An endogenous neuroprotectant substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), prevents the behavioral and neurochemical effects of cocaine reinstatement in drug-dependent rats.

Drug abuse disorder is induced by a variety of substances and results from their interaction with the brain reward system. It is characterized by a high frequency of relapse, usually associated with to craving. In this study we investigated the effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound with antidopaminergic and neuroprotective activity, on cocaine-induced reinstatement in cocaine-dependent, self-administering rats. 1-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg/kg i.p.) completely inhibited the expression of reinstatement of cocaine self-administration and accompanying neurochemical changes induced by a single priming cocaine dose (10 mg/kg i.p.). The priming cocaine dose inhibited dopamine metabolism in the structures containing nerve endings (frontal cortex, nucleus accumbens, and striatum) but not in the substantia nigra and ventral tegmental area. A behaviorally active dose of 1-methyl-1,2,3,4-tetrahydroisoquinoline administered 30 min before a priming dose of cocaine significantly increased the dopamine concentration in the limbic structures, and strongly inhibited dopamine metabolism in the substantia nigra and ventral tegmental area. Cocaine also inhibited noradrenaline and serotonin metabolism, and 1-methyl-1,2,3,4-tetrahydroisoquinoline abolished the inhibition in noradrenaline metabolism, while it intensified the inhibition of serotonin metabolism. Our results strongly support the view that 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound, has considerable potential as a drug for combating substance abuse disease through the attenuation of craving.

Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties.

The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine-stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA, (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)-dependent catabolic pathway and significantly activated the catechol-O-methyltransferase (COMT)-dependent O-methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.

Conditions of application of repeated transcranial magnetic stimulation to rats may mask the effects of the treatment.

Rats of sham repeated transcranial magnetic stimulation (rTMS) group, kept in noisy room and transiently immobilized (5 min) for 12 consecutive days, showed similar inhibition of body weight gain, increase in exploratory locomotor activity, and elevation of motor response to apomorphine as rats undergoing magnetic stimulation of the brain, and had only slightly lower response in apomorphine stereotypy. Some of the responses ascribed to antidepressant action of rTMS in animal experiment may be due to environmental conditions, and not alternating magnetic field passing the brain.

Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol.

Immediate behavioral and biochemical effects of single doses of 1,2,3,4-tetrahydroisoquinoline (TIQ, 50 mg/kg) and salsolinol (100 mg/kg), suspected of involvement in etiology of Parkinson's disease, were investigated. Apomorphine (0.25 mg/kg) or haloperidol (1 mg/kg) were administered to TIQ or salsolinol pretreated Wistar rats. In additional experiment the displacement of [3H]apomorphine by TIQ, salsolinol and dopamine receptor agonists and antagonists was tested. Both tetrahydroisoquinolines only slightly affected behavior and dopamine metabolism in naive rats, but very effectively abolished the behavioral and biochemical effects of apomorphine (hyperactivity, depression of striatal HVA level). The behavioral and biochemical effects of haloperidol were unchanged by administration of TIQ nor salsolinol. The tetrahydroisoquinolines displaced [3H]apomorphine from its binding sites with effectiveness comparable to that of dopamine. The results support the hypothesis that endogenous tetrahydroisoquinolines may play an important role in regulation of dopaminergic activity in non-senescent organisms.

Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain.

The finding that endogenous tetrahydroisoquinolines may be involved in the etiology of Parkinson's disease suggests that their administration may cause changes resembling those observed in parkinsonian brain. We tested, using a high-performance liquid chromatography method, how single and chronic administration of 1,2, 3,4-tetrahydroisoquinoline and salsolinol affects dopamine and serotonin metabolism in the neurons of extrapyramidal and mesolimbic dopaminergic systems. We report that chronic administration of tetrahydroisoquinoline and salsolinol causes a decrease in a dopamine metabolism: the effect of tetrahydroisoquinoline was limited to the striatum, while salsolinol caused also a dramatic decline of dopamine level in the substantia nigra. The effect of both compounds on serotonin metabolism was small or absent. The tetrahydroisoquinolines produced no changes in the nucleus accumbens. The results indicate that tetrahydroisoquinoline and salsolinol specifically affect the nigrostriatal dopamine system, but only when administered chronically, and thus are compatible with the view that endogenous tetrahydroisoquinolines may participate in pathogenesis of Parkinson's disease.

Effects of various Ca2+ channel antagonists on morphine analgesia, tolerance and dependence, and on blood pressure in the rat.

Following the finding that nifedipine enhances morphine analgesia and prevents the development of dependence, we have now compared the effect of nifedipine with these of other L-type Ca2+ channel antagonists, nimodipine (a dihydropyridine) and verapamil (a phenylethylalkylamine). Male Wistar rats received the antagonist 20 min before each injection of morphine. Analgesia was measured in a hot-plate test, and the development of dependence was assessed in the naloxone precipitation test after 13 days of morphine (20-30 mg/kg i.p.) administration. L-type Ca2+ channels were assayed in the cerebral cortex as [3H]nitrendipine binding sites. Blood pressure was monitored from the tail by a non-invasive method. We found that all three Ca2+ antagonists enhanced the analgesia, and prevented development of the naloxone-precipitated withdrawal syndrome, although they differed in their efficacy. Nifedipine and verapamil effectively blocked the development of tolerance. While chronic morphine up-regulated L-type Ca2+ channels, co-administration of the antagonists completely prevented this effect. The effects of Ca2+ channel antagonists cannot be ascribed to their potential circulatory effects as, at the dose used, none affected significantly the arterial blood pressure.

Different effects of chronic administration of haloperidol and pimozide on dopamine metabolism in the rat brain.

We investigated the differences between the action of haloperidol and pimozide on dopamine metabolism and on catalepsy in periods up to 6 weeks after cessation of chronic administration of the neuroleptics to male Wistar rats. Dopamine and its metabolites (dihydroxyphenylacetic and homovanillic acids) were measured, using high-performance liquid chromatography (HPLC), in the frontal cortex, nucleus accumbens, and striatum. Both neuroleptics produced similar effects after a single dose: catalepsy and an increase of dopamine metabolism in the brain structures. However, haloperidol and pimozide differed after chronic treatment. In haloperidol-treated rats hypersensitivity of the dopaminergic system developed at the end of 2 weeks' administration, as evidenced by depression of dopamine metabolism. The biochemical changes were accompanied by behavioral hyperactivity that lasted up to 3 weeks. Dopamine metabolism in rats treated with pimozide was normal from 24 h after the end of the treatment, while catalepsy was maintained at the high level for up to 8 days and was observable up to 3 weeks after the last dose. Our results suggest that in contrast to haloperidol, pimozide is not able to produce adaptive changes leading to supersensitivity of the dopaminergic system. This may be the consequence of its potent Ca2+ channel blocking action.

Differences between haloperidol- and pimozide-induced withdrawal syndrome: a role for Ca2+ channels.

We investigated the behavioral and biochemical events appearing in rats after withdrawal for 24 h or 8-12 days from two classical neuroleptics, haloperidol and pimozide. The neuroleptics were given for 14 days alone or shortly after injection of the Ca2+ channel blocker nifedipine. We have found that withdrawal effects after haloperidol and pimozide were different. After haloperidol treatment we observed an increase in cortical Ca2+ channel and limbic dopamine D1 receptor density and an increase in spontaneous motor activity and apomorphine-induced hyperactivity and stereotypy. In contrast no biochemical changes were observed during pimozide withdrawal, and locomotor activity and responses to apomorphine were depressed. Co-administration of nifedipine with haloperidol prevented the observed biochemical and behavioral symptoms of withdrawal. Nifedipine administration did not change the depressant effects of pimozide. Our results suggest that the voltage-dependent Ca2+ channel is involved in the observed withdrawal syndrome of neuroleptics, and that the absence of this syndrome after pimozide may be related to its considerable Ca2+ channel-blocking properties.

Modification of effects of chronic electroconvulsive shock by voltage-dependent Ca2+ channel blockade with nifedipine.

A single electroconvulsive shock produced analgesia (expressed as prolongation of hot-plate latency) in Wistar rats 45 min after the shock. The analgesic action was prevented by administration of nifedipine, 5 mg/kg i.p., 15 min before the electroconvulsive shock, while nifedipine injection after electroconvulsive shock did not affect the analgesia significantly. At the same time single electroconvulsive shock counteracted the reduction of [3H]nitrendipine binding to cortical and hippocampal membranes from rats pretreated with nifedipine. Chronic administration of electroconvulsive shock (once daily for 8 days) produced hyperalgesia, augmented locomotor responses to low doses of apomorphine and upregulation of cortical (but not hippocampal) voltage-dependent Ca2+ channels (assessed from [3H]nitrendipine binding). In rats receiving electroconvulsive shock chronically, always 15 min after nifedipine injection, neither behavioral hyperresponsiveness nor Ca2+ channel upregulation was observed. The results suggest that the primary event in post-electroconvulsive shock analgesia depends on Ca2+ influx into neurons through voltage-dependent Ca2+ channels, and that given under conditions of Ca2+ channel blockade electroconvulsive shock is unable to trigger changes leading to Ca2+ channel upregulation, and this is possibly the reason for prevention of development of hyperalgesia and increased responsiveness to dopaminergic stimulation.

Differential involvement of voltage-dependent calcium channels in apomorphine-induced hypermotility and stereotypy.

The involvement of the voltage-dependent calcium channel in behavioral effects of apomorphine was tested in naive rats and in animals which were morphine-abstinent or were subjected to chronic electroconvulsive treatment (ECS). In naive rats a calcium channel blocker, nifedipine, which by itself does not affect locomotor activity, inhibited the locomotor stimulation induced by apomorphine, while it facilitated stereotyped behavior. Morphine-abstinent and ECS-treated rats displayed elevated responsiveness to apomorphine, reflected by hypermotility and stereotyped behavior after a dose of 1 mg/kg IP that does not produce overt behavioral effects in naive animals. Nifedipine, 5 mg/kg IP, significantly reduced hypermotility produced by apomorphine in morphine abstinent or ECS-treated rats. The calcium channel blocker did not, however, antagonize enhanced stereotyped behavior. The results indicate that apomorphine hypermotility is controlled by dihydropyridine calcium channels and that enhancement of calcium channel density produced by morphine abstinence and by chronic ECS potentiates the hypermotility response. Calcium channels seem to be differently involved in control of apomorphine-induced hypermotility and stereotypy.

The effect of calcium channel blockade during electroconvulsive treatment on cerebral cortical adrenoceptor subpopulations in the rat.

Chronic administration of nifedipine (5 mg/kg/day for 10 days) induced some biochemical effects consistent with those of antidepressants: a significant depression in cortical alpha 2-adrenoceptor density and reduction of beta-adrenoceptor affinity; nifedipine co-administration with electroconvulsive treatment potentiated the beta-downregulatory effect of the latter.

Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine.

Nifedipine, 5 mg/kg IP, potentiated the morphine-induced analgesia measured in the hot-plate, but not in the tail-flick test. Further experiments were carried out using the hot-plate test only. Pretreatment with nifedipine partially restores the analgesic action of morphine in morphine-tolerant rats. Co-administration of nifedipine with morphine in a chronic experiment did not prevent the loss of morphine efficiency (an increase in latency of 44% was not significant) and did not prevent the debilitating effect of chronic morphine administration reflected by an inhibition of the body weight gain, but prevented naloxone-induced withdrawal syndrome (quantified by counting head shakes) in the test carried out 24 h after the injection of nifedipine, when the drug did not affect morphine analgesia. Chronic treatment with either morphine or nifedipine did not produce a significant increase in the density of [3H] naloxone or [3H]prazosin binding sites in the cortex and in the rest of the brain (measured 24 h after the last dose), but the combined treatment resulted in a significant increase in the cortical [3H]prazosin binding site density. The present results suggest that opiate tolerance and physical dependence may be separated by co-administration of nifedipine and suggest that the combined chronic treatment with morphine and nifedipine may increase the efficacy of morphine during chronic treatment and prevent development of abstinence.

Opiate and alpha 1-adrenergic receptors in mice responding to morphine with sedation or with running fit.

Two subpopulations of Albino Swiss mice were selected on the basis of their response to a dose of 20 mg/kg ip of morphine: individuals in which the drug constantly produced sedation, and those which responded with running fit. Both subpopulations of mice had cerebral opiate delta and mu receptors (defined as [3H]DADLE and [3H]naloxone binding sites) of similar Bmax and KD values but mice responding with sedation showed lower density of alpha 1-adrenoceptors (defined as [3H]prazosin binding sites) as compared both with mice reacting with running fit or randomly selected animals. Chronic administration of imipramine resulted in a significant increase in the density of [3H]prazosin binding sites in the mice responding with sedation, but not in the animals responding with running fit.

Chronic electroconvulsive treatment counteracts cortical beta-adrenoceptor upregulation induced by morphine abstinence.

Morphine treatment (20 mg/kg for 7 consecutive days) did not affect the density of [3H]dihydroalprenolol ([3H]DHA) binding sites in the cortical membranes of the rat, but during naloxone-precipitated abstinence syndrome the density of these sites increased. Electroconvulsive treatment for 6 days, which by itself decreased the density of [3H]DHA binding sites, prevented the increase.

Role of calcium channels in effects of antidepressant drugs on responsiveness to pain.

The effect of acute and chronic treatment with three antidepressant drugs on the cortical L-type calcium channel (measured as [3H]nitrendipine binding sites) and on the responsiveness to pain (assessed in the hot-plate test) was tested on the Wistar rat. Acute administration of antidepressants did not affect the characteristics of calcium channels and did not significantly prolong the hot-plate latency. However, a combination of antidepressants with nifedipine brought about analgesia. Chronic administration of imipramine did not significantly affect the characteristics of calcium channels but produced a moderate analgesic effect. In contrast, chronic administration of citalopram and chlorprothixene increased the density of [3H]nitrendipine binding sites and induced hyperalgesia, which was nullified by acute administration of nifedipine. The results confirm that calcium channels may be involved in analgesia and hyperalgesia and indicate that chronic treatment with some antidepressant may induce an increase in the density of cortical calcium channels.

Cortical dihydropyridine binding sites and a behavioral syndrome in morphine-abstinent rats.

The density of cortical [3H]nitrendipine binding sites was elevated by over 40% in rats rendered morphine-abstinent by administration of naloxone after chronic treatment with morphine. The morphine-abstinent rats had significantly shortened response latencies in the hot-plate test. Nifedipine treatment abolished the signs of abstinence and normalized the hot-plate latencies in morphine-dependent, naloxone-treated rats. The results indicate that the symptoms of abstinence are related to a functional state of cortical dihydropyridine-sensitive calcium channels.

Effect of repetitive electroconvulsive treatment on sensitivity to pain and on [3H]nitrendipine binding sites in cortical and hippocampal membranes.

The effect of electroconvulsive shock (ECS) on the responsiveness to pain (measured by the hot-plate test) and on the characteristics of L-type calcium channels (measured as [3H]nitrendipine binding sites) in the cortex and hippocampus was tested on the Wistar rat. In animals receiving a single ECS, the calcium channel density and affinity 24 h after treatment did not differ from the controls; the response to pain was also at the control level. Repeated ECS (eight once-daily shocks) resulted in an increased responsiveness to pain (shortening of response latency) and in an increase in the density of cortical, but not hippocampal, calcium channels. The KD value for [3H]nitrendipine binding sites in either brain region remained unaltered by ECS. The calcium channel antagonist nifedipine, which by itself did not significantly alter the response to pain, prevented the enhancement of pain sensitivity brought about by ECS. The results suggest activation of calcium-dependent mechanisms by repeated ECS and confirm the involvement of calcium channels in pain mechanisms.

Stability and variability of locomotor responses of laboratory rodents. III. Effect of environmental factors and lack of catecholamine receptor correlates.

The exploratory locomotor activity of rats differs between groups, and the results suggest the involvement of a seasonal factor. The body weight and the state of satiety do not appear to influence the locomotor activity. The individual activities of rats are correlated in subsequent tests only if the period between the tests is not long. The foehn wind changes the locomotor activity in the second test, depending on the animals' experience. No correlation between the native locomotor activity and cortical and striatal binding sites for [3H]prazosin and [3H]spiroperidol was found.

The effect of morphine dependence and abstinence on opioid receptors in the cerebral cortex and spinal cord of the rat.

The characteristics of cerebral cortical and spinal cord opiate mu, delta and kappa receptors were investigated by measuring of the specific binding of [3H]naloxone, [3H]DADLE and [3H]bremazocine in drug-free rats and in rats rendered tolerant to morphine and in those in which morphine abstinence syndrome was precipitated with naloxone. The opiate receptors in the spinal cord were less dense than those in the cortex; the difference was most pronounced in the case of delta receptors. The characteristics of the investigated opioid receptors did not change in the state of tolerance or abstinence.

A comparison of locomotor responses to some psychotropic drugs and cerebral receptors in the Acomys cahirinus and the laboratory mouse.

Comparative studies of the laboratory mouse and Acomys cahirinus have shown differences in their motor activity patterns and motor responses to morphine, apomorphine and clonidine. The two species also differed in respect of the density of cerebral alpha 2-adrenergic receptors, but no significant differences between other types of receptors (alpha 1-adrenergic, beta-adrenergic, opiate mu and delta, and spiroperidol binding sites) were found. It is suggested that the high excitability of the Acomys may be related to a deficit in the inhibitory noradrenergic transmission in the central nervous system.