Ipsilateral Rotation Research Articles

Amphetamine-induced rotation reveals post 6-OHDA lesion neurochemical reorganization

Early postlesion amphetamine-induced contralateral rotation has been linked to intraneuronal dopamine (DA) accumulation and transmitter release associated with axonal degeneration. Animals in the present study sustained severe unilateral depletion of striatal DA with or without a near-complete loss of ipsilateral mesolimbic DA. Contralateral rotation to 1.0 mg/kg (+)-amphetamine was observed on days 1 and 4 postlesion, and was greatly enhanced in mesolimbic-lesioned animals on day 4. On days 7 and 14, very little contralateral turning was observed and there was an emergence of low-rate ipsilateral rotation. These changes in direction and magnitude of rotational response suggest neurochemical adaptations which continue beyond initial periods of intraneuronal accumulation and degeneration-induced release.

Stimulant drugs as conditioned and unconditioned stimuli in a classical conditioning paradigm

AbstractA number of important ways in which drugs interact with learning processes have been identified in studies of the behavioral pharmacology of centrally active drugs. For example, drugs can act as discriminative and as reinforcement stimuli or as unconditioned stimuli eliciting unconditioned responses. Regarding the latter, it has been shown that a number of drug effects can be conditioned to exteroceptive stimuli, providing a mechanism by which drug effects can be transferred from the drug itself to external environment stimulus control. This paper focuses on the development of conditioned drug responses using drug‐induced rotational behavior in rats with unilateral lesions of dopamine neurons. A particularly useful advantage of this model is that the drug‐induced response is mediated by a specific central nervous system (CNS) substrate and the criterion rotational response is unambiguous and easily quantified. Additionally, different drugs can elicit the same response of rotation but in a different direction (i.e., depending on the drug used to induce rotation, ipsilateral or contralateral to the dopamine‐denervated hemisphere). This difference in directionality of drug‐induced rotation provides an opportunity to condition responses to different stimulant drugs differentially, which is not possible in the intact animal, since these drugs tend to evoke similar responses (e.g., hyperactivity or stereotypy). Another advantage of directionality differences in rotational responses associated with different stimulant drugs is that one can assess conditioning interactions between drugs. For example, if one drug that elicits an ipsilateral rotation is paired with another drug that elicits contralateral rotation, then, through a conditioning paradigm of paired drug presentations, one might shift the direction of rotation of the one drug used as the conditioned stimulus to that of the other drug used as the unconditioned stimulus. A number of procedures are described in which the anticholinergic drug scopolamine (which elicits ipsilateral rotation) is paired as the conditioned stimulus with the dopaminergic drug apomorphine (which elicits contralateral rotation) as the unconditioned stimulus, and, as a result, the scopolamine comes to elicit contralateral rotation when subsequently given alone. Observation of such effects points to the importance of drug–drug interactions influenced by Pavlovian conditioning processes.

Yaw direction neurons in the cat inferior olive.

1. Single units that responded to yaw rotation were recorded extracellularly in the caudal inferior olive (IO) of barbiturate-anesthetized cats. Of 276 neurons, 55 responded reliably to yaw, and extensive quantitative data were recorded from 25. 2. No yaw-sensitive IO neuron responded to somatosensory or auditory stimuli but two responded, though unreliably, to flash. 3. Yaw-sensitive IO cells fired at low (1-4 spikes/s), irregular rates during one direction of rotation. Though cells responded reliably during yaw, firing rates varied considerably from cycle to cycle. Rotation speed and acceleration were not represented in any cell's firing rate. 4. Eighty five percent (47/55) of yaw-sensitive cells fired during contralateral rotation, 9% (5/55) during ipsilateral rotation, and 6% (3/55) fired from late in the ipsilateral phase of a sinusoidal oscillation to the middle of the contralateral phase. 5. Responses were tested to 0.1-Hz sinusoidal yaw oscillations with a range of peak angular velocities (1-200 degrees/s). Thresholds were not sharp because of the cycle to cycle variability in response rates but were estimated using averaged responses. The peak rate of the most sensitive cell was driven to criterion (2 SD above spontaneous rate) by an oscillation with a peak velocity of 1 degrees/s. Other cells reached criterion between 5 and 50 degrees/s. 6. Sinusoidal oscillation at all frequencies tested (0.01-0.5 Hz) elicited approximately the same firing rates. Even at 0.01 Hz cells responded well. Responses lagged acceleration by approximately 25 degrees at 0.01 Hz and shifted to later parts of the cycle as frequency increased so that firing lagged acceleration by approximately 200 degrees at 0.5 Hz. 7. Histological reconstruction showed that yaw-sensitive neurons were recorded in olivary subnucleus beta (N beta), the dorsal cap of Kooy (DC), the posterior medial region of the medial accessory division of the inferior olive (MAO), and in the medial-lateral center of the caudal MAO. 8. Yaw-sensitive neurons in the inferior olive provide a signal to the cerebellum that indicates the direction of passive rotation over a wide range of velocity and acceleration. The signal from individual neurons does not reliably encode either rotation velocity or acceleration. Yaw-sensitive IO neurons are therefore unlike other central vestibular neurons but are similar to somatosensory IO cells which signal the presence, but not the intensity of a stimulus.

Intrastriatal dopaminergic grafts restore inhibitory control over striatal cholinergic neurons.

The aim of the study was to examine the influence of intrastriatal dopaminergic grafts on the functioning of striatal cholinergic neurons using an in vitro superfusion method. Rats bearing unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system received a cell suspension obtained from ED 14 rat embryonic mesencephali which was injected into the denervated striatum. Lesioned animals displayed an ipsilateral rotation in response to amphetamine (5 mg/kg i.p.). This rotational response disappeared following grafting and there was even a significant contralateral rotation in response to the drug. Apomorphine (0.1 mg/kg s.c.) induced a contralateral rotation following the lesion. This latter response was attenuated in the grafted group. Three months after grafting 350 microns thick slices were prepared from striata from the control and experimental sides of lesioned and graft-bearing animals. The slices were preincubated either with 3H-dopamine (10(-7) M) or 3H-choline (10(-7) M) and then superfused with an oxygenated Krebs-Ringer solution. Stimulation with electrical pulses following preincubation with 3H-dopamine elicited a marked increase of tritium outflow from control slices. Stimulation-evoked overflow was of similar magnitude from slices from striata containing the graft, while it was much reduced in slices from lesioned striata. Amphetamine markedly potentiated the effect of electrical stimulation in slices obtained from control and graft-containing striata. Nomifensine (a dopamine uptake blocker) led to a significant decrease of the overflow of 3H-acetylcholine evoked by electrical stimulation from control striatal slices. This inhibition was antagonized by domperidone, a D2 dopamine receptor blocker, a finding which indicates that the action of nomifensine was indeed due to a potentiation of the action of endogenous dopamine released by the electrical stimulation. A similar, although somewhat attenuated, action of nomifensine and domperidone was observed for striatal slices containing the graft. Amphetamine inhibited the stimulation evoked overflow of 3H-acetylcholine in a dose-dependent manner from striatal slices obtained both from the intact and experimental sides of graft-bearing animals, while it had no action on slices from denervated striata. Finally, the dose-response curve for the inhibition of 3H-acetylcholine release by apomorphine was significantly shifted to the left for slices from the lesioned striata as compared with control slices. This leftward shift was totally abolished in the slices from the graft-containing striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Morphology of physiologically identified second-order vestibular neurons in cat, with intracellularly injected HRP.

The morphology of horizontal canal second-order type I neurons was investigated by intracellular staining with horseradish peroxidase (HRP) and three-dimensional reconstruction of the cell bodies and axons. Axons penetrated in and around the abducens nucleus were identified as originating from type I neurons by their characteristic firing pattern to horizontal rotation and by their monosynaptic response to stimulation of the ipsilateral vestibular nerve. A total of 47 type I neurons were stained. The cell bodies were located in the rostral portion of the medial vestibular nucleus (MVN) and were large or medium sized and had rather elongated shapes and rich dendritic arborizations. The neurons were divided into two groups: those which projected to the contralateral side of the brain stem (type Ic neurons) and those which projected to the ipsilateral side of the brainstem (type Ii neurons). All stem axons of type Ic neurons crossed the midline and bifurcated into rostral and caudal branches in the contralateral medial longitudinal fasciculus (MLF). Two or three collaterals arising close to this bifurcation distributed terminals in a relatively wide area in the contralateral abducens nucleus. Some of these collaterals projected further to the contralateral MVN and thus are vestibular commissural axons. Some of the rostral and caudal stem axons had collaterals which projected to the contralateral nucleus prepositus hypoglossi (PH), nucleus raphe pontis, or medullary reticular formation. There were at least six classes of type Ii neurons, most of which distributed to a relatively limited region in the ipsilateral abducens nucleus and they were categorized according to their future projections into the following categories: A) no further collaterals beyond the abducens nucleus; B) collaterals in the abducens nucleus and a branch descending and terminating in ipsilateral PH; C) projected to the abducens nucleus, PH, and an area rostral to the abducens nucleus; D) projected to the abducens nucleus and to ipsilateral reticular formation rostral and caudal to the abducens nucleus; E) collaterals in the abducens nucleus and a thick caudal stem axon entering and descending in ipsilateral MLF; F) a thick caudal stem axon entering and descending in ipsilateral MLF and no collaterals to the abducens nucleus. Some type Ii neurons also had recurrent collaterals which projected back to the ipsilateral MVN; these may inhibit type II neurons during ipsilateral rotation.

GABAergic mechanisms mediating rotational behavior in rats: Differences between dorsal and ventral striatum

Local injection of muscimol into the dorsal or ventral striatum of rats did not induce any rotational activity, but injection of picrotoxin into ventral striatal aspects induced an intense contralateral rotation. Amphetamine pretreatment resulted in an ipsilateral rotation after muscimol injection into dorsal striatum and in a complex rotational pattern after ventral injection, characterized by an initial short-lasting ipsilateral rotation followed by a long-lasting contralateral rotation. The contralateral rotation induced by picrotoxin was abolished by amphetamine pretreatment. These results indicate a functional heterogeneity between dorsal and ventral striatal mechanisms mediating rotational behavior, and a different pattern of dopamine-GABA interactions between dorsal and ventral striatum.

Different patterns of rotational behavior in rats after dorsal or ventral striatal lesions with ibotenic acid

Rats with total, dorsal or ventral ibotenic acid striatal lesions were challenged with DA agonists apomorphine and d-amphetamine. In rats with total lesions, both drugs induced an intense ipsilateral rotation, as did apomorphine in the dorsally lesioned. In Amphetamin indcuced ipsilateral rotation in ventrally lesioned rats, but this effect may represent a non-specific potentiation of spontaneous ipsilateral rotation observed in this group. These results indicate that the neostriatum of the rat is not an homogenous structure concerning the expression of rotational behavior after DA receptor stimulation.

Spontaneous bodily rotations and direction of locomotion at different times after radio frequency lesions at sites in and near the substantia nigra

Rats were prepared with radio frequency lesions of the dorsolateral or ventromedial regions of the substantia nigra. Other rats were prepared as operated and unoperated controls for each type of lesion. Their behavior was evaluated in an open field at postoperative days 2, 7, 10, and 15. Three types of behavorial changes were observed over time: those noticeable for a brief period, i.e., a few days, after the lesion (rotational behavior), those lasting 7–10 days after the lesion (turning preferences) and those lasting through the end of the experiment that may be permanent (enhanced locomotion). The early effect of the medioventral lesions was pronounced contralateral rotation while the early effect of the dorsolateral lesion was ipsilateral rotation. This effect of the dorsal lateral lesions was reversed on test days 7 and 10. Lesion-induced turning changes associated with forward locomotion were observed on these two test days as well. By 15 days after surgery the only demonstrable effect of either lesion was enhanced locomotion. The results are discussed in terms of various theories of substantia nigra regulation of motor activities.

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC- 4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392. 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.

Rotation following intranigral injections of a selective D 1 or a selective D 2 dopamine receptor agonist in rats

Injections of various nonselective dopamine agonists into the substantia nigra, pars reticulata (SNpr), have been reported to produce contralateral rotation in rats. Since a number of recent dopamine receptor distribution studies have indicated a preponderance of D 1 compared to D 2 dopamine receptor subtypes within the SNpr, we examined the relative behavioral functions of these two subtypes within the nigra by studying rotation following unilateral, local injections of a D 1 (SKF38393) and D 2 (quinpirole) agonist, Significant, dose-dependent contralateral rotation was observed following injections of R,S-SKF38393. This effect was found to be stereoselective to the R-enantiomer, suggesting that the effect is receptor mediated. In contrast, quinpirole (LY171555) produced significant, dose-dependent ipsilateral rotation following nigral injection. These results suggest that the rotation seen following intranigral injections of nonselective dopamine agonists is due to the stimulation of the D 1 dopamine receptor, and that nigral D 1 and D 2 dopamine receptors may play opposite roles in the control of behavior.

Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses

Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0-50.0 micrograms/ul), contralateral rotation. However, while apomorphine produced ipsilateral rotation in rats with unilateral striatal kainic acid lesions, a response considered to be dependent upon normosensitive dopamine receptors, neither caffeine nor theophylline produced rotational responses. As for apomorphine, the rotational behaviour elicited by caffeine (15.0 mg/kg SC) and theophylline (25.0 mg/kg SC) was inhibited by the dopamine antagonists cis-(Z)flupentixol, haloperidol and sulpiride. Nevertheless, despite the fact that cis-(Z)flupentixol was the most potent inhibitor of the caffeine response, no more than 50% inhibition was produced with doses as high as 1.0-10.0 mg/kg SC of cis-(Z)flupentixol. Pretreatment with alpha methyl-p-tyrosine inhibited the rotational response produced by caffeine in 6-OHDA-lesioned animals, but did not significantly modify the apomorphine response. Furthermore, the benzodiazepine diazepam produced a dose-dependent inhibition of the caffeine rotation, but again, the apomorphine response, although qualitatively modified, was not significantly inhibited.

Neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol, an inhibitor of the uptake of dopamine and noradrenaline

AbstractThe neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol has been characterized and compared with that of a series of inhibitors of biogenic amine uptake. Lu 17‐133 inhibits the uptake of dopamine and noradrenaline in the nanomolar range, but it has only a weak effect on serotonin uptake. Blockade of receptors for dopamine (D‐1, D‐2), noradrenaline (α1, α2), histamine (H1), acetylcholine (muscarinic), and serotonin (5‐HT2) was absent or seen only at micromolar concentrations. The biochemical profile is close to that of GBR 13.069, GBR 12.921, and Lu 19‐005 (INN name, Indatraline). Lu 17‐133 shows only weak behavioural effects. In high doses, it potentiates apomorphine and 5‐HTP and reverses the effect of tetrabenazine in mice. It has minimal stimulatory property, as it increases very weakly the locomotor activity in mice and does not induce stereotypy (either low‐component or oral stereotypy) in rats. It does not induce ipsilateral circling behaviour in 6‐OHDA‐lesioned rats, although in combination with scopolamine, a full ipsilateral rotation is seen. Lu 17‐133 has no anticataleptic effect and does not generalize to the discriminative stimulus properties induced by d‐amphetamine. Experiments have shown that there is no clear correlation between inhibitory effect on dompamine uptake and in vivo effects in the models detecting dopamine‐stimulating compounds; nor is there any obvious correlation between effects in different in vivo test models. The neurochemical and behavioural characteristics of Lu 17‐133‐inhibition of dopamine‐ and noradrenaline‐uptake in vitro with low stimulatory properties in vivo make it an interesting candidate as a new antidepressant drug.

Transplant-induced recovery from 6-OHDA lesions of the nigrostriatal dopamineneurones in mice.

Attempts to reconstruct the damaged nigrostriatal pathway in experimental models of Parkinson's disease have thus far been carried out in animals with neurotoxically induced dopamine deficiency. Our study established that unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) neurons produced a well-characterized functional asymmetry in the behaviour of the C57BL/6 (H-2b) mice. The intraperitoneal administration of methamphetamine induced ipsilateral rotation at 7-20 turns/min 1 x 10(6) syngenic DA-rich cells of embryonic ventral mesencephalon were stereotaxically transplanted in the caudate-putamen. A complete recovery of methamphetamine-induced rotational response was produced around the 60th day after the syngenic cell suspension graft. And a complete compensation of the rotational response was also brought about with the DA-rich cells from embryonic ventral mesencephalon (crown-rump length; 10-13 mm) of allogenic C3H/HeN (H-2k) mice. The FACS IV analysis revealed no H-2 (Kk and Iak) antigens before transplantation of these embryonic cells. Immunohistochemistry showed that the dopaminergic fibers had grown predominantly into the ipsilateral caudate-putamen. These results provide evidence of integration of syngenic and allogenic grafts and host tissue. And the immunological response in the transplanted brain are under investigation.

Behavioural evidence for a selective GABA-A antagonistic activity of SR 95103 and SR 42641 after intrastriatal injection in mice

Two pyridazinyl GABA derivatives, SR 95103 and SR 42641 have recently been described as selective GABA A receptor antagonists. We have now investigated the behavioural effects of SR 95103 and SR 42641 after intrastriatal injection in mice. When injected into the right striatum, SR 95103 (0.01–0.5 μg), SR 42641 (0.0001–0.01 μg) and bicuculline methiodide (0.005–0.05 μg) induced contralateral rotations which were antagonized by intraperitoneal injection of muscimol. In contrast, the intrastriatal injection of the GABA A receptor agonist muscimol induced ipsilateral rotations. Muscimol-induced turning was antagonized by SR 95103 (10–30 mg/kg), SR 42641 (1–10 mg/kg) and (+)-bicuculline (0.125–0.5 mg/kg) injected intraperitoneally, but not by strychnine. Intrastriatal glycine also induced ipsilateral rotations which were antagonized by strychnine (0.01–0.3 mg/kg i.p.) but not by (+)-bicuculline, SR 95103 or SR 42641. These results suggest that SR 95103 and SR 42641 induce turning through a selective blockade of GABA A receptors within the striatum.

Inhibition of enkephalinase activity attenuates naloxone-precipitated withdrawal symptoms

1. 1. In this study we examined the effects of the enkephalinase inhibitor, thiorphan, on the naloxone-precipitated withdrawal syndrome in chronic morphine dependent rats. 2. 2. Intracerebroventricular administration of thiorphan (40 μg/2 μl) in morphine dependent rats, inhibited the severity of the naloxone-precipitated abstinential syndrome. 3. 3. Administration of thiorphan (20 μg/0.5 μl) in the periaqueductal grey matter of morphine dependent rats, in addition to explosive motor behaviour and ipsilateral rotation, also significantly suppressed most of the naloxone-precipitated withdrawal symptoms. 4. 4. It is suggested that a decreased biotransformation of endogeneous opioid peptides might replace the relative shortage of morphine during withdrawal in opiate addicted subjects and attenuate the abstinence symptoms.

Influences of neck receptors on soleus motoneuron excitability in man

We studied the influence of the asymmetric tonic neck reflexes on the excitability of the human soleus motoneuronal pool by mapping the H amplitude as a function of rotation of the body relative to the fixed head. Eight normal adult volunteers were tested. On each subject 15 consecutive H reflexes were recorded from the right soleus muscle, for each of the following test positions, 4°, 8°, 12°, 16°, as well as at the control position (0°), both before and after each change in body position. Our results showed that the H reflex amplitude was progressively facilitated for contralateral rotation in respect to the recording side and conversely inhibited for ipsilateral rotation. The results indicate that neck receptors of one side enhance the excitability of the contralateral soleus motoneurons and depress the ipsilateral ones.

Dopamine-like activities of an aminopyridazine derivative, CM 30366: a behavioural study.

The behavioural effects of CM 30366, an aminopyridazine derivative, on dopamine-mediated neurotransmissions, have been studied in mice and rats. CM 30366 induced stereotyped behaviour and antagonized haloperidol-induced catalepsy in rats, after parenteral and oral administration. In 6-hydroxy dopamine (6-OHDA)-lesioned mice, CM 30366 induced contralateral rotations and, when injected before 6-OHDA, protected mice against its neurotoxicity. CM 30366 also provoked contralateral rotations when injected directly into the mouse right striatum. After parenteral injection, CM 30366 slightly increased motility in mice, at least at low doses. The stereotypies and rotations (after intrastriatal injection) induced by CM 30366 were antagonized by haloperidol, alpha-methyl-p-tyrosine and reserpine. The effects of CM 30366 were compared to those of direct and indirect dopamine-like drugs. Bromocriptine induced a behavioural profile, which in most aspects, was qualitatively and quantitatively similar to that of CM 30366. Apomorphine was found slightly more potent than CM 30366, but in contrast to the latter, apomorphine-induced stereotypies were insensitive to alpha-methyl-p-tyrosine or reserpine. (+)-Amphetamine and nomifensine were less potent than CM 30366, and unlike CM 30366, induced ipsilateral rotations in 6-OHDA-lesioned mice. These results indicate that CM 30366 is a potent atypical dopamine-like drug of potential therapeutic usefulness.

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D 2-antagonist sulpiride but not by the D 1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.

Striato-nigral dynorphin and substance P pathways in the rat

The effect of striatal ibotenic acid lesions on dynorphin-, substance P- and enkephalin-like immunoreactivities in the substantia nigra has been studied with immunohistochemistry as well as biochemistry. A comparison was made with the effects produced by intranigral ibotenic acid lesion and by 6-hydroxy-dopamine injection into the medial forebrain bundle. In addition, the effect of the striatal lesions on nigral glutamic acid decarboxylase (GAD)-positive structures was analysed with immunohistochemistry. The effect of the lesions was analysed functionally in the Ungerstedt rotational model, in order to obtain a preliminary evaluation of the extent of the lesions. The striatal lesions produced a parallel depletion of dynorphin and substance P levels in the substantia nigra, pars reticulata, ipsilateral to the treated side, which was dependent upon the extent and location of the lesion. Ibotenic acid lesions into the tail and the corpus of the striatum produced stronger nigral-peptide depletion than lesions in the head and the corpus of the striatum. Comparison of placement of lesions and localization of depleted area in the substantia nigra revealed a topographical relationship. Furthermore, the nigral depletion patterns of dynorphin and substance P were similar. The immunohistochemical analysis revealed that also GAD-positive fibers in the pars reticulata to a large extent disappeared after striatal lesions, in parallel to the dynorphin- and substance P-positive fibers. However, the depletion was less pronounced for GAD than for the peptides, probably related to presence of local GABA neurons in the zona reticulata of the substantia nigra. These results indicate that with the types of lesion used in this study it is not possible to provide evidence for a differential localization within the striatum of dynorphin-, substance P- and GABA-positive cell bodies projecting to the substantia nigra. The radioimmunoassay showed that (Leu)- but not (Met)-enkephalin was affected to the same extent as the dynorphin peptides, supporting the view that (Leu)-enkephalin in the pars reticulata of the substantia nigra is derived from proenkephalin B and not from proenkephalin A. In the immunohistochemical analysis (Met)-enkephalin-like immunoreactivity could only be detected in the pars compacta of the substantia nigra and did not seem to be affected by any of the lesions. The striatal lesions produced a behavioural asymmetry, which could be disclosed by stimulating the rats with apomorphine, which produced ipsilateral rotation.(ABSTRACT TRUNCATED AT 400 WORDS)

Depletion of central β-endorphin blocks midbrain stimulation produced analgesia in the freely-moving rat

The present study examines the role of central β-endorphin in the generation of stimulation-induced analgesia from the ventral midbrain periaqueductal gray of freely-moving rats. Electrical stimulation of the ventral midbrain periaqueductal gray led to an antinociception against noxious heat which gradually subsided post-stimulation over a period of about 15 min. Locomotor effects (ipsilateral rotation) were also seen which were not correlated in intensity with the analgesia and which disappeared immediately with termination of stimulation. There was no indication of any aversive effects. Application of the opioid antagonist, naloxone, 10 min pre-stimulation, strongly attenuated the anti-nociception without changing basal thresholds. It did not influence the locomotor changes. Bilateral, radiofrequency lesions of the mediobasal arcuate hypothalamus greatly depleted immunoreactive β-endorphin from brain tissues without affecting its levels in plasma. Lesioned rats showed a pronounced reduction of stimulation-produced antinociception in the absence of any change in basal thresholds; the locomotor effects of stimulation were not influenced. The degree of depletion of immunoreactive-βendorphin significantly correlated with the degree of attenuation of antinociception. These data suggest: 1. (1) stimulation of the ventral midbrain periaqueductal gray leads both to an antinociception and locomotor effects in freely-moving rats: these can be clearly dissociated from each other; 2. (2) the antinociception (but not locomotor effects) are mediated by an endogenous opioid sensitive to blockade by naloxone; and 3. (3) central β-endorphin may be the (a) endogenous opioid mediating stimulation-produced antinociception from the ventral midbrain periaqueductal gray in the rat.