Electroencephalographic correlates of the sedative effects of dopamine agonists presumably acting on autoreceptors.

Alterations both in the activity of the cortical EEG and behaviour were studied after administration of dopamine receptor agonists. In addition to apomorphine, which provided contrasting effects, both on the EEG and behaviour, when small and large doses were compared, alterations elicited by the D2 agonist, quinpirole and another agonist, with preference for dopamine D2 autoreceptors, talipexole (B-HT 920), were evaluated by using telemetric EEG recordings in rats. Similarly to apomorphine, quinpirole produced opposite effects after small and large doses: a small dose (0.05 mg/kg) led to sedation and an increase of EEG power spectra in all of the bands, except beta 2, whereas a larger dose (0.5 mg/kg) elicited stereotypy and desynchronization of the EEG, with a characteristic increase of power in the alpha 1 band. The effects on the EEG and on behaviour, obtained with the small dose of quinpirole were very similar to those of a small dose of apomorphine (0.05 mg/kg) and a small dose of talipexole (0.02 mg/kg) but even the large dose of talipexole (0.5 mg/kg) produced similar effects: all of these treatments produced behavioural sedation and an increase of power in the EEG in all of the bands, except beta 2; such increases appeared most pronounced in the delta band. The present study provides further evidence that drugs, which are assumed to activate dopamine autoreceptors, are effective in inducing sedation. This sedation was accompanied by a characteristic pattern, observed in EEG power spectra analysis.

Effects of stimulation of dopamine D1 receptors on the cortical EEG in rats: different influences by a blockade of D2 receptors and by an activation of putative dopamine autoreceptors.

The effects of a stimulation of dopamine D1 receptors by using (+/-)SKF 38393 on the cortical EEG in rats which were chronically implanted with electrodes were studied. Administration of SKF 38393 (3 or 9 mg/kg, s.c.) produced alterations suggesting an arousal in the EEG: the power in all of the frequency bands decreased to a level of 70-80% of baseline activity, which effect was dose- and time-dependent. In behaviour, episodes of intensive grooming (face-washing) alternated with those of lack of spontaneous motility and occasionally chewing movements were noted. In contrast, apomorphine (0.5 mg/kg, s.c.) produced a selective increase in power in the alpha 1 band, accompanied by stereotyped sniffing and licking. The effects of SKF 38393 (9 mg/kg) were completely blocked by pretreatment with the selective antagonist at D1 dopamine receptors, SCH 23390 (0.2 mg/kg, i.p.). The application of haloperidol (0.1 mg/kg, i.p.), which is mainly a D2 blocker, failed to influence the alterations induced by SKF 38393 (9 kg/kg, s.c.). In a further experimental group, the effects produced by stimulation of D1 receptors (SKF 38393 9 mg/kg), followed by activation of putative dopamine autoreceptors by a small dose of apomorphine (0.05 mg.kg, s.c.) were studied: in this case, the effects of SKF 38393 were abolished and typical effects of small doses of apomorphine were manifest, such as hypokinesia and sedation, accompanied by large increases of power in all of the frequency bands, except beta 2. The results suggest that stimulation of D1 receptors produces some desynchronization in the EEG.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the substantia nigra in motility of the rat. Muscular rigidity, body asymmetry and catalepsy after injection of morphine into the nigra.

Unilateral injection of morphine (1.0, 2.5 or 5.0 micrograms/0.5 microliter) into the substantia nigra pars reticulata produced, in a dose-dependent way, tonic activity in the electromyogram (EMG) recorded from the ipsilateral gastrocnemius-soleus muscle of unanaesthetized rats. The effect produced by 5 micrograms of morphine was antagonized by co-administration of 5 micrograms of naloxone. Bilateral injection of morphine (5 micrograms each side) also produced a tonic activity in the EMG and catalepsy, but no asymmetry of posture. Unilateral injection of morphine (5 micrograms) into the substantia nigra pars compacta produced contralateral turning and/or stereotypy, but no tonic activity in the EMG. Naloxone (5 micrograms), when injected into the substantia nigra failed to produce any tonic activity in the EMG or any catalepsy. Larger doses of naloxone (10 or 20 micrograms) produced slight to moderate tonic activity in the EMG when injected into the pars reticulata. Injections of saline (0.5 microliter) into either the reticulata or compacta were ineffective. Bilateral lesions of the caudate nucleus with kainic acid (1 microgram each side) did not prevent the development either of the tonic activity in the EMG or of the catalepsy, which were both produced by unilateral injection of morphine (5 micrograms) into the pars reticulata. These results suggest that opioid mechanisms in the nigra might play a role in the regulation of posture and muscle tone and participate in the expression of motor functions controlled by the striatum (and probably also by the nucleus accumbens).

Motility, rigidity and turnover of dopamine in the striatum after administration of morphine to rats: a re-evaluation of their mechanisms.

Whether the delayed behavioural activation and the increase in dopamine (DA) turnover in the striatum reflect signs of rebound effects or of counter-regulatory processes directed against locomotor depression and/or muscular rigidity was studied in rats. Administration of a large dose of morphine (30 mg/kg i.p.) induced strong muscular rigidity, which was measured as tonic activity in the electromyogram (EMG). This effect was maximal after one hour and disappeared during the fourth hour. The locomotor activity, on the other hand, disappeared after 30 min and re-appeared during the fourth hour, followed by a locomotor stimulation with a maximum after 4.5 hr. Striatal lesions produced with kainic acid did not affect the complete locomotor depression (akinesia), except by slightly prolonging this effect, and did not influence the delayed locomotor stimulation. These lesions did not inhibit, but, on the contrary, enhanced the increase in striatal concentration of 3,4-dihydroxyphenylacetic acid (DOPAC). Injections of morphine (10 micrograms) into the substantia nigra led to an increase in the level of DOPAC in the ipsilateral, but not the contralateral striatum. These results, in conjunction with those of other authors, suggest that the increase in DA turnover in the striatum and the delayed locomotor stimulation ought to be regarded as actions of morphine on sites different from those mediating muscular rigidity.

The binding of 3H-digitoxigenin by guinea-pig atrial tissue.

1. The uptake and release of (3)H-digitoxigenin by electrically driven, guinea-pig isolated atria (frequency 180/min) has been determined for two different medium concentrations of the genin. Both concentrations-1 x 10(-7) and 5 x 10(-7) g/ml.-caused a pronounced increase in contractile force.2. The uptake of (3)H-digitoxigenin reached equilibrium after approximately 2 hr of incubation. At equilibrium, the tissue/medium radioactivity ratio reached a value of about 8 for both concentrations studied. After initial saturation of the atria with (3)H-digitoxigenin, approximately 60% of the accumulated genin was released on wash-out in genin-free Tyrode solution for 2 hr.3. After presaturation of the atria with equimolar concentrations of either digitoxigenin or digitoxin (both non-radioactive) the uptake of (3)H-digitoxigenin occurred more slowly. After 2 hr of incubation approximately 60-70% of the tissue bound digitoxigenin or digitoxin had exchanged against (3)H-digitoxigenin from the medium. Presaturation of the atria with ouabain in equimolar concentration did not significantly affect the uptake of (3)H-digitoxigenin.4. The release process of (3)H-digitoxigenin was not affected by the same concentration of non-radioactive digitoxigenin as used for the accumulation of the genin.5. The kinetic properties of (3)H-digitoxigenin, determined by means of isotope techniques, are very similar to those of (3)H-digitoxin. The discrepancy between kinetic and pharmacological behaviour is, however, much larger for digitoxigenin than for digitoxin. Obviously, the presence or absence of the sugar moieties considerably influences the behaviour of the molecule towards the specific receptors, without particularly affecting the binding to unspecific, cellular structures.

Effects of morphine on EEG in rats and their possible relations to hypo- and hyperkinesia.

It was previously shown in rats that administration of cocaine or d-amphetamine in moderate doses produced alterations in EEG characteristic for activation of D1 dopamine receptors, whereas large doses induced alterations resembling activation of D2 dopamine receptors. Since morphine, among other effects, enhances the dopaminergic transmission, it was investigated whether this effect might be apparent in the EEG which was recorded telemetrically in awake, not restrained rats. In a moderate dose (3 mg/kg IP), morphine produced a desynchronisation and a general decrease of power in all of the frequency bands except beta-2. This effect was antagonized by naloxone (0.5 mg/kg IP) but only in part by the blocker of D1 receptors SCH 23390 (0.2 mg/kg IP) and not by haloperidol in a dose which mainly blocks D2 receptors (0.1 mg/kg IP). The dose of morphine used (3 mg/kg IP) produced only slight signs of behavioural activation. The results suggest that the decrease in power observed after this dose of morphine was only in part due to an activation of dopaminergic mechanisms via D1 receptors and partly must be explained by other actions of morphine. A large dose of morphine (15 mg/kg IP) at the beginning produced catalepsy and muscular rigidity and subsequent behavioural activation; in the EEG during both behavioural phases a general increase in power in all of the frequency bands was observed which was most pronounced in the alpha-2 band (9.75-12.50 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical studies support the assumption that dopamine plays a minor role in the EEG effects of nicotine.

In a previous study, it was shown that a moderate dose of nicotine (0.2 mg/kg s.c.) produced a desynchronization in the EEG and a decrease of power which was not antagonized by blockade of D1-like dopamine receptors, although this EEG pattern seemed to be characteristic for activation of D1-like rather than D2-like receptors. This seemed surprising, since nicotine is known to enhance dopaminergic neurotransmission in the basal ganglia. Since there is a strong reciprocal connection between the cortex and the striatum, dopaminergic effects on the striatum should lead to alterations in the cortical EEG. Therefore, the release of dopamine was studied in the striatum by using microdialysis in awake rats, and in parallel studies, the EEG was studied for administration of a larger dose of nicotine (0.4 mg/kg s.c.). This is a dose which does not induce toxic side effects. This dose produced a desynchronization in the EEG and a release of power. The increase in extracellular dopamine in the striatum was very moderate (by about 30%) and of shorter duration than the EEG effect. Therefore, activation of striatal dopaminergic neurotransmission does not seem to be relevant for the EEG effect studied.

On the possible involvement of glutamate receptors in conditioning of behavioural effects of apomorphine.

It was shown previously that behavioural effects of apomorphine (locomotor activation and stereotyped behaviour) can be conditioned when they are associated with well-defined environmental stimuli. In the present study, the hypothesis was tested that glutamatergic mechanisms play an important role either in formation of conditioned responses to apomorphine or in the expression of previously established conditioned responses. For this purpose, two blockers of glutamate receptors were applied, either MK-801 (dizocilpine), a non-competitive, but selective blocker of NMDA-type receptors or MLV-6976, a non-selective blocker of glutamate receptors. MK-801 produced some locomotor activation by itself in a dose-dependent way (0.125-0.50 mg/kg ip). The locomotor activation produced by 0.25 mg/kg could not be conditioned. When rats were conditioned 9 times with 2 mg/kg apomorphine after pretreatment with 0.25 mg/kg of MK-801, this pretreatment did not prevent the development of apomorphine-conditioned locomotor activity or stereotypies which appeared when the rats were treated with saline in presence of the conditioned stimuli. Similar results were obtained when rats were conditioned 7 times with the same dose of apomorphine after pretreatment with 20 mg/kg ip MLV-6976, which drug did not induce any visible alterations in motility by itself. When rats were conditioned 7 times with 2 mg/kg apomorphine alone and tested with MK-801 (0.25 mg/kg) in the presence of the conditioned stimuli, neither locomotor activity nor stereotypies appeared as conditioned responses. When rats were conditioned with the same dose of apomorphine alone and tested with MLV-6976 (20 mg/kg ip), stereotypies did not appear as conditioned responses, but some locomotor activity occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on electroencephalogram (EEG) in rats suggest that moderate doses of cocaine or d-amphetamine activate D1 rather than D2 receptors.

The effects of cocaine and d-amphetamine, two psychomotor stimulant drugs with pronounced addictive properties, on the electroencephalogram (EEG) of rats were studied by telemetric recordings from the skull in non-anesthetized, freely moving rats. The electrocorticogram (ECoG) was recorded. Both cocaine (10 mg/kg IP) and d-amphetamine (0.4 mg/kg IP) produced a desynchronization, characterized by a general lowering in power in all of the frequency bands. These effects of both drugs were mimicked by the selective agonist at D1 receptors SK&F 38393 (3 mg/kg SC) and were reversed by the antagonist at D1 receptors SCH 23390 (0.2 mg/kg IP) but not influenced by haloperidol (0.1 mg/kg IP) in a dose which is likely to block D2 rather than D1 receptors. These doses of cocaine or d-amphetamine did not produce stereotyped behaviour and slight, if any, increases in locomotor activity only. Large doses of cocaine (30 mg/kg IP) or d-amphetamine (4 mg/kg IP) produced stereotyped behaviour and alterations in EEG which are, based on previous own studies, characteristic for additional stimulation of D2 receptors. This was manifest in a selective increase in power of the alpha-1 band. A similar effect was also produced by the agonist both at D1 and D2 receptors, apomorphine (0.5 mg/kg SC). These results suggest that moderate, but probably rewarding doses of cocaine or d-amphetamine mainly activate D1 dopamine receptors. This activation might be relevant for the rewarding properties of these drugs.

Conditioning of behavioural signs produced by nomifensine and by B-HT 920 in rats.

Conditioning of behavioural effects produced by two drugs acting differently upon dopaminergic neurotransmission was studied. Nomifensine and the putative dopamine autoreceptor agonist B-HT 920 produce contrasting effects on motility, namely increases in locomotor activity and stereotypies as compared to hypokinesia and ptosis. The administration of each of these drugs (US) was repeatedly associated with well-defined environmental stimuli (CS): a wire cage associated with an auditory and on olfactory stimulus. The rats were conditioned for 7 days with 20 mg/kg nomifensine IP each day. After conditioning, the rats were treated with the solvent alone in presence of the CS. Not only did sniffing and licking occur, but also gnawing, even though the latter response was not evident after acute administration of the drug or during the conditioning period. Nomifensine (20 mg/kg IP) also acutely decreased the ratio of 3,4-dihydroxyphenylacetic acid/dopamine concentrations (DOPAC/DOPAMINE); this ratio was not altered in the conditioned rats, 60 min after solvent administration in presence of the CS. Rats were conditioned with 0.02 mg/kg IP B-HT 920 daily for 8 days. During the conditioning phase, akinesia and ptosis showed a slight enhancement and a faster onset. After conditioning, when the rats were treated with the solvent alone, the majority of them showed akinesia and/or ptosis during the observation period, in contrast to pseudoconditioned controls. When these rats were conditioned or pseudoconditioned, respectively, with B-HT 920 for further 5 days using 0.02 mg/kg again, treatment with the same dose in presence of the CS produced a significant enhancement and acceleration of these signs in conditioned as compared with pseudo-conditioned control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats.

We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus ("conditioned rats"). Control animals ("pseudoconditioned" rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described. The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Individual and morphological differences in the behavioural response to apomorphine in rats.

The topography of stereotyped behaviour produced by apomorphine in rats was studied by using either a scoring system, based on observation in a wire cage, or by quantification of horizontal and vertical activities, and of the total distances run in an open field, using an automatic recording system. The latter design was combined with a classification of the type of stereotyped behaviour observed during recording. In addition, the reproducibility of the nature of the stereotyped behaviour and its dose-dependence in individual animals was evaluated. In rats observed in a wire cage, apomorphine at lower doses (0.25 or 0.50 mg/kg SC) produced stereotyped sniffing. Increasing the doses led to stereotyped licking and the largest dose (5.00 mg/kg SC) produced predominantly stereotyped gnawing, as was demonstrated graphically. The type of behaviour produced by 2 mg/kg apomorphine in the open field was reproduced well in individuals after a second administration 4 days later. The shift from sniffing to gnawing was observed in most, but not all of the individually classified animals after administration of the largest dose (5 mg/kg). The locomotor part of motility was highest in "sniffing animals" and lower when gnawing occurred. The non-locomotor part of motility was low in "sniffing rats" and increased when licking and gnawing occurred. In some of the animals a characteristic "climbing" behaviour was observed in addition after the larger doses, which did not interfere with sniffing, licking or gnawing. A combination of classification by observation and automatic recording seems the most appropriate way to study the topography of stereotyped behaviour produced by apomorphine.

Neurochemical aspects of the opioid-induced 'catatonia'.

In this review, the symptoms contributing to the opioid-induced 'catatonia' are presented in detail, and efforts are made to relate these symptoms to opioid-induced alterations in neurotransmitter metabolism in several parts of brain, in particular in the basal ganglia. One important symptom is the muscular rigidity, which is, at least to a great part, mediated by opioid receptors in the striatum. This effect is probably not due to an action on opioid receptors located on endings of nigro-striatal dopaminergic neurones (localization I in Fig. 2), but on receptors located on neurones, the cell bodies of which are within the striatum (localization II) or much less likely on receptors on endings of glutamergic, cortico-striatal neurones (localization IV). Another characteristic symptom, the akinesia, can be induced by injections into the nucleus accumbens, which do not lead to any significant muscular rigidity. Accordingly, opioid-induced muscular rigidity and akinesia can be dissociated topographically, and it is shown by this observation that the opioid-induced 'catatonia' is due to an interference of at least two different signs. 'Catalepsy', on the other hand, is probably the consequence of a very pronounced akinesia, and spontaneously occurring rigidity does not seem to contribute to it. In addition, opioids can induce-after low doses immediately, after high doses subsequently to the depressory phase-signs of behavioural stimulation (locomotor stimulation, some stereotypic behaviour), which seem to be antagonistic to the 'catatonia' from the functional standpoint. Several types of behavioural stimulation seem to exist, with different localizations. An activation of nigro-striatal and mesolimbic dopaminergic neurones seems to be of particular relevance in the behavioural stimulation, which is due to actions of opioids on receptors located within the substantia nigra (on endings of afferent neurones, localization III in Fig. 2) and/or within the ventral tegmentum. Part of this dopaminergic activation might be, in addition, due to actions on opioid receptors located on dopaminergic nerve endings within the striatum (localization I) or the nucleus accumbens. A hypothesis for the biphasic action of opioids (first behavioural depression, then activation is presented, involving a lower sensitivity (eg affinity) of those receptors mediating 'catatonia'. Finally, it is discussed that a detailed study of opioid action on basal ganglia might perhaps give relevant information about some pathophysiological mechanisms in schizophrenic diseases, in Parkinson's disease and in psychic dependence on opioids.

Development of tolerance to the muscular rigidity produced by morphine and replacement by stereotypic behaviour.

After chronic treatment with morphine, the muscular rigidity mediated by opioid receptors in the striatum, was gradually replaced by stereotypic behaviour indicating an increased nigrostriatal dopaminergic activity. These results suggest that one behavioural pattern, originating in the striatum, was replaced by another one, which is antagonistic to the first one.

Comparison of two independent aromatic hydroxylation assays in combination with intracerebral microdialysis to determine hydroxyl free radicals.

The phenylalanine- and salicylate assay were compared to investigate the production of hydroxyl free radicals. In vitro experiment: Phenylalanine (100 micromol/l) or salicylic acid (100 micropmol/l) were incubated in a hydroxyl radical generating in vitro Fenton system with increasing concentrations (1.25--40 micromol/l) of equimolar hydrogen peroxide and ferrous ions. Both, phenylalanine and salicylic acid were able to trap hydroxyl radicals in a reliable way indicated by the linear relationship between the concentration of the Fenton reagents and either the phenylalanine derived products (ortho-, meta-, para-tyrosine) or the salicylic acid-derived products (2,3- and 2,5-dihydroxybenzoic acid (DHBA)). In vivo experiment: Wistar rats were implanted with microdialysis probes and striatal perfusion with either 5 mmol/l phenylalanine or 5 mmol/l salicylic acid was performed. Addition of the dopaminergic neurotoxin 6-hydroxydopamine (100 micromol/l, flow rate 2 microl/min, 60 min) to the perfusion fluid significantly increased the concentrations of ortho- and meta-tyrosine or 2,3-DHBA in comparison to control animals. All increases determined were rapidly reversible after changing back to pre-stimulation conditions. The results demonstrate that aromatic hydroxylation of phenylalanine or salicylic acid is a useful technique to investigate hydroxyl free radical formation in vitro and in vivo. Advantages and disadvantages of both methods are discussed.

Evidence that opioid receptors in the substantia nigra pars reticulata are relevant in regulating the function of striatal efferent pathways.

A tonic activity in the electromyogram (EMG) was induced in conscious rats by injections of morphine either systemically or into the caudate nucleus. This activity was antagonized by injections of naloxone into the substantia nigra pars reticulata. These findings suggest that opioid receptors in this brain area are relevant in regulating the function of striatal efferent pathways.

GABAergic mechanisms in mediating muscular rigidity, catalepsy and postural asymmetry in rats: differences between dorsal and ventral striatum.

In rats, the GABAergic agonist muscimol was injected unilaterally either into the mid ventroposterior striatum (ventral striatum) or into the mid dorsoposterior striatum (dorsal striatum), and the following parameters were estimated: (1) a tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus (GS) muscle, which appears to reflect a muscular rigidity; (2) catalepsy, and (3) asymmetries in posture. Injection of muscimol (25 or 50 ng) into the ventral striatum produced tonic EMG activity, catalepsy and ipsiversive posture; these signs were much less pronounced or not observed after injections into the dorsal striatum. Co-administration of bicuculline (500 ng) into the ventral striatum, or simultaneous injection of muscimol (25 ng) into the substantia nigra pars reticulata (SNR), antagonized both the tonic EMG activity and the catalepsy produced by injection of 50 ng muscimol into the ventral striatum. These results seem to support the assumption that all 3 symptoms mentioned can be produced by an inhibition of striatonigral GABAergic neurones. These symptoms are probably due to a disinhibition of nigrofugal neurones, originating in the SNR.

Morphine-induced alterations of local cerebral glucose utilization in the basal ganglia of rats.

The actions of various doses of morphine on the local cerebral glucose utilization (LCGU) were studied by means of the autoradiographic [14C]2-deoxyglucose technique. Morphine (1-15 mg/kg i.p.) decreased LCGU in most areas of the basal ganglia (caudate nucleus, globus pallidus, nucleus accumbens), but not in the substantia nigra pars compacta. LCGU was also decreased in limbic nuclei, such as septum, hippocampus and amygdala, and in most thalamic areas. In most cortical regions, a decrease was found as well. Findings in some efferent nuclei seemed of particular interest, namely in the substantia nigra pars reticulata, anteroventral and lateral nucleus of the thalamus and the subthalamic nucleus, where decreases in LCGU were found after administration of 7.5 mg/kg or sometimes lower doses, but not after 15 mg/kg of morphine. The decreases seem to reflect a general depressory effect of morphine on neuronal activity which is known from electrophysiological studies. Part of these effects might be, in addition, due to an activation of dopaminergic neurons, since dopamine mainly acts as an inhibitory neurotransmitter. This dopaminergic activation leads to characteristic behavioral effects after lower doses of morphine. The largest dose used (15 mg/kg) produces muscular rigidity, probably by a direct action on the striatum. This effect antagonizes and masks the dopaminomimetic effects. The results suggest that it also antagonizes the functional alterations in some efferent nuclei of the basal ganglia manifest after lower doses of morphine. Local injections of morphine (15 micrograms) led to decreases of LCGU in the various parts of the striatum, but to increases in lateral and anteroventral thalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

On the mechanisms of the development of tolerance to the muscular rigidity produced by morphine in rats.

The development of tolerance to the muscular rigidity produced by morphine was studied in rats. Saline-pretreated controls given a test dose of morphine (20 mg/kg i.p.) showed a pronounced rigidity recorded as tonic activity in the electromyogram. Rats treated for 11 days with morphine and withdrawn for 36-40 h showed differences in the development of tolerance: about half of the animals showed a rigidity after the test dose of morphine that was not significantly less than in the controls and were akinetic (A group). The other rats showed a strong decrease in the rigidity and the occurrence of stereotyped (S) licking and/or gnawing in presence of akinetic or hyperkinetic (K) behaviour (AS/KS group), suggesting signs of dopaminergic activation. The rigidity was considerably decreased in both groups after 20 days' treatment. In a further series of experiments, haloperidol (0.2 mg/kg i.p.) was used in order to block the dopaminergic activation and to estimate the real degree of the tolerance to the rigidity without any dopaminergic interference. Haloperidol enhanced the rigidity in the A group. However, the level in the AS/KS group remained considerably lower than in the A group. The results suggest that rigidity, which is assumed to be due to an action of morphine in the striatum, can be antagonized by another process leading to dopaminergic activation in the striatum. Nevertheless, there occurs some real tolerance to this effect. The rapid alternations of rigidity and the signs of dopaminergic activation observed in the animals of the AS/KS group might be due to rapid shifts in the predominance of various DA-innervated structures.

Nigral GABAergic mechanisms and EMG activity in rats: differences between pars reticulata and pars compacta.

The effects of GABAergic drugs, injected unilaterally either into the substantia nigra pars compacta (SNC) or pars reticulata (SNR) of rats, on motility (tonic activity in the gastrocnemius-soleus muscle, turning behaviour, catalepsy) were studied. Administration of the GABAergic antagonist bicuculline (12.5-50 ng) into the SNR produced tonic activity in the EMG, catalepsy and an ipsiversive posture. The tonic EMG activity was prevented by co-administration of muscimol (25 ng), but not by bilateral lesions of the striatum with kainic acid. Tonic activity in the EMG was also produced by injections of muscimol (25 ng) into the SNC, whereas injections into the SNR led to contraversive circling and no tonic activity in the EMG. Because a new parameter was used--the tonic activity in the EMG--our results support the assumption that GABAergic mechanisms in both parts of the substantia nigra play a different role in regulating and mediating striatal function.