Supersensitive State Research Articles

Dopamine D2 up-regulation in psychosis patients after antipsychotic drug treatment.

Recently, it has been questioned whether the re-emergence of psychotic symptoms following antipsychotic discontinuation or dose reduction is attributable to underlying psychotic vulnerability or to rebound effects of chronic use of antipsychotic medication. It was repeatedly shown that relapse rates are high after discontinuation of maintenance treatment. A potential contributing factor could be the increase in density of postsynaptic dopamine D2 receptors in the striatum and the higher affinity of D2 receptors for dopamine after chronic blockade. To date, little clinical evidence is available for the mechanisms involved in postsynaptic striatal D2 receptor up-regulation after use of antipsychotic medication, and most knowledge comes from animal studies. Further research is needed to investigate whether antipsychotic medication causes neuroadaptations leading to a dopamine supersensitive state in humans, how long such hypersensitive states may last and what differences exist between high and low D2 affinity antipsychotic drugs. Further, information is needed on discontinuation schedules that provide optimal protection for relapse during hypersensitive periods.

5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity

Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025–0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

Dopamine receptor inactivation in the caudate-putamen differentially affects the behavior of preweanling and adult rats

The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in young and adult rats. Most notably, systemic administration of EEDQ blocks the DA agonist-induced behaviors of adult rats, while leaving the behavior of preweanling rats unaffected. The purpose of the present study was to: (a) determine whether the age-dependent actions of EEDQ involve receptors located in the dorsal caudate-putamen (CPu) and (b) confirm that EEDQ’s behavioral effects result from the inactivation of DA receptors rather than some other receptor type. In Experiment 1, EEDQ or DMSO was bilaterally infused into the CPu on PD 17 or PD 84. After 24h, rats were given bilateral microinjections of the full DA agonist R(−)-propylnorapomorphine (NPA) or vehicle into the dorsal CPu and behavior was assessed for 40min. In Experiment 2, preweanling rats were treated as just described, except that DA receptors were protected from EEDQ-induced alkylation by administering systemic injections of D1 (SCH23390) and D2 (sulpiride) receptor antagonists. As predicted, microinjecting EEDQ into the dorsal CPu attenuated the NPA-induced locomotor activity and stereotypy of adult rats. In contrast, rats given bilateral EEDQ infusions on PD 17 exhibited a potentiated locomotor response when treated with NPA. Experiment 2 showed that DA receptor inactivation was responsible for NPA’s actions. A likely explanation for these results is that EEDQ inactivates a sizable percentage of DA receptors on PD 17, but leaves the remaining receptors in a supersensitive state. This receptor supersensitivity, which probably involves alterations in G protein coupling, could account for NPA-induced locomotor potentiation. It is likely that adult rats to not show a similar EEDQ-induced change in receptor dynamics or DA receptor inactivation was more complete in older animals and effectively eliminated the expression of DA agonist-induced behaviors.

Role of serotonin neurons in the induction of levodopa‐ and graft‐induced dyskinesias in Parkinson's disease

Recent studies in animal models of Parkinson's disease (PD) have provided evidence that dopamine released from spared serotonin afferents can act as a trigger of dyskinetic movements induced by repetitive, low doses of levodopa. Serotonin neurons have the capacity to store and release dopamine synthesized from systemically administered levodopa. However, because of the lack of any autoregulatory feedback control, dopamine released from serotonin terminals results in excessive swings in extracellular dopamine levels after peripheral administration of levodopa. Such "dysregulated" release of levodopa-derived dopamine is likely to be responsible for the appearance of the abnormal movements in levodopa-primed animals. This mechanism may also play a role in the development of graft-induced dyskinesias in patients that receive fetal neuron transplants, possibly due to the inclusion of serotonin neurons in the grafted ventral midbrain tissue, which contribute to maintain dopamine receptors of the denervated striatum in a supersensitive state.

P-17-6 - A study of regional cerebral blood flow with 99TC-HMPAO-SPECT in eating disorders

The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in young and adult rats. Most notably, systemic administration of EEDQ blocks the DA agonist-induced behaviors of adult rats, while leaving the behavior of preweanling rats unaffected. The purpose of the present study was to: (a) determine whether the age-dependent actions of EEDQ involve receptors located in the dorsal caudate-putamen (CPu) and (b) confirm that EEDQ’s behavioral effects result from the inactivation of DA receptors rather than some other receptor type. In Experiment 1, EEDQ or DMSO was bilaterally infused into the CPu on PD 17 or PD 84. After 24 h, rats were given bilateral microinjections of the full DA agonist R(−)-propylnorapomorphine (NPA) or vehicle into the dorsal CPu and behavior was assessed for 40 min. In Experiment 2, preweanling rats were treated as just described, except that DA receptors were protected from EEDQ-induced alkylation by administering systemic injections of D1 (SCH23390) and D2 (sulpiride) receptor antagonists. As predicted, microinjecting EEDQ into the dorsal CPu attenuated the NPA-induced locomotor activity and stereotypy of adult rats. In contrast, rats given bilateral EEDQ infusions on PD 17 exhibited a potentiated locomotor response when treated with NPA. Experiment 2 showed that DA receptor inactivation was responsible for NPA’s actions. A likely explanation for these results is that EEDQ inactivates a sizable percentage of DA receptors on PD 17, but leaves the remaining receptors in a supersensitive state. This receptor supersensitivity, which probably involves alterations in G protein coupling, could account for NPA-induced locomotor potentiation. It is likely that adult rats to not show a similar EEDQ-induced change in receptor dynamics or DA receptor inactivation was more complete in older animals and effectively eliminated the expression of DA agonist-induced behaviors.

Levodopa or D2 agonist induced dyskinesia in MPTP monkeys: correlation with changes in dopamine and GABA A, receptors in the striatopallidal complex

Dopamine D1 and D2 receptors as well as the GABA/benzodiazepine receptor complex in the striatum and the globus pallidus (internal: GPi and external: GPe) were studied by autoradiography using [ 3H]SCH 23390, [ 3H]spiperone, and [ 3H]flunitrazepam ([ 3H]FNZ) respectively, in five groups of cynomolgus monkeys. These included (i) untreated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-monkeys; (ii) MPTP monkeys treated chronically with levodopa injections; (iii) MPTP monkeys treated chronically with injections of the novel D2 agonist U91356A; (iv) MPTP monkeys treated chronically with U91356A delivered through an osmotic mini-pump; and (5) naive controls. Animals treated in a pulsatile mode with U91356A or levodopa injections showed progressive sensitization to their respective drug and developed choreic dyskinesia. In contrast, animals treated in a continuous mode with U91356A showed behavioral tolerance but did not develop dyskinesia. A trend for a down-regulation of putaminal D2 receptors was observed following D2 agonist stimulation with U913356A. Striatal [ 3H]FNZ binding was significantly decreased only in animals treated in a continuous mode with U91356A. The dopamine receptor decrease in the striatum could be implicated with the development of tolerance but cannot explain the appearnce of dyskinesia. Denervation by MPTP was associated with a decrease of the GPe/GPi [ 3H]FNZ binding ratio which reflects an imbalance of striatal output pathways; this ratio was not reversed by any of the treatments although changes were observed in the GPe and GPi. Indeed, pulsatile U91356A treatment restored the decreased [ 3H]FNZ binding in the GPe near control values and levodopa showed a similar tendency. A significant increase of [ 3H]FNZ binding in the GPi only of dyskinetic monkeys, namely those treated with pulsatile U91356A or levodopa was seen compared to untreated MPTP or naive controls. This GABA A receptor up-regulation might lead to a supersensitive state of the GPi to gabaergic input which may be involved in the mechanism underlying the development of dopaminomimetic-induced dyskinesia.

Molecular Mechanisms of Regulation of Neuronal Muscarinic Receptor Sensitivity

Like other neurotransmitter receptors, muscarinic acetylcholine receptors are subject to regulation by the state of receptor activation. Prolonged increases in the concentration of muscarinic agonists result in a decrease in receptor density and loss of receptor sensitivity, both in vivo and in vitro. On the other hand, when the receptor is deprived of acetylcholine for a long duration in vivo, the receptor becomes more sensitive in responding to muscarinic agonists. However, it has been more difficult to demonstrate increases in receptor concentration that accompany this supersensitive state. The purpose of this review is to provide current information related to the characteristics of muscarinic receptor regulation and the molecular mechanisms underlying this phenomenon, regarding both the density of receptors and their transduction mechanisms. Furthermore, possible feedback regulatory roles of different second messenger signals are discussed. Particular emphasis is dedicated to molecular mechanisms of regulation of neuronal muscarinic receptors.

Reversal of the increase in apomorphine-induced stereotypy and aggression in REM sleep deprived rats by dopamine agonist pretreatments.

REM sleep deprivation (REMSD) induces augmented responses to dopaminergic agonists. Prolonged administration of neuroleptics induces a similar state, probably by the production of supersensitivity of dopaminergic receptors. Such a supersensitive state could be induced by REMSD as a result of impairment of dopamine neurotransmission. In order to test this hypothesis, bromocriptine, nomifensine, amphetamine, L-dopa, imipramine and electroconvulsive shock (ECS) were administered to rats during REMSD, and aggressive and stereotyped behaviors were measured. Amphetamine and L-dopa pretreatment attenuated the increases in apomorphine-induced stereotypy and aggression in REMSD rats, but ECS selectively reduced apomorphine-induced aggression. The other drugs tested were ineffective on both behavioral tests. Such a selective action may reflect different effects of ECS on different dopaminergic systems such as those involved with stereotypy and aggression. The results suggest that REMSD induces an increase in dopaminergic sensitivity which may be reversed by pretreatment with some dopaminergic agonists.

Apomorphine response plasticity in lesioned rats: supersensitivity dependency and lack of drug- or non-drug-associated environmental cuing.

Low doses of apomorphine can induce biphasic, contralateral circling behaviour in rats having unilateral, 6-hydroxydopamine lesions of the substantia nigra. The present studies examined the extent to which this is linked to the supersensitive state, the possible contribution of apomorphine's actions in the intact striatum, and the extent to which response differentiation might be linked to drug- or non-drug-associated environmental cuing. In the first instance, weekly administration of 0.4 mg/kg SC apomorphine to "normosensitive" rats having electrolytic ablation of one caudate failed to result in biphasic circling, whereas clear biphasic responses developed in supersensitive, 6-hydroxydopamine lesioned animals receiving 0.05 mg/kg SC apomorphine at weekly intervals. In the second instance, 6-hydroxydopamine-lesioned animals exhibiting biphasic responses after three exposures to apomorphine continued to do so after additional electrolytic ablation of the contralateral caudate, indicating a primary role for apomorphine's interaction within the denervated striatum. In studying the possible role of drug- or non-drug-associated environmental cuing effects it was found that repeated exposure of 6-hydroxydopamine-lesioned rats to 0.05 mg/kg SC apomorphine at 2-h intervals failed to elicit biphasic responses, although these were evident when the same animals were tested 1 and 2 weeks later. However, studies combining weekly exposure to the test cages with saline or apomorphine administration failed to reveal a role of drug- or nondrug-associated environmental cuing in response differentiation. The latter findings are supported by those from supplementary studies employing opaque contact lenses, in which lesioned animals continued to respond biphasically to apomorphine when deprived of visual input.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogenesis of dopaminergic neurons in the post-natal rabbit retina: Pre- and post-synaptic elements

The post-natal development of several aspects of the dopaminergic system in the rabbit have been examined. Dopamine (DA) itself was barely detectable from soon after birth up to about 7 days of age. Thereafter, dramatic increases in the retinal content of DA and also of the two major enzymes involved in its biosynthesis were observed, approaching adult values by about 16 days. These changes occur when functional synapses are being formed as judged by electrophysiological and anatomical studies. On the other hand, the post-synaptic target of these neurons, DA-stimulated adenylate cyclase could be easily detected at 3 days of age and did not appear to undergo any dramatic changes in activity during development. The affinity of haloperidol for this receptor did, however, appear to decrease with age suggesting that the receptor is ‘born’ in a supersensitive state but attains ‘normal’ properties after the onset of DA neurotransmission. Depletion of DA stores during these early stages by irreversible inhibition of biosynthesis in vivo did not appear to halt the development of tyrosine hydroxylase or have any irrevocable effects on DA neurons. This suggests that the continued presence of neurotransmitter is not necessary for the developmental process to continue and that the commitment of particular neurons to become dopaminergic may be made earlier than 5–6 days post-natally.

Changes in tissue sensitivity to drugs in relation with alteration in receptors by treatment of drugs.

Tissues responses for drugs are often altered by chronic administration of drugs and this alteration is one kind of functional abnormality of the tissues. One mechanism under this functional abnormalities is considered to be in changes in receptors for drugs. In this study, we examined amounts and properties of receptors in sub- and supersensitive states caused by pre-exposure of tissues to drugs and the results obtained were summarized as follows. Long term exposure of tissue to agonists or to conditions which elevate concentration of agonist around the receptor caused reduction in amount of receptor without change in its property. Short term exposure to agonists altered the configuration of the receptor accompanying reduction in sensitivity of the tissue to drugs. But amount of receptor in the tissue was not changed. Heterologous desensitization was observed in some cases by exposure to drugs and no significant change was observed in the receptor of the tissue, qualitatively and quantitatively, indicating dysfunction in the process(es) after activation of the receptor. Denervation and chronic treatments with antagonist and ganglion blocker caused supersensitive state accompanying increase in amount of receptor. But in some cases, qualitative change of receptor, increase in affinity of receptor for agonist, seemed to relate with supersensitive state of tissues.