Apomorphine Sensitization Research Articles

Inhibition of apomorphine-induced behavioral sensitization in rats pretreated with fluoxetine.

Despite a number of clinically useful effects, there is growing evidence that psychosis and impulse control disorders develop in patients on apomorphine therapy. Evidence suggests a critical role of serotonin-1A receptors in psychosis, drug abuse, and in the mechanism of action of the prototypical selective serotonin reuptake inhibitor fluoxetine. We investigated whether fluoxetine can prevent apomorphine-induced behavioral sensitization in a rat model of psychosis. Animals treated with fluoxetine (5 and 10 mg/kg) for 2 weeks were subsequently cotreated with apomorphine (1.0 mg/kg) for 7 days. A single injection of apomorphine increased motor activity, whereas repeated daily injections produced a progressive sensitization of motor behavior. The sensitization effects of apomorphine did not occur in fluoxetine-pretreated and subsequently cotreated animals. To further elucidate the mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-treated animals, we found that apomorphine-induced motor behavior was much greater in repeated apomorphine-treated than repeated saline-treated animals. It was also greater in apomorphine and fluoxetine-cotreated animals, but not in animals pretreated and cotreated with fluoxetine. The mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-pretreated animals is discussed. The findings introduce an innovative approach for extending the therapeutic use of apomorphine and classical psychostimulant drugs.

Increase in medial frontal cortex ERK activation following the induction of apomorphine sensitization

Repeated high dose injections of the direct acting D1/D2 agonist apomorphine (APO) induces context specific behavioral sensitization. We assessed the effects of 2.0mg/kg APO on open-field locomotor responses of rats over a 30min period following either single or five daily APO injections. Acute injections increased locomotor activity, which was markedly increased in rats given 5 daily APO injections. This progressive increase in locomotion during the repeated APO treatments is indicative of behavioral sensitization. Immediately following the open-field test for the acute and the fifth apomorphine injection, the animals were euthanized and their brain tissue was prepared for immunohistochemistry. ERK immunoreactive nuclei in the medial prefrontal cortex (PFC), nucleus accumbens (NAcc), amygdala (AMYG) and lateral hypothalamus (LH) were quantified. The acute apomorphine injections increased ERK in all brain areas as compared to vehicle. Following the fifth apomorphine injection, ERK significantly increased in the PFC, decreased in the amygdala but was unchanged in the LH and NAcc. The selective increase in ERK activity in the PFC associated with behavioral sensitization, points to a possible pivotal role of the dopamine projection to the medial frontal cortex in the mediation of neural plasticity, considered to underlie the sensitization processes induced by dopaminergic drugs.

Enhancement and inhibition of apomorphine-induced sensitization in rats exposed to immobilization stress: Relationship with adaptation to stress

Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre-dispose to depression. Pre-clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress. The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine-induced sensitization. Apomorphine was injected either before exposure or after the termination of immobilization, daily for 5days, to monitor drug-induced behavioral sensitization and tolerance in immobilization stress-induced anorexia. We find that apomorphine-induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode. Conversely, apomorphine-induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode. It shows that apomorphine, if experienced during stress, produces greater sensitization and impairs stress tolerance. Conversely, sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode. It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and 5-HT-1A influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress. The results may help develop potential pharmacotherapies when substance abuse/dependence disorder and depression occur together.

Opposite effects of typical and atypical anti-psychotic drugs on sensitized dopamine receptors: Sub-chronic low dose Olanzapine exposure reverses sensitization but a similar regimen of low dose haloperidol potentiates sensitization effects

Both typical and atypical antipsychotic drugs are D2 receptor antagonists but yet appear to have markedly different effects upon the induction of dopamine sensitization. This study aims to compare the effects of subchronic regimens of low-dose olanzapine and haloperidol administered to rats previously sensitized to apomorphine. Initially, rats received apomorphine (2.0mg/kg) or vehicle treatments for five consecutive days followed by a conditioning test and an apomorphine challenge test. Next, there was an antipsychotic exposure phase in which three vehicle groups and three apomorphine groups received 10 daily injections of either vehicle, haloperidol (0.03mg/kg) or olanzapine (0.01mg/kg). In the final phase, all groups were given a second conditioning test and apomorphine challenge test. Apomorphine induced sensitization and conditioning effects. Following haloperidol exposure, apomorphine conditioned and sensitization effects were potentiated but, in contrast, olanzapine exposure eliminated apomorphine sensitization effects. In addition, the sensitization induced by apomorphine transformed the low-dose haloperidol treatment into a potent locomotor stimulant treatment. In the vehicle groups, haloperidol and olanzapine exposure effects were equivalent and not different from vehicle treatment. The profound differences observed between typical and atypical antipsychotic exposure in animals with an upregulated dopamine system are consistent with clinical evidence for lower risk of psychomotor disturbances with chronic treatment with atypical antipsychotic. Importantly, the finding that a very low dose of olanzapine reversed sensitization effects suggests that low-dose olanzapine may have clinical utility in a variety of disorders linked to sensitization of the dopamine system.

Residual dopamine receptor desensitization following either high- or low-dose sub-chronic prior exposure to the atypical anti-psychotic drug olanzapine

Anti-psychotic drugs are antagonists of dopamine D2 receptors and repeated administration may lead to the development of dopamine receptor supersensitivity. The objective of this study is to investigate the effects of sub-chronic olanzapine treatments upon the induction of dopamine receptor supersensitivity. Rats were administered ten daily low or high doses of the atypical anti-psychotic drug olanzapine (0.01 or 1.0 mg/kg). After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on five successive days. Five days after the apomorphine sensitization protocol, in separate experiments, either a conditioning test or an apomorphine sensitization test was conducted. During the anti-psychotic treatment the high dose of olanzapine induced profound locomotion suppression, whereas the low dose had no effect upon locomotion. The apomorphine treatments given to the vehicle control group generated locomotor sensitization. This sensitization effect was attenuated by the same degree for both the low or high dose prior olanzapine treatments. Also, the low and high-dose olanzapine pre-treatments diminished subsequent apomorphine-conditioned and apomorphine-sensitized locomotor responses. The equivalent attenuation of the apomorphine sensitization produced by both olanzapine doses indicates that this effect was unrelated to the direct effects of olanzapine upon locomotion. Furthermore, the persistence of the desensitization effects well after the termination of the olanzapine treatments is indicative of a residual desensitization of the dopamine system. These findings are of importance when considering the use of atypical anti-psychotic drugs in the treatment of psychoses and other disorders in which overactivity of the dopamine system is considered a contributory factor.

Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: Evidence that at a very low dose haloperidol acts as an indirect dopamine agonist

Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.

Memory re-consolidation and drug conditioning: an apomorphine conditioned locomotor stimulant response can be enhanced or reversed by a single high versus low apomorphine post-trial treatment

Psychostimulant sensitization can have transformative effects upon contextual stimuli such as acquired conditioned stimuli and conditioned incentive motivational properties. The aim of this study is to induce apomorphine sensitization and conduct non-drug exposures to the contextual cues followed by post-trial treatments designed to associate increases/decreases in dopamine activity with re-consolidation of the contextual cue conditioned stimulus. Separate groups received five daily apomorphine (2.0mg/kg) treatments, paired or unpaired to the test environment. Two days later, a 30-min non-drug conditioning test was performed. Subsequently, there were three brief (5min) conditioning tests on successive days. After removal from the test environment on the three test days, all groups received post-trial treatment with vehicle, 0.05, and 2.0mg/kg apomorphine. One day later, a second 30-min conditioning test was conducted. There was a sensitized and a conditioned locomotor stimulant response in the paired groups. After the first and second post-trial treatments with 0.05mg/kg apomorphine, the conditioned stimulant response in the paired group was transformed into a conditioned inhibitory response. In contrast, the conditioned stimulant response of the paired group administered with apomorphine 2.0mg/kg post-trial was amplified. The apomorphine post-trial treatments administered to the unpaired groups or 2h post-trial to paired groups were without effect. These findings suggest that sensitization substantially enhances the associative sensitivity of contextual stimuli and imply that brief exposure to cues linked to drugs of addiction followed by treatments that inhibit neurotransmitter systems may provide a new direction in drug abuse treatment.

Apomorphine conditioning and sensitization: The paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects

Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization.

Apomorphine-induced context-specific behavioural sensitization is prevented by the D1 antagonist SCH-23390 but potentiated and uncoupled from contextual cues by the D2 antagonist sulpiride

In the study of behavioural sensitization induced by dopamine agonists, D1 and D2 receptors have a critical, but a puzzling role. The objective of this study is to examine the effects of the D1 antagonist SCH-23390 and the D2 antagonist sulpiride given repeatedly alone or in combination with apomorphine upon apomorphine conditioning and sensitization. Apomorphine-induced (2.0 mg/kg) conditioning and sensitization were assessed following five paired/unpaired treatments. Sulpiride (10, 30 and 100 mg/kg) and SCH-23390 (0.01, 0.02 and 0.05 mg/kg) were administered alone or in combination with apomorphine. In experiment 1, the effect of 5 days of sulpiride and SCH-23390 treatments given alone were assessed on apomorphine reactivity. In experiment 2, sulpiride and SCH-23390 were co-administered with apomorphine for 5 days and subsequently, conditioning and sensitization tests were performed. In experiment 3, following five apomorphine treatment sessions, sulpiride and SCH-23390 were administered prior to the conditioning and sensitization tests. SCH-23390 and sulpiride induced hyper-reactivity to apomorphine. SCH-23390 when given after the induction of apomorphine sensitization, blocked the expression of apomorphine sensitization. When given in combination with apomorphine, SCH-23390 blocked the apomorphine conditioning and sensitization, whereas low-dose sulpiride permitted conditioning and enhanced apomorphine sensitization and high-dose sulpiride blocked conditioning but permitted apomorphine sensitization. Both sulpiride doses transformed apomorphine sensitization from context-specific to context-independent sensitization. The SCH-23390 findings are supportive of a critical role for D1 receptors in apomorphine effects whereas the sulpiride effects diminish the importance of conditioning and dopamine autoreceptor subsensitivity mechanisms in the mediation of apomorphine sensitization.

Apomorphine sensitization: evoking conditions, context dependence, effect persistence and conditioned nature.

When repeatedly administered a dose of apomorphine (Apo), pigeons, much like rodents, show behavioural sensitization. In birds this sensitization expresses itself as an increasing pecking response to the drug and is found to be partially dependent on the environmental context in which Apo takes effect. In the first experiment we examined what effect different inter-Apo administration intervals have on the development of Apo sensitization and found that, with some smaller variations, intervals between 3 hours and 5 days all yielded comparable courses of sensitization. In the second experiment we examined how long pigeons had to be exposed to the same distinct cage to reveal a maximal context-dependent sensitization. Pigeons were therefore repeatedly injected with Apo and consistently placed in an experimental cage for different lengths of time (5 to 60 min; the overall drug effect lasted for about 1 h) before being returned to their standard home cages. Subsequent tests in the experimental cage and a standard cage showed that 20-min post-injection exposures were sufficient to yield a maximal response in the experimental cage. After training with 20- and 60-min exposures, the pigeons pecked about three times more in the experimental cage than in the standard cage. This confirmed the marked context dependency of the sensitization effect. In the third experiment, groups of pigeons were injected repeatedly with Apo and directly afterwards placed either consistently into the same experimental cage or into different experimental cages. The same-cage group evidenced a significantly much stronger sensitization than the different-cage group. A cage-habituation group served as a control for the possibility that the weaker sensitization of the different-cage group might be due to a cage novelty effect. This cage-habituation group was run under the same conditions as the different-cage group but with additional exposures to the crucial cage while injected with saline. This extra treatment did not augment the pecking response to Apo in that cage. In the fourth experiment we examined how long the sensitization to Apo lasts and found that, even after 2 years of drug abstinence, it only waned to 50% of the original asymptotic response. The overall results support the hypothesis that a very major part of the sensitization to Apo in pigeons is due to a conditioning to the environmental context and to the drug state itself.

Apomorphine sensitization effects: Evidence for environmentally contigent behavioral reorganization processes

Apomorphine-induced behavioral sensitization was investigated with a Pavlovian conditioning paradigm. Rats were administered apomorphine (2.0 mg/kg SC) daily for 7 days either paired or unpaired with a 10-min test environment placement. Initially, apomorphine induced hypolocomotion, but by treatment day 5, hyperlocomotion developed. Utilizing a videoimage analysis program which quantitated angular movement, it was determined that the increase in locomotion induced by repeated apomorphine treatment was due to an increase in rotational locomotion. Critically, rotation per se did not increase, but rather wide angle rotation toward the periphery of the test environment increased. Furthermore, a directional bias of rotation developed and stabilized which was unrelated to the animal's initial asymmetry bias. This emergence of a new locomotion pattern in conjunction with hyperlocomotion pointed to the need to reconceptualize behavioral sensitization phenomena into a new framework consistent with a progressive change in behavioral structure. Behavioral reorganization is presented as an alternative formulation to that of behavioral sensitization, as a drug-environment interactive process which is more compatible with the behavioral dynamics that emerge with repeated intermittent dopaminergic psychostimulant drug treatment.