Search

Kainate or electrolytic lesions were placed unilaterally in the dorsal mesencephalic reticular formation (MRF) or in the deep layers of the superior colliculus (DLSC) on the same side of a unilateral lesion of the medial forebrain bundle with 6-OHDA. Before the lesions the rats turned contralaterally when challenged with 0.25 mg/kg of apomorphine. After lesions of the MRF most rats turned ipsilaterally in response to the same dose of apomorphine. After lesions of the DLSC apomorphine-induced contralateral turning was significantly reduced but not abolished. The results indicate that the MRF and DLSC play a primary role in the expression of turning originated from the striatum.

Kainic acid (50 nmol), applied intravitreally to the eyes of chicks, produces within 6 h a loss of more than 50% of biochemical markers for cholinergic and GABAergic neurons in the retina. Repeated peripheral administration of benzodiazepines, such as diazepam and clonazepam, protects from the kainate-induced loss of cholinergic and GABAergic markers in the retina. Histologically diazepam reduces the nuclear pyknosis induced by kainate particularly at the level of the amacrine cell-layer.

SKF 38393 (2 mg/kg s.c.), a reportedly selective D-1 agonist, failed to induce contralateral turning behaviour in naive rats bearing 12 days old unilateral 6-hydroxydopamine lesions. On the other hand strong contraversive turning in response to SKF 38393 was obtained if rats had been tested 2 or 7 days before with apomorphine (0.1 mg/kg s.c.) or with LY 171555 (0.2 mg/kg s.c.), a selective D-2 receptor agonist. Contraversive turning in response to SKF 38393 was blocked by a low dose (0.05 mg/kg s.c.) of the specific D-1 antagonist SCH 23390. The results indicate that the behavioural expression of D-1 receptor supersensitivity following lesion of dopaminergic neurons depends on previous exposure to a stimulation of D-2 receptors.

To identify the mechanisms and the sites of the diurnal fluctuation in glucose tolerance in humans, we selectively quantitated the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose output, as well as peripheral glucose uptake, by combining tritiated glucose infusion with hepatic and femoral venous catheterization. The studies were carried out in 11 healthy volunteers at 8:00 A.M. and at 6:00 P.M. on different days after 12 h of fasting. After intravenous glucose infusion (6.5 mg.kg-1.min-1 for 120 min) blood glucose rose twofold at 8:00 A.M. and threefold at 6:00 P.M. (P less than 0.01). Insulin levels did not differ significantly between the two series of tests. Splanchnic glucose balance switched from the net output of the basal state to a net uptake in both morning and afternoon studies. However, this effect was more marked at 6:00 P.M. than at 8:00 A.M. (at 60-120 min, P less than 0.05). The different pattern of splanchnic glucose balance was entirely accounted for by a greater rise in splanchnic glucose uptake in the afternoon, as the suppression of endogenous glucose output by the glucose load was practically complete in both series of studies. In contrast, glucose uptake by leg tissues increased less at 6:00 P.M. than at 8:00 A.M. (at 30-60 min, P less than 0.05; at 75 and 90 min, P less than 0.01; at 105 and 120 min, P less than 0.005). These data indicate that the mechanism responsible for the reduced glucose tolerance later in the day resides in the peripheral tissues whose ability to dispose of a glucose load is drastically decreased.

The effect of intraperitoneal administration of tryptophan (50, 100, or 200 mg/kg) on extracellular concentrations of tryptophan, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in the cortex of freely moving rats by transcerebral dialysis. Rats were implanted with dialysis probes in the frontal cortex, and experiments were performed 24 h later. Tryptophan, 5-HT, and 5-HIAA were quantified in 20-min samples of dialysate by HPLC with electrochemical detection after separation on reverse-phase columns. Tryptophan administration resulted in a significant increase of tryptophan, 5-HT, and 5-HIAA levels in dialysates. The maximal increase of 5-HT and 5-HIAA output was approximately 150% over basal values. Perfusion with Ringer's solution containing tetrodotoxin (1 microM) reduced 5-HT output by 90% and prevented the increase of 5-HT and 5-HIAA content after 100 mg/kg of tryptophan. Similar results were obtained after perfusion with Ringer's solution without Ca2+. The results indicate that a tryptophan load stimulates the physiological release of 5-HT.

Fifteen days after bilateral lesions of the substantia nigra by local infusion of kainic acid (0.75 microgram) or after intranigral injection of vehicle, rats were administered 0.1, 0.25, 1.0 and 2.5 mg/kg s.c. of apomorphine and the stereotyped items (locomotion, sniffing and gnawing) were recorded on an event-recorder and motility was measured by a photocell apparatus. After low doses of apomorphine (0.1, 0.2 mg/kg), rats lesioned in the substantia nigra with kainic acid showed a degree of stimulation of motility and of sniffing similar to controls; on the other hand, in rats lesioned with kainic acid in the nigra, a dramatic reduction of gnawing and its replacement by sniffing was observed after administration of higher doses of apomorphine (1.0, 2.5 mg/kg). Bilateral infusion of kainic acid (0.75 microgram) into the reticular information, 2.0 mm dorsal to the substantia nigra, had no effect on apomorphine-induced stereotyped behaviour. These results are in agreement with the concept that the substantia nigra, through non-DA pars reticulata neurons, mediates motor and behavioural syndromes of striatal origin.

Dihydroergotoxine (DHET), a dopamine (DA) receptor agonist, induced hypomotility in rats at doses of 0.125-0.5 mg/kg s.c., (-)sulpiride a D-2 receptor antagonist, a dose which did not affect spontaneous activity (10 mg/kg s.c.) counteracted the hypomotility induced by DHET. Thioridazine (THR), a widely used neuroleptic, reduced motility (2.5-10 mg/kg i.p.) when given alone; this effect was potentiated by DHET when the two drugs administered in doses of 1 mg/kg THR/0.05 mg/kg DHET and 2.5 mg/kg THR/0.125 mg/kg DHET; higher doses of THR (5 and 10 mg/kg i.p.) which by themselves induced marked inhibition of motility, were not potentiated by doses of DHET of 0.25 and 0.5 mg/kg s.c. THR and DHET influenced in an opposite manner the levels of DA-metabolites dihydroxyphenylacetic acid and homovanillic acid in the caudate; while THR (1-10 mg/kg i.p.) increased, DHET (0.25-0.5 mg/kg s.c.), decreased DA-metabolite levels. The association of THD and DHET resulted in a reciprocal antagonism of their effects on DA-metabolite levels.

Insulin, glucagon, and somatostatin concentrations were measured in 7 lean and 7 obese non-diabetic subjects over 7 days of fasting. In addition each subject was given a 75 g oral glucose tolerance test after fasts of 12 h and 7 days. In lean subjects complete food deprivation induced a significant decrease in the circulating levels of both insulin and somatostatin, while glucagon nearly doubled by 48 h and then remained constant for the duration of starvation. Refeeding with oral glucose suppressed the increased plasma glucagon, but insulin and somatostatin responses were enhanced in comparison with the prefast values, as assessed by the integrated areas of change. In obese subjects peripheral insulin and somatostatin levels were significantly lowered, but plasma glucagon level was unchanged at the end of the starvation period. In the same group glucose-induced insulin and somatostatin release were greater than in the fed state. Suppression of plasma glucagon by glucose appeared less complete in obese than in lean subjects. It is concluded that prolonged starvation enhances D-cell responsiveness to glucose in lean and obese subjects.

A unilateral kainate (KA) infusion (2 x 0.15 micrograms, 2 x 0.25 micrograms) in the ventral mesencephalic reticular formation (MRF) resulted in spontaneous contraversive turning lasting only a few days. Upon challenge with apomorphine (0.5 mg/kg s.c.) or amphetamine (5 mg/kg i.p.) the contraversive turning could be reinstated. The incidence, as well as the intensity, of the drug-induced response decreased over the 45 days of observation. KA infused in the ventral MRF induced typical lesions after doses of 2 x 0.15 micrograms but resulted in demyelination after 2 x 0.25 micrograms. These lesions failed to reduce noradrenaline (NA), serotonin (5 HT) or dopamine (DA) in various forebrain areas. Unilateral lesion of ascending NA projections by 6-OHDA infusion (4 micrograms) within the NA bundles coursing in the mesencephalon or near the locus coeruleus, failed to induce motor asymmetries. Unilateral selective lesion of the ventral NA bundle by local 6-OHDA (2 micrograms) infusion also failed to induce motor asymmetries, either spontaneously or in response to dopaminergic drugs. Unilateral lesion of ascending 5-HT projections by the tegmental infusion of 5,7-dihydroxytryptamine (10 micrograms) also failed to induce motor asymmetries in response to dopaminergic drugs but resulted in contraversive circling in response to 5-hydroxytryptophan. These data indicate that intrinsic neurones of the ventral MRF play a role in turning behaviour and exclude, in contrast with previous studies, a role of NA or 5-HT projections in the contraversive turning responses to DA receptor agonists obtained after lesions of the ventral MRF.

The effect on dopamine (DA) release of D-1 and D-2 receptor agonists and antagonists applied locally in the caudate through a trans-striatal dialysis probe was studied in freely moving rats. D-2 agonists (LY 171555 and BHT 920) reduced DA release in a concentration-dependent manner. The same local application of haloperidol abolished the effect of 10 microM LY 171555 and BHT 920. A specific D-1 agonist, the catechol benzazepine SKF 38393, reduced DA release and this effect was not modified by systemic or local administration of the D-1 antagonist, SCH 23390, nor by the D-2 antagonist, haloperidol. In contrast, the non-catechol D-1 agonist, CY 208243, failed to modify DA release. Local application of the D-1 antagonist, SCH 23390, or of the D-2 antagonist, (-)-sulpiride, stimulated DA release in a concentration-dependent manner. The D-1 agonist, CY 20843, reversed the stimulatory effect of SCH 23390 but not that of (-)-sulpiride. It is concluded that D-1 and D-2 receptors located in the caudate control DA release separately in this area.

SCH 23390, from doses of 0.012 mg/kg s.c., dose dependently stimulated the release of dopamine (DA) and the output of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, in the dorsal caudate of freely moving rats implanted with transcerebral dialysis fibers. SKF 38393 failed to modify DA release and metabolism at doses of 5, 10 and 25 mg/kg s.c. but at 25 mg/kg s.c. it abolished the effect of 0.025 mg/kg of SCH 23390. Administration of gamma-butyrolactone (700 mg/kg s.c.), which blocks the firing of DA neurons, prevented the effect of 0.050 mg/kg s.c. SCH 23390. The results indicate that D-1 receptors control the release of DA, probably through stimulation of the firing of DA neurons.

The syndrome of behavioral stimulation induced in male Sprague-Dawley rats by two dopaminergic agents was studied by distinguishing specific behavioral items and quantifying them in terms of their incidence. The specific D-2 agonist LY 171555 elicited yawning, genital grooming, exploratory behavior, downward sniffing and licking but failed to induce gnawing even at high doses. On the other hand, the D-1/D-2 agonist apomorphine elicited the full stereotyped syndrome including gnawing. Depletion of endogenous dopamine (DA) by alpha-methyltyrosine (alpha-MT) prevented the ability of LY 171555 to elicit all the items of behavioral stimulation including the stereotyped ones (sniffing and licking). In contrast, the ability of apomorphine to induce stereotypies was not reduced by depletion of endogenous DA by alpha-MT pretreatment. Blockade of D-1 receptors with SCH 23390 abolished the capacity of both LY 171555 and apomorphine to elicit all the items of behavioral stimulation. In alpha-MT pretreated rats, administration of low doses of the D-1 agonist SKF 38393 (2.5 mg/kg s.c.) reinstated the ability of LY 171555 to elicit behavioral stimulation and eventually conferred the ability of inducing gnawing. The results support the hypothesis that stimulation of D-1 receptors exerts a permissive role for the expression of behavioral stimulation following D-2 receptor stimulation. Endogenous DA appears to provide sufficient D-1 input to permit full expression of yawning, genital grooming, exploratory behavior, downward sniffing and licking following D-2 stimulation; pharmacological stimulation of D-1 in addition to D-2 receptors seems however necessary for full expression of the highest rank stereotypy item, gnawing.

CY 208-243, a novel D-1 agonist structurally unrelated to other D-1 agonists, at doses which elicited behavioural stimulation with locomotion, sniffing and grooming, failed to modify the release and metabolism of dopamine (DA) in the nucleus accumbens and in the dorsal caudate of freely moving rats, as estimated by transcerebral dialysis. CY 208-243 prevented the increase of DA release and metabolism elicited by the specific D-1 antagonist, SCH 23390, but not by the specific D-2 antagonist, sulpiride. The results support the conclusion that CY 208-243 is an effective and specific D-1 agonist in vivo.

Administration of morphine HCl (20 mg/kg SC) to male C57Bl/6 mice evoked hypermotility. Pretreatment with low doses of the specific D-1 antagonist SCH 23390 (0.006, 0.012, 0.025 mg/kg SC) dose-dependently inhibited morphine-evoked hypermotility. The results suggest that dopamine is the essential mediator of opiate hypermotility and indicate that D-1 receptors play an important role in this effect.

Unilateral infusion of GABA-receptor antagonists (picrotoxin, bicuculline) in the mesencephalic reticular formation-deep layers of the superior colliculus (MRF-DLSC) elicits tight head-to-tail contralateral posturing but not active circling. Bilateral infusion of the GABA antagonists in the MRF-DLSC elicits compulsive gnawing and biting but not licking or sniffing. Infusion of GABA-receptor agonists (muscimol, THIP) in the MRF-DLSC while producing only minor or no motor or behavioural effects, drastically altered apomorphine effects; thus, unilateral infusion of muscimol resulted i tight, head-to-tail ipsiversive circling while bilateral infusion of muscimol converted the apomorphine-syndrome from stereotypy of high-intensity into pure compulsive forward locomotion devoid of sniffing. The results indicate that GABAergic mechanisms in the MRF-DLSC are of primary importance in the expression of motor and behavioural syndromes arising from the striatum.

Using the technique of brain dialysis in freely moving rats we have investigated the effect of various dopamine (DA) receptor agonists on the release and metabolism of DA in two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of various DA receptor agonists such as apomorphine (12-100 micrograms/kg s.c.), LY 171555 (5-50 micrograms/kg s.c.), pergolide (5-25 micrograms/kg s.c.), (+)-3PPP (0.5-2.5 mg/kg s.c.) and BHT 920 (10-250 micrograms/kg s.c.) reduce DA release and elicit hypomotility. The potency of the drugs and their effectiveness is similar in the two areas. Inhibition of DA release appears related to the ability of the various agonists to stimulate D-2 rather than D-1 receptors. Thus, the reportedly selective D-1 agonist, SKF 38393, was inactive on DA release and metabolism even at doses fully active in eliciting D-1-mediated effects (grooming); on the other hand apomorphine, a D-1/D-2 agonist, and pergolide, a D-2 agonist with rather weak D-1 activity, reduced DA release in a manner which was related to their agonist activity at D-2 receptors; finally LY 171555, (+)-3PPP and BHT 920, which selectively stimulate D-2 receptors, were fully active at reducing DA release in vivo. Apomorphine, pergolide, LY 171555 and (+)-3PPP given at higher doses elicited behavioral stimulation. In contrast, BHT 920 failed to do so. In further contrast (-)-3PPP (0.1-10 mg/kg s.c.), which failed to reduce DA release at low doses, actually stimulated it at high doses (10 mg/kg s.c.) and elicited hypomotility, thus resembling DA receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nigro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turning, while haloperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.

The effect of concurrent D-1 receptor stimulation by SKF 38393 on the expression of yawning elicited by D-2 receptor stimulation with LY 171555 was studied in the rat. A low dose of SKF 38393 (2.5 mg/kg SC), while failed to elicit yawning, potentiated the effectiveness of LY 171555 in eliciting yawning at all the doses tested (12.5, 25 and 50 micrograms/kg SC) and this effect was abolished by SCH 23390 (0.012 mg/kg SC). The results indicate that in analogy with typical post-synaptic dopaminergic effects (hypermotility-stereotypy), yawning elicited by a D-2 agonist is facilitated by concurrent stimulation of D-1 receptors and therefore is consistent with previous evidence that yawning in response to a D-2 agonist is not mediated by autoreceptors.

A low dose of the D-1 receptor agonist SKF 38393 (2.0 mg/kg s.c.) 14 days post-lesion failed to induce contraversive turning in male Sprague-Dawley rats lesioned unilaterally in the medial forebrain bundle with 6-hydroxydopamine (6OHDA). Priming with a single administration of the specific D-2 agonist LY 171555 (0.2 mg/kg s.c. 3 days before), which itself elicited contraversive turning, made SKF 38393 (2.0 mg/kg s.c.) very active to produce contraversive turning. Priming with LY 171555 (0.2 mg/kg s.c. 3 days before) potentiated the contraversive turning in response to a low dose of LY 171555 (0.05 mg/kg s.c.). In naive 6OHDA-lesioned rats a rather high dose of SKF 38393 (10 mg/kg s.c.) was needed to induce a low intensity contraversive turning. Priming with a single administration of SKF 38393 (10 mg/kg s.c. 3 days before) made an otherwise ineffective dose of SKF 38393 (2.0 mg/kg s.c.) very effective to produce contraversive turning. The results indicate that the sensitization to the behavioural expression of supersensitivity for a given DA-receptor type follows not only priming with agonists for the same DA-receptor type (homologous sensitization) but also priming with agonists for a different DA-receptor type (heterologous sensitization).

Blood glucose, insulin and prolactin concentrations were determined before and after sulpiride injection (50 mg i.m.) in 20 non-insulin-dependent diabetic patients (10 with retinopathy and 10 without evidence of retinal damage) and 10 subjects with normal glucose tolerance. Prolactin response to sulpiride was significantly higher in diabetics than in controls (at 20 min., p less than 0.01; at 30 and 60 min., p less than 0.005; at 90 min., p less than 0.01; at 120 min., p less than 0.05). The sulpiride induced hyperprolactinemia did not influence blood glucose and plasma insulin levels in controls as well as in diabetic patients. Prolactin response to sulpiride was the same in diabetics with and in those without retinal changes. We conclude that acute hyperprolactinemia seems to have no influence on glucose homeostasis in normal and non insulin-dependent diabetic subjects.

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.

Locally applied kainic acid was used in order to destroy pallidal perikarya without damaging axons en passage, in an effort to clarify the role of the globus pallidus as a source of nigral GABAergic terminals. Rats were microinjected unilaterally with kainic acid in the globus pallidus, head, body and tail of the caudate and were sacrificed 7 days later. The forebrain of each rat was examined histologically in order to establish the extent of the lesion and nigral glutamate decarboxylase (GAD) was assayed as a marker of GABAergic terminals. Kainic acid produced in the globus pallidus loss of neuronal perikarya and reactive gliosis. Large multipolar neurons of the globus pallidus were characteristically absent on the lesioned-side. Lesions of the pallidum resulted in a non-significant (5.5%) reduction of nigral GAD. Kainate lesions restricted to the head of the caudate resulted in a significant (19%) drop of nigral GAD, while lesions of the caudate body provided the largest reductions of nigral GAD (53%). Lesions of the caudate tail were without effect. The results indicate that nigral GAD arises mostly from the body and, in part, also from the head of the caudate but not from the globus pallidus or from the tail of the caudate.

Bromocriptine produces long-lasting hypomotility and decreases brain dihydroxyphenylacetic acid (DOPAC) in mice. These effects are obtained with doses much lower than those which produce hypermotility. The decrease of brain DOPAC is correlated to the hypomotility both on a dose and on a time basis. Potent DA receptor blockers as pimozide, benzperidol and droperidol antagonize the hypomotility and the decrease of brain DOPAC produced by bromocriptine. These effects are obtained with very low doses (0.05-0.3 mg/kg) of neuroleptics which per se do not affect motility or brain DOPAC. The maximal decrease of brain DOPAC produced by bromocriptine is similar to that produced by apomorphine and the combination of these drugs does not result in a further decrease. On the basis of these results it is postulated that bromocriptine decreases DA turnover and produces hypomotility by acting on "regulatory" DA receptors different from the postsynaptic ones of the "terminal" dopaminergic areas.

The effect of the i.p. administration of ethanol on the release of dopamine (DA) and on the output of its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, was estimated in the rat by transcerebral dialysis of two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of ethanol (0.25-0.5 g/kg i.p.) stimulated DA release specifically in the n. accumbens and elicited pure behavioral stimulation. Higher doses of ethanol (1.0-2.5 g/kg) elicited sedation and hypnosis and stimulated further DA release and dihydroxyphenylacetic acid and homovanillic acid output in the accumbens and, although less, also in the caudate. High doses of ethanol (5 g/kg i.p.) elicited long-lasting hypnosis and sedation and induced a depression followed by stimulation of DA release in the accumbens. DA release in the caudate was stimulated further. Low doses of apomorphine (0.05 mg/kg s.c.) reversed completely the stimulant effect of 0.5 g/kg of ethanol on behavior and on DA release in the accumbens. Moreover, the stimulation of behavior and of DA release in the accumbens elicited by 0.5 g/kg of ethanol were abolished completely by pretreatment with 700 mg/kg of gamma-butyrolactone, an agent which blocks DA firing and DA release. The results indicate that ethanol preferentially stimulates DA transmission in the mesolimbic system probably by activating the firing activity of mesolimbic DA neurons and provide direct evidence that these changes are involved in the motor stimulant effects of ethanol.

There is much debate on the role of the superior colliculus (SC) in turning behaviour. In order to clarify this issue, unilateral kainate lesions were made by infusing 0.25 microgram of kainate at two different anterior planes (0.8 mm apart), in the lateral or in the medial aspects of the deep collicular layers (DLSC), in the dorsal mesencephalic reticular formation (MRF), or in the lateral periaqueductal grey (PAG), both in normal rats and in rats made unilaterally supersensitive to DA-receptor agonists by unilateral infusion of 6-OHDA in the rostral substantia nigra. The effect of kainate lesions on spontaneous and apomorphine-induced motor behaviour was studied. In normal rats, unilateral kainate lesions of lateral DLSC or dorsal MRF resulted in short-lasting, spontaneous ipsiversive turning and persistent ipsiversive circling after peripheral administration of apomorphine. In 6-OHDA rats, kainate lesions of lateral DLSC or of dorsal MRF ipsilateral to 6-OHDA denervation reduced or even reversed the contralateral circling normally elicited in these rats by peripheral administration of apomorphine. Lesions of dorsal MRF, when compared with lesions of lateral DLSC, were more effective in producing these changes. Kainate lesions restricted to medial DLSC or to the PAG failed to elicit motor asymmetries in normal rats or to significantly modify the intensity of contralateral turning in 6-OHDA rats. These results clearly indicate that the SC plays an important role in turning behaviour. Failure of previous studies to research this conclusion probably derives from inadequate localization of collicular lesions and from the use of bilateral lesions.

The ability of apomorphine to induce yawning (YWG) in normal and reserpinized rats and its interaction with SCH 23390, a potent and specific D-1 receptor antagonist, was studied. Apomorphine was more potent in inducing YWG in reserpine-pretreated as compared to control rats. SCH 23390, in low doses (0.05 mg/kg SC), was able to significantly reduce the YWG evoked by apomorphine both in control and in reserpine-pretreated rats. The results indicate that D-1 receptors contribute to YWG elicited by apomorphine and contradict the idea that this effect is mediated by DA autoreceptors.

A method for the estimation in rats of the in vivo release and metabolism of dopamine (DA) is described. The method is based on the dialysis principle and consists of inserting transversally in the striatum a thin (0.2 mm) dialysis tube (Amicon Vitafiber) which is then perfused with Ringer. The Ringer, flowing at a constant rate of 2 microliters/min in the dialysis tube, extracts low molecular weight substances from the surrounding tissue by way of simple diffusion along a concentration gradient. At the distal end of the dialysis tube, the Ringer is collected every 10 to 20 min and directly injected into a high performance liquid chromatographer (HPLC) equipped with reverse phase octadecyl sulfate columns which separate DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). These substances are then quantitatively estimated by oxidative electrochemical detection. The basal output of DA is 0.3 pmol/20 min, whereas the outputs of DOPAC and HVA are 60 and 20 pmol/20 min, respectively. In basal conditions the output of DA, DOPAC, and HVA is stable over at least 10 hr. Histological examination of the track left by the dialysis probe in rats after 10 hr of continuous dialysis reveals very little damage and normal neuronal morphology in the vicinity of the dialysis tube. Increase of the K+ concentration in the Ringer to 30 mM produced a sharp, reversible increase of DA output. Both the basal and K+-stimulated release were Ca++ dependent, because omission of Ca++ abolished basal and K+-stimulated DA release. Electrical stimulation of the nigrostriatal DA neurons in the medial forebrain bundle sharply increased DA output. Amphetamine sulfate in low doses (1.0 mg/kg, i.v.) produced a 9-fold increase in DA release and decreased DOPAC and HVA output. alpha-Methyl tyrosine (150 mg/kg, i.v.) reduced within 2 hr DA release to 15% of basal values and in parallel also decreased the output of DOPAC and HVA. Reserpine (5 mg/kg, i.p.) reduced DA release but in a slower fashion than alpha-methyl tyrosine and increased DOPAC and HVA. Pargyline (75 mg/kg, i.p.) produced a 4-fold increase of DA release, while it rapidly brought to zero DOPAC and HVA output. gamma-Butyrolactone (700 mg/kg, i.p.) rapidly and lastingly reduced DA, DOPAC, and HVA output. The biochemical and histological results obtained indicate that the method is suitable to estimate in the rat the changes in the release o f endogenous DA and its metabolites which take place in vivo under administration of centrally acting drug.

The effect of two potent and specific antagonists of 5HT3 receptors, ICS 205-930 and MDL 72222, on the reinforcing properties of amphetamine, morphine and nicotine was studied in rats. Drug-induced reinforcement was assessed by measuring drug-conditioned place preference. ICS 205-930 and MDL 72222 dose-dependently reduced the place preference induced by morphine (1.0 mg/kg SC). At doses of 0.030 mg/kg SC the two antagonists completely blocked morphine-induced place preference while doses of 0.015 mg/kg SC significantly reduced it. ICS 205-930 and MDL 72222 at doses of 0.030 mg/kg SC also prevented the place preference induced by nicotine (0.6 mg/kg SC). In contrast, ICS 205-930 and MDL 72222 up to doses of 0.030 mg/kg SC failed to modify the place preference elicited by amphetamine (1.0 mg/kg SC). The results indicate that 5HT3 receptors are specifically involved in the reinforcing properties of morphine and nicotine.

Opioid agonists having different affinity for delta and mu receptors were injected bilaterally in the substantia nigra (SN) of rats. The selective agonist of mu receptors N-MePhe3,-D-Pro4 morphiceptin (PLO 17) produced a stereotyped behavior characterized by stereotyped sniffing and gnawing antagonized by the irreversible antagonist of mu receptors beta-funaltrexamine. In contrast, bilateral intranigral injection of the selective delta agonist D-Pen2,D-Pen5 enkephalin (DPDPE) elicited dose-dependent exploratory behavior and rearing but failed to produce gnawing. The behavioral syndrome induced by DPDPE was significantly reduced by the selective delta antagonist ICI 174,864. Naloxine, a non-selective opioid antagonist, antagonized the effects of both compounds. SCH 23390 and haloperidol, two antagonists of dopaminergic D1 and D2 receptors, respectively, blocked the effects of PLO 17 and DPDPE. The results indicate that stimulation of specific opioid receptor types in the SN elicits specific behavioral syndromes and suggest that the SN might be the site of origin of certain items of the behavioral syndrome evoked by systemic opiates. These items might be mediated by activation of dopaminergic neurons of the ventral mesencephalon.

Apomorphine, a central dopamine-receptor agonist, is well known to produce excitatory effects in animals. However, low doses exert depressant effects as hypomotility, sedation and sleep. The mechanism of these effects are discussed in terms of a stimulation by apomorphine of DA-receptors, different from the post-synaptic ones, provided of an inhibitory effect on DA-synthesis and on the firing of dopaminergic neurons.

The turning effects of the unilateral intranigral injection of morphine and of different analogs of dynorphin and enkephalin were studied. All injections were made in awake rats through cronically implanted guide cannulae. Dynorphin1-13 at a dose of 10 micrograms (0.6 nmol) and dynorphin1-17 at a dose of 2 micrograms (0.9 nmol) produced contralateral circling when injected unilaterally in the substantia nigra (SN), lasting for about 1 h. D-Ala-dynorphin1-17, a more stable analog of dynorphin, produced at a dose of 2 micrograms (0.9 nmol), a longer-lasting effect. Injections of different enkephalin analogs were also made into the SN, [D-Ser2]-Leu-enkephalin (10 micrograms, 14.5 nmol) and [D-Ala2,D-Ala3]-Met-enkephalin (10 micrograms, 15 nmol) also produced contralateral circling after unilateral intranigral injection. This behavior lasted for 60-90 min, depending on the different enkephalins used. As already reported by Iwamoto and Way18 morphine also produced contralateral circling when injected into the SN. The circling evoked by all these opiates was completely antagonized by 5 mg/kg of naltrexone s.c. In order to study the role of the dopaminergic nigrostriatal system, we made unilateral lesions of the medial forebrain bundle (MFB) with 6-hydroxydopamine (6-OHDA) and kainic acid lesions of the striatum and we looked at the effect elicited by these lesions on the behavior produced by the above compounds when injected into the SN. The lesion of the dopaminergic nigrostriatal system failed to affect either the number of turns or the duration of the contralateral circling produced by unilateral injections of morphine, dynorphin and enkephalin analogs into the SN correspondent to the lesioned side. On the other hand kainate lesions of the body of the caudate potentiated the turning induced by intra-SN morphine and dynorphin. Therefore it appears that the dopaminergic nigrostriatal system is not essential in the expression of the contraversive turning behavior produced by intranigral injections of endogenous opiates or morphine and that opiates might produce dopamine-like effects indirectly, through the inhibition of nigral non-dopaminergic output neurons.

The influence of the D1 antagonist SCH 23390 on the motivational properties of rewarding (morphine, nicotine and diazepam) and aversive (naloxone, phencyclidine and picrotoxin) drugs was studied in the rat in a two-compartment place-conditioning paradigm, which included a pre-conditioning test for spontaneous place-preference. The specific D1 dopamine-receptor antagonist SCH 23390 (0.05 mg/kg SC), paired with both compartments or, separately, with the preferred or with the non-preferred compartment, failed to affect the spontaneous unconditioned preference of the animal. Pairing of morphine (1.0 mg/kg SC), nicotine (0.6 mg/kg SC) or diazepam (1.0 mg/kg IP) with the less preferred compartment induced significant preference for that compartment. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments completely blocked the place-preference induced by morphine, nicotine and diazepam. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) or picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited place-aversion. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments abolished also the place-aversion induced by naloxone, phencyclidine and picrotoxin. The results indicate that blockade of dopamine transmission blocks the motivational properties of rewarding as well as aversive stimuli. It is suggested that neuroleptics rather than simply blocking the rewarding impact of positive reinforcers (anhedonia, lack of pleasure) exert a more general influence on conditioned behaviour by blocking the affective impact of negative as well as positive reinforcers (apathy, lack of motivation).

[3H]Sulpiride bound to substantia nigra homogenates in a saturable manner and with a pharmacological profile typical of a specific D-2 ligand. Unilateral 6-OH-dopamine (DA) lesions of the nigrostriatal DA neurons reduced by 27-46% the Bmax of the specific [3H]sulpiride binding in substantia nigra homogenates depending on the time after 6-OHDA lesion and significantly increased the Bmax in the caudate. KDs remained unchanged in both areas. The localization of specific [3H]sulpiride binding and its reduction in the substantia nigra of the 6-OHDA-lesioned side were confirmed by quantitative autoradiography. The results provide evidence for the existence of D-2 autoreceptors in substantia nigra.