Repeated Administration Of Apomorphine Research Articles

Repeated apomorphine administration alters dopamine D1 and D2 receptor densities in pigeon basal telencephalon

When pigeons are repeatedly administered a dose of apomorphine they show an increasing behavioral response, much as rodents do. In birds this expresses itself in an augmented pecking response. This sensitization is assumed to be largely due to a conditioning process. Here we present evidence that sensitization is accompanied by an alteration of the D(1) to D(2) dopamine receptor densities. An experimental group of pigeons was repeatedly injected with apomorphine, and a control group with saline. The basal forebrain tissue, known to be rich in dopamine receptors, was subjected to binding assays using tritiated specific D(1) and D(2) dopamine receptor antagonists. There was a trend towards an increase in D(1) and a significant decrease in D(2) receptor densities in apomorphine-treated birds compared to the saline-treated controls. We conclude that extended apomorphine treatment modifies the D(1) dopamine receptor density in the opposite manner to the D(2) dopamine receptor density.

Apomorphine-induced aggressive behaviour in para-chlorophenylalanine-treated male rats: implications to brain.

The aim of this study was to investigate the role of serotoninergic neurotransmission and the effect of acute para-chlorophenylalanine (350 mg/kg, intraperitoneally) treatment on apomorphine-induced aggressive behaviour in adult male Wistar rats. In addition, [3H]ketanserin binding and monoamine content were studied. Repeated administration of apomorphine (1.0 mg/kg, subcutaneously, once daily for two weeks) gradually induced aggressive behaviour. Acute p-chlorophenylalanine treatment down-regulated the [3H]ketanserin binding and reduced over 90 per cent the content of serotonin and 5-hydroxyindolacetic acid. In a half of the p-chlorophenylalanine-treated animals, the aggressive behaviour was suppressed, while there was no difference in [3H]ketanserin binding or monoamine content between the p-chlorophenylalanine treated aggressive and non-aggressive animals. In conclusion, the acute p-chlorophenylalanine treatment attenuates the aggressiveness only in half of the animals, while the latter phenomenon is independent on the CNS monoamine content or [3H]ketanserin binding.

Effects of repeated administration of l-DOPA and apomorphine on circling behavior and striatal dopamine formation

We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA–carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.

The effect of nigral implantation on sensitization to dopamine agonists in 6-hydroxydopamine-lesioned rats

The implantation of fetal nigral tissue into the striatum of patients with Parkinson's disease is a promising approach to treatment which may produce clinical benefit partly by influencing drug responsiveness. The purpose of the present study was to determine the pharmacological mechanisms which drug response changes by measuring to what extent sensitization produced by repeated apomorphine treatment was attenuated by tissue implantation in rats with nigrostriatal lesions. Prior to implantation of nigral cell suspensions, the daily administration of apomorphine to rats with unilateral 6-hydroxydopamine lesions produced a progressive increase in the magnitude and duration of rotational behaviour. After implantation, apomorphine-induced rotational effects were reduced to levels observed upon the initial exposure to drug and did not increase following repeated treatment. Attenuated responses to selective D 1 and D 2 agonists were also observed after implantation. In vehicle-implanted rats, the initial response to apomorphine was attenuated but then increased following repeated apomorphine administration. No attenuation in responses to selective D 1 and D 2 agonists was observed in this group. Cell suspensions prepared from fresh and cyropreserved tissue produced similar behavioural effects, even though the volume of transplanted striatum exhibiting tyrosine hydroxylase activity was greater with fresh tissue. The duration of rotational behaviour induced by apomorphine was not affected by cell implantation. These findings suggest that the expression of sensitization in an animal model of parkinsonism may disappear after a period without drug treatment. Implantation of nigral tissue may produce beneficial results in parkinsonism by limiting the development of dopamine agonist-induced sensitization.

Conditioned apomorphine-induced turning in 6-OHDA-lesioned rats

Apomorphine-induced turning has been used to evaluate the extent of unilateral nigrostriatal denervation after 6-hydroxydopamine (6-OHDA) lesions and subsequent functional striatal reinnervation by catecholaminergic grafts. It has been noted that the pregraft rotational pattern is usually double peaked and that fetal ventral mesencephalic grafts or dopaminergic drugs will alter the second peak but leave the first relatively unchanged. We hypothesized that the first peak may be the result of factors extrinsic to the nigrostriatal dopamine system, specifically a conditioned turning response, and would, therefore, be unperturbed by the above treatments which increase dopaminergic (DA) inputs. This was investigated by injecting 6-OHDA, unilaterally, into the nigrostriatal pathway of several groups of young Fisher 344 rats. One experimental group was repeatedly tested with 0.05 mg/kg apomorphine and the rotations quantified. A second group received similar injections of apomorphine but were prevented from rotating. Vehicle control animals were also studied for both of the above experimental groups. Subsequent to the above treatment, all animals were tested unrestrained repeatedly on apomorphine. Our results support the conditioned response hypothesis in that the first peak is not present with the initial unrestrained apomorphine behavioral trial but is present upon the second and subsequent unrestrained trials. Moreover, the restrained but apomorphine-injected rats, as well as the control animals, manifest no first peak upon their first freely moving apomorphine test; the second and subsequent unrestrained apomorphine trials, in these groups, do manifest a first peak. We conclude that the first peak represents respondently (Pavlovian) conditioned rotations and is, therefore, an indirect secondary behavioral result of unilateral nigrostriatal dopaminergic denervation and repeated apomorphine administration in an environment allowing unimpeded movements. These rotations are unlikely to be directly related to the cellular changes induced by dopaminergic manipulations in this system and, therefore, their presence in studies of striatal denervation and reinnervation using apomorphine-induced turning behavior should be interpreted accordingly.

Behavioral tolerance to repeated apomorphine administration in parkinsonian monkeys

Four consecutive injections (s.c.) of apomorphine (Apo) were given to 5 parkinsonian monkeys after i.v. MPTP administration. The minimal effective dose (MED) of Apo was defined as that capable of reducing motor disability by 50% or more for a minimum period of 30 min. Repeated apomorphine injections were given with an interval of 30 min after the motor effect of the previous injection had worn off or with a separation of 3 h between injections. The doses used in different experiments were the MED (2.4 μg/kg), 4 MED and 8 MED. In every experiment the duration of motor benefit was longest with the first Apo injection. There was a decay in the duration of the response elicited by consecutive Apo injections when given 30 min after the previous effect had wanted. This was significant for the MED and 4 MED (ANOVA, P < 0.01). When Apo boluses were given with an interval of 3 h there was a significant reduction in the duration of the response elicited by the MED, 4 MED and 8 MED of apomorphine. For the MED the reduction in the duration of the motor response was significantly greater for injections given with a 30-min interval than 3-h interval. These findings indicate that behavioral hyposensitivity to repeated Apo administration in parkinsonian monkeys occurs preferentially when near threshold doses are given with short intervals.

Time interval between repeated injections conditions the duration of motor improvement to apomorphine in Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration occurs in fluctuating parkinsonian patients. To determine to what extent the interval between doses influences the response, we administered equal paired apomorphine injections to 10 fluctuating parkinsonian patients. Subjects received two apomorphine injections at 2-hour and at 4-hour intervals on different days after a 10- to 12-hour overnight period without levodopa. Following apomorphine doses at 2-hour intervals, the duration of response was reduced by 40% (61 versus 42 minutes, p less than 0.001) but was of equal duration when the doses were given at 4-hour intervals. These findings indicate that the interval between doses is a critical determinant of motor response. We postulate a time-dependent period of partial hyposensitivity to pulsatile DA stimulation.

The Motor Response to Repeated Apomorphine Administration in Parkinsonʼs Disease

Seven patients with Parkinson's disease and levodopa-induced motor fluctuations were studied with repeated injections of apomorphine over a 10-h period to explore possible changes in the latency, duration, and quality of motor response with recurrent dopaminergic stimulation. Doses were given when the motor effects induced by the previous dose had just worn off. No significant change in the motor response to repeated boluses of subcutaneous apomorphine was found. Our results do not support the suggestion that rapid changes in receptor sensitivity during repeated intermittent dopaminergic stimulation are a major factor in the pathogenesis of parkinsonian motor fluctuations.

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.

Undrugged rotational response in nigro-striatal system-lesioned rats is related to the previous early response to apomorphine when repeatedly administered

Development and time-course characteristics of undrugged rotational response weeks or months after repeated apomorphine administration in 6-hydroxydopamine-lesioned rats (1) were explored. In one series of experiments, all groups recieved several drug doses two-three weeks post-lesion and remained undrugged at different intervals from the last drug injection. Weeks or months later, they were injected with saline in the same environment where they previously had recieved apomorphine. In this way we studied acquisition, time-course and extinction of the rotational response after saline. Furthermore, we related this undrugged response which does not fully develop until two weeks after treatment (2), and which previously had not been related to a specific parameter of the rotational response to the drug, to a critical point of the time-course response to the drug, i.e., the early rotational response in the first minute after injection. This earlu response is a learning phenomenon based on the environmental cues where drug has been repeatedly administered. Finally, we state the concept of pharmacological conditioning using this animal model of Parkinson's disease, in agreement with our own results and the previous results of Silverman and Ho (1981).

Behavioral and neurochemical effects of apomorphine in the cat

Administration of apomorphine (2–10 mg/kg i.p.) elicited a number of behaviors, such as limb flicking, abortive grooming, investigatory and hallucinatory-like responses, head and body shakes, and excessive grooming, which we have previously proposed as an animal model for studying the actions of LSD and related hallucinogens. Repeated administration of apomorphine resulted in a significant tolerance, which occurred within 2h of the initial injection, and completely dissipated within 24 h. A pronounced LSD-apomorphine cross tolerance was observed; however there was no significant apomorphine-LSD cross tolerance. Apomorphine-induced behavioral changes were blocked by prior treatment with haloperidol, but were unchanged by pretreatment with L-DOPA. Administration of L-DOPA, in combination with a peripheral decarboxylase inhibitor, did not elicit these characteristic behavioral changes. Increasing synaptic serotonin levels by monoamine oxidase inhibition, precursor administration, or reuptake blockade in general did not alter the behavioral response to apomorphine. Similarly, pretreatment with serotonin receptor blockers produced no large changes in apomorphine-induced behaviors. Prior serotonin depletion with chronic p-chlorophenylalanine administration, however, potentiated certain apomorphine-induced behaviors. Neurochemical studies revealed that apomorphine administration increased striatal dopamine, and decreased dopamine metabolites. Norepinephrine levels were generally decreased throughout the CNS by apomorphine treatment. Administration of apomorphine increased CNS serotonin and 5-hydroxyindoleactic acid levels, while tryptophan levels were unchanged. The biological bases of the limb flick model is discussed in the context of these pharmacological and neurochemical studies.

Evidence for Dopamine Mediation of Submissive Gestures in the Stumptail Macaque Monkey

Evidence gathered from several experiments where stimulant drugs were given to selected members of adult Stumptail macaque social colonies is presented which suggests that dopamine systems play an important part in the mediation of submissive behavior in this species. Chronic administration of d-amphetamine, 3.2 mg/kg/day, for 12 days, induced a significant increase in submissive gestures displayed by some treated monkeys despite the lack of a significant concurrent increase in aggressive gestures directed toward these animals. This behavioral change was antagonized by haloperidol and pimozide, two agents with preferential dopamine receptor blocking properties. The dopamine receptor agonist apomorphine induced a large dose-dependent increase in submissive gestures displayed by treated monkeys. Repeated administration of apomorphine, 1.0 mg/kg/day, for 12 days, induced a significant increase in submissive gestures comparable to amphetamine in monkeys who had previously received chronic d-amphetamine treatment. In addition, it appears that the significant increase in submissive gestures by monkeys treated with the hallucinogen 5-methoxy N,N-dimethyltryptamine is also mediated through dopamine systems since the preferential dopamine receptor blockers haloperidol and trifluoperazine antagonized this response while the serotonin antagonists cinanserin, methysergide, metergoline, and cyproheptadine all failed to antagonize or even potentiate this behavioral change. These results have important implications in the study of animal behavior and may have relevance to drug-induced and endogenous psychopathologies in humans as well.