Subcutaneous Injection Of Apomorphine Research Articles

Evidence that apomorphine and (+)-amphetamine produce different types of circling in rats

Apomorphine and (+)-amphetamine are known to produce circling in naive rats. Frame by frame analysis of videotape recordings of the behaviour of Wistar rats treated with a subcutaneous injection of apomorphine (1.1 mg/kg; n = 8) or (+)-amphetamine (0.5 and 1.0 mg/kg; n = 8 and n = 8) was used to study this behaviour in more detail. In line with previously reported studies, apomorphine was found to change the functioning of hindlimb stepping. In contrast, (+)-amphetamine was found to change the functioning of forelimb stepping. These data imply that apomorphine and (+)-amphetamine produce their drug-specific circling via different substrates within the brain.

Motor response following repeated apomorphine administration is reduced in Parkinson's disease.

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.

Chapter 39 Somatosensory input to dopamine neurones of the monkey midbrain: responses to pain pinch under anaesthesia and to active touch in behavioural context

The somatosensory responses of single dopamine (DA) neurones were recorded in the pars compacta of substantia nigra and in neighbouring DA cell groups of four Macaca fascicularis monkeys. These neurones were electrophysiologically discriminated against other cells by their polyphasic, relatively long impulses (2.0-5.0 ms) occurring at low rates (mostly 1.0-5.0/s), by antidromic activation from caudate or putamen, and by reduction of impulse rate following subcutaneous injection of apomorphine (0.05-0.15 mg/kg). Of 140 DA neurones recorded in two monkeys under barbiturate anaesthesia, 51% showed reductions and 17% increases in impulse rate during intense noxious pinch stimulation. Neurones responded non-somatotopically to stimulation of the hand, foot, face, dorsum and tail on both sides of the body. Innocuous, even intense, surface or deep somatosensory stimuli were ineffective. Systemic injection of the DA receptor antagonist haloperidol (0.33-0.5 mg/kg) strongly reduced the pinch responses. Of 154 DA neurones recorded in two monkeys during self-initiated arm movements, 84% showed phasic activations with latencies of 65 ms when the monkey's hand touched a food morsel inside the target box. Responses were absent when touching other objects. Touch responses to food did not occur when the reaching movement into the same food box was performed in reaction to an external trigger stimulus. In conclusion, DA neurones were activated in specific behavioural contexts by somatosensory stimuli of low intensities while responding unconditionally to noxious input.

Neurobehavioral effects of intrathecal somatostatinergic treatment in subhuman primates.

We infused somatostatin and its long-acting analogue (SMS 201-995) into the intracranial subarachnoid space of eight monkeys. Chronic infusions of SMS 201-995 produced marked neurotoxic effects characterized by truncal ataxia, dysmetria, and severe bradykinesia, with normal level of consciousness. Subcutaneous injection of apomorphine, a dopaminergic agonist, promptly reversed these effects. Further studies are required before intrathecal somatostatin replacement therapy can be offered to patients with Alzheimer's disease.

Dysfunction of the midbrain angular complex can accentuate or attenuate circling behaviour in the rat.

The role of the midbrain angular complex (AC) in the execution of motor behaviours was investigated in the rat. In an automated holeboard apparatus bilateral AC electrolesions attenuated exploration and increased locomotor performance of drug-free rats on the first and second test occasions respectively; the latter result may signify a retarding of between-session habituation. Apomorphine also decreased locomotion and almost abolished head dipping and rearing in the holeboard; bilateral AC lesions reinstated locomotion to a normal level without modifying the other behavioural parameters. An electrolesion of one AC did not affect the animal's posture or spontaneous locomotion in the open field, but gave rise to pronounced ipsiversive circling when coupled with systemic administration of apomorphine. In unilaterally 6-hydroxydopamine (6-OHDA) treated rats subcutaneous injection of apomorphine evoked robust contraversive circling. A concomitant lesion of the ipsilateral AC introduced an additional ipsilateral bias to these animals' movements; contraversive circling was initially curtailed and posture reduced (or reversed), while stereotyped activities (particularly grooming) were suppressed. Contralateral orientation and circling were restored by subsequently lesioning the contralateral AC as well; bilateral AC lesions significantly potentiated circling to systemic apomorphine. Contralateral locomotor asymmetry was also produced by depositing apomorphine stereotaxically into the supersensitive caudate, or by microinjecting one substantia nigra zona reticulata with muscimol (in naive rats). Both rotational responses were facilitated by injury to the ipsilateral AC. The effects of electrocoagulating the AC were generally duplicated by discrete microinjection of muscimol or gamma-vinyl GABA into this area, suggesting GABA-mediated synapses are normally operative in this part of the brain. These results do not support the claim that the AC is specifically engaged in mediating postural asymmetry in the unilaterally 6-OHDA denervated rat. Instead, we believe that impairment of neurotransmission through one AC imposes an independent and reciprocal tendency to move towards that side of the brain, as well as attenuating stereotypy and facilitating locomotion. The resultant behavioural response to systemic apomorphine shown by animals bearing these two types of lesion embodies these separate actions.

Lateralizing effects of apomorphine on taxis, postural support and rotation in rats

1. Subcutaneous injections of apomorphine, a dopamine receptor agonist, induced a lateralization of taxis for edges in 16% of rats and a reliable lateralization of postural support in 82% of rats. 2. The relation among these effects and the lateralizing effects of apomorphine on rotational behavior were examined. Lateralized rotation did not reliably correlate with lateralized taxis. However, it correlated with a relatively large asymmetry of postural support. 3. The lateralizing effects of apomorphine on taxis and rotation may reflect attentional and directional asymmetries, respectively. It is proposed that apomorphine can induce different types of lateralizations, including attentional, postural and directional, and that the lateralizing effects of apomorphine on posture and locomotor direction are interrelated. Regional brain interhemispheric asymmetries in the responsiviness of dopamine receptors may underlie different types of apomorphine-induced lateralizations.

Effects of cholecystokinin on apomorphine-induced changes of motility in rats

Subcutaneous injection of apomorphine in small doses decreased, while larger doses increased motility in rats. The hypomotility was abolished by intracerebroventricular administration of sulphated cholecystokinin octapeptide [CCK-8(s)], but not by non-sulphated CCK-8 [CCK-8(ns)]. In contrast, the hypermotility was not influenced by CCK peptides. An antiserum directed against the C-terminus of CCK did not affect hypermotility induced by apomorphine but suppressed the apomorphine-induced hypomotility further. The results indicate that sulphated CCK-peptides contribute to the control of motility, which can be inhibited by apomorphine.

A biphasic influence of globus pallidus lesions: Spontaneous catalepsy followed by anticataleptic effect

The behavioural and histological effects of unilateral or bilateral lesions induced by kainic acid injections into the globus pallidus were investigated in rats. Both lesions provoked a behavioural syndrome similar to those seen in animals treated systemically with neuroleptics or opiates. Animals displayed akinesia, ptosis, catalepsy, hypothermia and muscular rigidity. Also a marked hypersensitivity to touch, and a sensory neglect to touch and pain limited to hindlegs, adipsia, aphagia and high mortality of lesioned rats were observed. These symptoms were much stronger and lasted longer (catalepsy lasted over 15 days) in bilaterally lesioned animals. Subcutaneous injections of apomorphine in bilaterally lesioned rats abolished akinesia and catalepsy while rigidity and ptosis were unaffected. In unilaterally lesioned rats in which the lesion-induced spontaneous catalepsy already disappeared the spiperone-induced catalepsy was suppressed while in bilaterally lesioned animals which showed still pronounced lesion-induced catalepsy the spiperone-induced catalepsy was unchanged when compared to the sham-operated rats. Our results and the literature data suggest that the lesions of the globus pallidus produce biphasic effects: spontaneous catalepsy and unchanged neuroleptic catalepsy in the first phase and suppression of the neuroleptic catalepsy in the second phase. The role of the globus pallidus as a distal link (for neostriatum and n. accumbens) in neuronal chain forming a matrix of central patterns of catalepsy, akinesia and rigidity is discussed.

Cerebral dopamine, apomorphine and oral activity in the neonatal pig.

Neonatal piglets in which oral stimulation associated with feeding was reduced by intragastric tube feeding displayed an increase in stereotyped snout rubbing, licking and chewing behaviour. An investigation of a possible neurochemical basis for this behaviour was made by using sensitive radioenzymatic and microfluorimetric assays to estimate the concentrations of the catecholamines and of the dopamine metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenyl-acetic acid (DOPAC) in different brain regions. These observations revealed that the increased non-nutritive oral activity of such piglets did not appear to be caused by an increased release of dopamine in the brain, since it was not associated with increases in the concentrations of the acidic metabolites of dopamine in either the caudate nucleus, the putamen, the nucleus accumbens, the olfactory tubercle, the hypothalamus, or the substantia nigra. The only neurochemical changes observed were small decreases in the concentration of HVA in the putamen and the nucleus accumbens. A lack of effect on catecholamine concentrations in any of the six brain regions examined suggested that the environmental manipulation caused no changes in the development of catecholamine-containing nerve endings. Subcutaneous injection of apomorphine was found to increase the non-nutritive oral activity of piglets. Apparent conditioning effects of the environment on apomorphine-induced stereotyped behaviour however, prevented any satisfactory testing of possible changes in cerebral dopamine receptor sensitivity following reduced oral stimulation.

Ontogenesis of rearing and stereotypy responses to apomorphine in the rat.

The ontogenesis of rearing and stereotype behavior in response to apomorphine were investigated in the developing rat. The rearing was rarely observed in 15-day-old rats but distinctly in 18-day-old ones. A subcutaneous injection of apomorphine in dose of 1 mg/kg or 2 mg/kg decreased the frequency of rearing in older animals than day 20. On the other hand, 15-day-old rats were already responsive to apomorphine in stereotypy behavior. There was a reciprocal relationship between rearing and stereotypy responses to apomorphine in rat older than 18 days. Functional relationship between rearing and stereotypy in response to apomorphine were discussed in view of the central dopaminergic mechanisms in developing rats.

Subcutaneous injections of apomorphine, stimulus generalization and conditioning: Serious pitfalls for the examiner using apomorphine as a tool

This report shows that stimulus generalization occurs in rats conditioned by a single injection of apomorphine. The data suggest that apomorphine initially acts as an unconditioned stimulus (UCS) of an unconditioned response (UCR) that, in turn, produces stimuli which become conditioned stimuli (CS) of a conditioned response (CR) having a nature identical to that of the UCR. The study also shows that behaviour elicited by a subcutaneous injection of apomorphine depends on the part of the body selected for administration. The mentioned properties should be taken into account when apomorphine is used as a tool in studies on brain and behaviour.

A study of viscerocardiac reflexes: II. The experimental production of cardiac irregularities in icteric dogs with an analysis of the rôle played by nausea and vomiting

The results of this study seem to indicate clearly that nausea, retching and vomiting (induced by the subcutaneous injection of apomorphine) may cause in normal unanesthetized dogs cardiac irregularities, such as heart-blocks, cardiac arrests, ventricular and auricular ectopic beats. These are most likely to occur during retching. There were also changes in rate, nausea causing usually a tachycardia and retching a bradycardia. The intravenous injection of atropine almost completely inhibited the cardiac irregularities associated with nausea, retching and vomiting following the injection of apomorphine. The results indicate that during marked excitation of the vomiting center the cardio-inhibitory mechanism is affected, the degree to which it is affected depending upon its sensitivity. Icterus per se caused both the appearance and the disappearance of electrocardiographic abnormalities in a few instances. The changes in rate were variable, but the tendency was towards an increase. Slowing of the heart rate, however, may occur. Preexisting icterus increased the occurrence of the cardiac irregularities which are associated with the elicitation of nausea, retching, vomiting and pain by distention of the biliary passages. The irregularities following the injections of apomorphine could not be said to parallel closely the degree of icterus; but the changes due to distention of the biliary system did parallel the degree of icterus. This may have been due to the probable fact that apomorphine is a stronger stimulus. The results of the experiments on the icteric animals, we believe, indicate that icterus sensitizes the cardiovagal mechanism. Electrocardiographic abnormalities, such as extrasystoles, arrests, ectopic, ventricular, A-V blocks, etc., occurred in 10 per cent of the students while nauseated or retching during the swallowing of a stomach tube. No change in the rate was observed in one student. In the others there was an increase in rate which was dependent upon the ease with which the tube was swallowed. It is interesting to note that a bradycardia did not occur, whereas in dogs during retching bradycardia occurred very uniformly. In all experimental procedures, changes in the P-wave, the QRS complex and the T-wave occurred, none of the changes being characteristic.