Naloxone attenuation of the effect of cocaine on rewarding brain stimulation

Antagonism of the threshold lowering effect of cocaine for brain stimulation reward by naloxone was investigated. Rats with bipolar electrodes implanted in either the median forebrain bundle (MFB) or the ventral tegmental area (VTA) were trained on a rate-independent threshold procedure. Effective threshold lowering doses of cocaine (10-15 mg/kg i.p.) were determined for each subject. A moderate dose of naloxone (4 mg/kg i.p.) effectively blocked the threshold lowering action of the cocaine. Lower (2 mg/kg) and higher (8 mg/kg) doses of naloxone attenuated but did not completely block the cocaine effect. These results provide further evidence for a catecholamine/endogenous opioid interaction in central reward.     

L-Histidine is a beneficial adjuvant for antiepileptic drugs against maximal electroshock-induced seizures in mice

Summary. Endogenous histamine has been reported to be involved in regulation of seizure susceptibility. Enhancement of histamine neurotransmission engendered by L-histidine treatment produces anticonvulsant effects in experimental animals. The present study investigated the influence of L-histidine on the protective effects of carbamazepine and phenytoin against maximal electroshock-induced seizures in mice.L-Histidine, administered at the doses that did not influence the threshold for electroconvulsions (250–500mg/kg), enhanced by nearly 30% the protective effects of carbamazepine against maximal electroshock-induced seizures. D-Histidine (1000mg/kg), an inactive isomer of histidine, was without any effect in this regard. L-Histidine (500mg/kg) also augmented the protective effects of phenytoin. Importantly, the enhancement of the anticonvulsant effects of these antiepileptic drugs produced by L-histidine co-administration was not associated with augmentation of their unwanted effects on memory and motor performance. A pharmacokinetic interaction was also excluded since the free plasma levels of these antiepileptics remained unchanged in the presence of L-histidine. It may be suggested that L-histidine could serve as a beneficial adjuvant for selected antiepileptic drugs.Present address: Integrative Neuroscience Section, Behavioral Neuroscience Branch, NIDA/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, U.S.A.     

Effects of antianxiety and antipsychotic drugs on DRL responding for brain stimulation

Satiated rats could be trained to give stable rates of responding for rewarding stimulation of the lateral hypothalamus delivered on differential reinforcement of low rate (DRL) schedule requiring 2 to 8 sec interresponse intervals for reinforcement (DRL-2 to 8). The performance on a DRL-8 schedule was tested 30 min after the oral administration of benzodiazepines. Diazepam (5 and 10 mg/kg) and meprobamate (200 mg/kg) caused significant increases in response rates during the first 5 min of a session, but not thereafter. Bromazepam (1 and 5 mg/kg) also caused a significant increase in the rates during the first and second 5 min. On the other hand, chlorpromazine (20 mg/kg) caused no effect in the first 5 min but decrease in second and third 5 min. These results indicate that DRL schedules with a brain stimulation reward provided a useful tool for evaluation of antianxiety drugs. The advantage of the brain stimulation reward over food reward is that the possible effects of the drugs on hunger motivation need not be considered.     

Brain histamine and histamine H3 receptors following repeated L-histidine administration in rats

In order to assess the importance of the chronic increase in precursor availability on central histaminergic mechanisms in rats, nine male Wistar rats received L-histidine orally at a dose of 1000 mg/kg, twice daily (07.00 h and 19.00 h) for 1 week; 9 rats were used as controls. Brain tissue histamine and tele-methylhistamine levels, as well as plasma histamine concentration were assayed. Binding properties and regional distribution of the autoregulatory histamine H3 receptors in brain were studied with [3H]-R-alpha-methylhistamine receptor binding and autoradiography. In L-histidine loaded rats, tissue histamine levels in cortex, hypothalamus, and rest of the brain were significantly increased by 40%-70%. Histamine concentrations in cerebellum and plasma, and tele-methylhistamine concentrations in cortex and hypothalamus did not change. The binding properties of H3 receptors in cortex were not altered. However, there were changes in the regional distribution of [3H]-R-alpha-methylhistamine binding sites, suggestive of a region-selective up-/down-regulation of histamine H3 receptors or their receptor sub-types. These results imply that following repeated L-histidine administration in the rat (1) there is enhanced synthesis of brain histamine not reflected in its functional release; (2) the excess of histamine is sequestered and stored rather than being metabolized; (3) histamine H(3) receptor binding properties are not altered, whereas receptor density is changed in selected regions. In conclusion, these results demonstrate that the neuronal mechanisms controlling histamine synthesis, storage, and release are adaptable and allow the sequestration of the excess of histamine in order to prevent excessively high neuronal activity.     

Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.     

Evidence for a supraspinal analgesic effect with cyclazocine and pentazocine

The antinociceptive effect of the benzomorphan class of opioid analgesics have been difficult to measure utilizing some of the standard animal pain models. This may be due, in part, to the sedative and/or motor effects associated with these drugs. In addition, it has been proposed that the major site of action for drugs with agonist activity at the kappa opiate receptor is exclusively at the spinal level opposed to both spinal and supraspinal as with the mu receptor agonists such as morphine. The present study examines the antinociceptive effect of the mixed agonist-antagonists cyclazocine and pentazocine utilizing electrical stimulation of the midbrain reticular formation (MRF) as the aversive stimulus in the rat. Animals were trained to escape MRF stimulation by turning a cylindrical manipulandum. An escape threshold was determined by varying the current intensity according to a modification of the psychophysical method of limits. In addition to the determination of the escape threshold the response latency and strength of response was also measured. Both cyclazocine (0.25-1.0 mg/kg) and pentazocine (2.5-12.5 mg/kg) raised the escape threshold in a dose-dependent manner without any concomitant change in the response latency or strength of response. These data suggest that the observed threshold elevation is due to a specific antinociceptive effect. Since the aversive stimulation was delivered supraspinally, the data also suggest that there are supraspinal mechanisms mediated by kappa receptors responsible for this analgesic effect.     

Ceruletide increases threshold and tolerance to experimentally induced pain in healthy man

Previous studies suggested that ceruletide might be endowed with analgesic and sedative properties. To investigate the effects of ceruletide on experimentally induced pain and on central nervous functions, two studies, each involving 24 healthy subjects, were carried out in random double-blind fashion. Every subject participated in three experiments one week apart. In study 1, 120 and 60 ng/kg/hr ceruletide IV increased threshold and tolerance to electrically and threshold to thermally induced cutaneous pain significantly more than saline (p<0.001), the higher dose being slightly more active. Only mild sedative effects occurred. Study 2 compared the effects of 60 and 6 ng/kg/hr ceruletide IV to those of 0.4 mg/kg/hr pentazocine IV and investigated whether these effects were naloxone reversible. Both ceruletide doses, 60 ng/kg/hr slightly more than 6 ng/kg/hr, elevated threshold and tolerance to electrically induced and threshold to thermally induced pain markedly, pentazocine acted stronger and longer than ceruletide (p<0.001). Naloxone reversed the effects of pentazocine but not of ceruletide. Conclusion: ceruletide (1) exerts potent naloxone resistant analgesic effects, which, however, are inferior to those of pentazocine, and (2) produces only mild sedation.     

Dynamics of the regulation of histamine levels in mouse brain

Abstract— The intraperitoneal administration of L-histidine in a dose of 1000 mg/kg increased threefold the whole brain levels of histamine in the mouse. This increase was evident in all brain regions except the medulla oblongata-pons. The subcellular localization of histamine and histidine was the same in mice administered bhistidine as in salinetreated animals. Cold exposure and restraint further augmented the elevation of histamine elicited by histidine treatment. a-Hydrazino-histidine and 4-bromo-3-hydroxybenzyloxyamine (NSD-1055) but not a-methyl-DOPA inhibited histidine decarboxylase [EC 4.1.1.221 activity in mouse brain homogenates and prevented the increase in brain histamine after histidine administration. NSD-1055 and a-hydrazino-histidine also lowered brain levels of histamine by 50 per cent. NSD-1055 lowered whole brain levels of histamine rapidly, with a half-life for the depletable histamine pool of about 5 min. Assuming that inhibition of histidine decarboxylase accounted for the reduction in histamine, then the rate of histamine decline reflects the rate of histamine turnover, and our results suggest that a portion of mouse brain histamine turns over quite rapidly. Reserpine lowered brain levels of histamine by about 50 per cent, whereas the antihistaminic agent, dexbrompheniramine, and sodium pentobarbital elevated histamine levels.     

pros-Methylimidazoleacetic Acid in Rat Brain: Its Regional Distribution and Relationship to Metabolic Pathways of Histamine

pros-Methylimidazoleacetic acid (p-MIAA; 1-methylimidazole-5-acetic acid), an isomer of the histamine metabolite, tele-methylimidazoleacetic acid (t-MIAA), is present in brain and CSF. Its relationship to histamine synthesis and catabolism was assessed in brains of rats. p-MIAA distribution in brain regions was heterogeneous although the concentrations in regions with the highest (hypothalamus) and the lowest (medulla-pons) levels differed less than four-fold. There was no significant correlation between the regional distributions of p-MIAA with those of histamine or its metabolites. pros-Methylhistidine (1 g/kg, i.p.) produced a 20-fold increase in mean levels of p-MIAA and up to a 50-fold increase in levels of pros-methylhistamine (p-MH), a putative intermediate; levels of histamine and its metabolites were unaltered. L-Histidine (1 g/kg, i.p.) or alpha-fluoromethylhistidine (100 mg/kg, i.p.), the irreversible inhibitor of histamine synthesis, did not alter the levels of p-MIAA in brain. Like the levels of t-MIAA, the levels of p-MIAA were unaltered after probenecid administration. Contrary to its effects in lowering t-MIAA levels, pargyline (75 mg/kg, i.p.) produced a slight rise in levels of p-MIAA in all regions. These findings suggest that, in brain, the metabolic pathways of histamine are independent of pathways that generate p-MIAA. Further, since brain is capable of p-MH formation, its use as an internal standard in analytical methods merits caution.     

Brain histamine-plasma corticosterone interactions

Significant elevation in plasma corticosterone of rats achieved by intraperitoneal (i.p.) administration of corticosterone (2.4 mg/kg) was associated with a rapid (2.5 min) and significant increase in hypothalamic histamine (HA) levels which persisted for 60 min. Midbrain and cortical HA concentrations were not affected. Significant and prolonged elevation of hypothalamic, midbrain and cortical HA levels was achieved by L-histidine administration (500 mg/kg i.p.). The most significant increase was noted in the hypothalamus and persisted for 10 hours. The elevated brain HA levels were associated with significant increase in plasma corticosterone levels which lasted for 120 mins. Present data supports the involvement of central HA in endocrine function.     

Influence of renin on the effects of electric stimulation on the ventromedial hypothalamus

The influence of intraventricular injection of different doses of renin on the effects of electrical stimulation of the ventromedial hypothalamus was studied. Injection of renin (10 micrograms/kg) into the lateral ventricles of the brain of experimental animals elicited a prolonged elevation of arterial pressure and a decrease of the heart rate, while given in doses of 20 and 30 micrograms/kg it also provoked arrhythmias and ventricular extrasystoles, and a lowering of the threshold of ventromedial hypothalamus stimulation. It was found that under the central action of renin, a short-term stimulation of the ventromedial hypothalamus provoked ventricular extrasystoles.     

Possible analgesic and anti-inflammatory interactions of aspartame with opioids and NSAIDs

The purpose of the present study was to investigate analgesic and anti-inflammatory properties of aspartame, an artificial sweetner and its combination with various opioids and NSAIDs for a possible synergistic response. The oral administration of aspartame (2-16mg/kg, po) significantly increased the pain threshold against acetic acid-induced writhes in mice. Co-administration of aspartame (2mg/kg, po) with nimesulide (2 mg/kg, po) and naproxen (5 mg/kg, po) significantly reduced acetic acid-induced writhes as compared to effects per se of individual drugs. Similarly when morphine (1 mg/kg, po) or pentazocine (1 mg/kg, po) was co-administered with aspartame it reduced the number of writhes as compared to their effects per se. Aspartame (4,8,16 mg/kg, po) significantly decreased carrageenan-induced increase in paw volume and also reversed the hyperalgesic effects in rats in combination with nimesulide (2 mg/kg, po).The study indicated that aspartame exerted analgesic and anti-inflammatory effects on its own and have a synergistic analgesic response with conventional analgesics of opioid and non-opioid type, respectively.     

Regulation of Histamine Turnover via Muscarinic and Nicotinic Receptors in the Brain

To clarify the regulation of central histaminergic (HAergic) activity by cholinergic receptors, the effects of drugs that stimulate the cholinergic system on brain histamine (HA) turnover were examined, in vivo, in mice and rats. The HA turnover was estimated from the accumulation of tele-methylhistamine (t-MH) during the 90-min period after administration of pargyline (65 mg/kg, i.p.). In the whole brain of mice, oxotremorine, at doses higher than 0.05 mg/kg, s.c., significantly inhibited the HA turnover, this effect being completely antagonized by atropine but not by methylatropine. A large dose of nicotine (10 mg/kg, s.c.) also significantly inhibited the HA turnover. This inhibitory effect was antagonized by mecamylamine but not by atropine or hexamethonium. A cholinesterase inhibitor, physostigmine, at doses higher than 0.1 mg/kg, s.c., significantly inhibited the HA turnover. This effect was antagonized by atropine but not at all by mecamylamine. None of these cholinergic antagonists used affected the steady-state t-MH level or HA turnover by themselves. In the rat brain, physostigmine (0.1 and 0.3 mg/kg, s.c.) also decreased the HA turnover. This inhibitory effect of physostigmine was especially marked in the striatum and cerebral cortex where muscarinic receptors are present in high density. Oxotremorine (0.2 mg/kg, s.c.) and nicotine (1 mg/kg, s.c.) also decreased the HA turnover in the rat brain. However, these effects showed no marked regional differences. These results suggest that the stimulation of central muscarinic receptors potently inhibits the HAergic activity in the brain and that strong stimulation of central nicotinic receptors can also induce a similar effect.     

Effects of (S)-alpha -fluoromethylhistidine and metoprine on locomotor activity and brain histamine content in mice.

We examined the effects of (S)-alpha -fluoromethylhistidine (FMH), an inhibitor of histidine decarboxylase, and metoprine, an inhibitor of histamine N-methyltransferase, on the locomotor activity and the brain histamine content of ICR mice. The brain histamine content was decreased by FMH (12.5 or 50 mg/kg, i.p.) and increased by metoprine (4 mg/kg, i.p.). Under these conditions, the locomotor activity and the number of rearing were significantly decreased and increased by FMH and metoprine, respectively. The higher the brain histamine content, the greater the locomotor activity and vice versa. In a previous paper [Sakai et al., Life Sciences, 48, 2397-2404 (1991)], we showed that thioperamide, a histamine H3 antagonist, which enhances the release of histamine from histaminergic neurons, in doses of 12.5 and 25 mg/kg, i.p. increases the locomotor activity, whereas it decreases the brain histamine content. Taken together, these results support the hypothesis that central histaminergic neurons may be involved in the control of state of locomotion and rearing.     

The effects of morphine and various narcotic antagonist type analgesics on body temperature in rats

ED50s were determined for morphine, nalorphine, butorphanol and pentazocine induced hyperthermia in rats. Morphine produced a significant hyperthermia with the doses of 5–160 mg.kg in rats. The peak hyperthermic effect was found 1 hr after 5–20 mg/kg doses of morphine. Nalorphine, butorphanol and pentazocine produced biphasic effects on rectal temperature. Initially they produced a dose-dependent hyperthermia and later hypothermia. In a comparison of the hyperthermic ED50's of morphine, nalorphine, butorphanol and pentazocine it was found that butorphanol is more active than the others (ED50s were 4.7, 4.3, 0.54 and 11.5 mg/kg respectively). The narcotic antagonist naloxone significantly inhibited both morphine and antagonist type analgesic induced hyperthermia. These results suggests that a different mechanism(s) is involved in the hyperthermic actions of antagonist type analgesics and agonist drugs.     

Effect of Cocaine on the Histaminergic Neuron System in the Rat Brain

Abstract: To examine the effect of cocaine on the brain histamine neuron system, histamine levels and histamine N -methyl-transferase activity in the rat brain were measured after the administration of cocaine. Moreover, we examined the effect of l -histidine on cocaine-induced wheel-running behavior. The administration of cocaine (20 mg/kg) increased histamine levels and histamine N -methyltransferase activity in the striatum, nucleus accumbens, and amygdala 1 h later. The pretreatment with l -histidine (350 and 700 mg/kg) inhibited the cocaine (20 mg/kg)-induced increase of wheel-running activity in a dose-dependent manner. These findings suggest that cocaine activates the brain histamine neuron system, which may play the role of inhibiting the cocaine-induced wheel-running behavior.     

Histamine and histamine receptors: behavioral thermoregulation in the salamander Necturus maculosus

Low doses (0.01, 0.1 mg/kg, i.p.) of histamine (HA) caused selection of significantly lower temperatures, and higher doses (0.5, 1.0 mg/kg) increased temperatures by mudpuppies in linear thermal gradients. Injection of the HA precursor, L-histidine (500 mg/kg) produced an increase in the temperatures selected. Results from injections of HA H1-receptor agonist (2-pyridylethylamine) and antagonist (pyrilamine), and H2-receptor agonist (dimaprit) and antagonist (cimetidine) had significant effects on thermoregulation; H1-receptors may mediate behavioral hyperthermia and H2-receptors behavioral hypothermia. Responses to these histaminic compounds are significantly influenced by the time of day at which the responses are measured and by season and acclimation temperature. The equivalent behavioral responses in both endotherms and ectotherms to agents which produce physiological hyperthermia and hypothermia are probably behavioral hypothermia ("cold seeking") and behavioral hyperthermia ("heat seeking"), respectively.     

Study of the in-vivo antioestrogenic action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), a novel intracellular histamine antagonist and antioestrogen binding site ligand

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE) binds with high affinity to the antioestrogen binding site (AEBS), but not to the oestrogen receptor. There is an association of AEBS with a novel intracellular histamine receptor (H1C) of micromolar affinity through which histamine acts as a second messenger. An optimal dose of 4 mg DPPE/kg antagonized the uterine growth-stimulating effects of oestradiol in immature oophorectomized rats. Unlike tamoxifen, DPPE alone was not a partial agonist, but decreased uterine size and weight below control values at concentrations between 0.1 and 75 mg/kg. DPPE also antagonized oestradiol-stimulated uterine growth at 72 h; the inhibition observed was not significantly different from that seen with tamoxifen. Oestradiol-treated animals receiving the combination of DPPE (4 mg/kg) + low dose tamoxifen (0.04 mg/kg) for 72 h had significantly smaller uteri than did those receiving the same dose of DPPE or tamoxifen alone. Histologically, either DPPE or tamoxifen antagonized oestradiol stimulation of eosinophil migration and glandular epithelial proliferation; the latter inhibition was significantly greater for DPPE + tamoxifen (0.04 mg/kg) than for the same dose of DPPE or tamoxifen alone. Unlike tamoxifen, DPPE did not antagonize oestradiol stimulation of luminal epithelial proliferation, but in the presence of oestradiol, DPPE significantly decreased tamoxifen (0.65 mg/kg)-induced hypertrophy of the luminal epithelium. Based on these findings, we suggest that binding to the AEBS/intracellular histamine receptor is important to the action of antioestrogens.     

Lack of a Precursor-Product Relationship Between Histamine and Its Metabolites in Brain After Histidine Loading

Abstract: Levels of histamine and its major metabolites in brain, tele -methylhistamine (t-MH) and tele -methylimidazoleacetic acid (t-MIAA), were measured in rat brains up to 12 h after intraperitoneal administration of l -histidine (His), the precursor of histamine. Compared with saline-treated controls, mean levels of histamine were elevated at 1 h (+ 102%) after a 500 mg/kg dose; levels of t-MH did not increase. Following a 1,000 mg/kg dose; levels mean histamine levels were increased for up to 7 h, peaked at 3 h, and returned to control levels within 12 h. In contrast, levels of t-MH showed a small increase only after 3 h; levels of t-MIAA remained unchanged after either dose. Failure of most newly formed histamine to undergo methylation, its major route of metabolism in brain, suggested that histamine was metabolized by another mechanism possibly following nonspecific decarboxylation. To test this hypothesis, other rats were injected with α-fluoromethylhistidine (α-FMHis; 75 mg/kg, i.p.), an irreversible inhibitor of specific histidine decarboxylase. Six hours after rats received α-FMHis, the mean brain histamine level was reduced 30% compared with saline-treated controls. Rats given His (1,000 mg/kg) 3 h after α-FMHis (75 mg/kg) and examined 3 h later had a higher (+112%) mean level of histamine than rats given α-FMHis, followed by saline. Levels of t-MH and t-MIAA did not increase. These results imply that high doses of His distort the simple precursor-product relationship between histamine and its methylated metabolites in brain. The possibility that some His may undergo nonspecific decarboxylation in brain after His loading is discussed. These findings, and other actions of His independent of histamine, raise questions about the validity of using His loading as a specific probe of brain histaminergic function.     

Effects of the Histamine H3-Agonist (R)-α-Methylhistamine and the Antagonist Thioperamide on Histamine Metabolism in the Mouse and Rat Brain

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.