechanism of at least the acute behavioral effects of the drugs and could implicate aberrant neurolipid signaling in the pathophysiology of depression.     

Influence of 6-hydroxydopamine on the behavioral effects induced by apomorphine or clonidine in rats

The aim of this paper is to examine if central chemical sympathectomy induced by two injections of 6-hydroxydopamine (6-OHDA) in a dose of 250 g intracerebroventricularly (k.c.v.) affects behavioral phenomena elicited by apomorphine (AP) (1 or 1.2 mg/kg i.p.) or clonidine (CL) (0.1 mg/kg, 5 or 1 g/kg i.p.).Experiments were carried out on male Wistar rats. The time of duration of several components of behavior and the degree of irritability of rats were measured. Moreover, open field and hole test were performed. The lower dose of AP did not affected behavior of rats. The higher dose increased the locomotor and exploratory activity of animals. 6-OHDA potentiated these effects of AP. CL (0.1 mg/kg) had a depressive effect on the rats' behavior, which was potentiated by 6-OHDA. CL (5 g/kg) had no effect on the rats' behavior, but in a dose of 1 g/kg caused excitatory behavior. This type of behavior was abolished by 6-OHDA. In conclusion, central chemical sympathectomy caused increased sensitivity of the central nervous system on AP. Excitatory behavioral effects of CL in low dosage may be connected with stimulation of central adrenergic receptors. Depressive behavioral effect of CL in high dosage is unspecific. Central chemical sympathectomy affects by different methods the reactivity of dopaminergic and noradrenergic neurons.