Development Of Supersensitivity Research Articles

Pentadecapeptide BPC 157 and the central nervous system.

We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157, three very recent demonstrations that may be essential in the gut-brain and brain-gut axis operation, and therapy application in the central nervous system disorders, in particular. Firstly, given in the reperfusion, BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke, sustained brain neuronal damages were resolved in rats as well as disturbed memory, locomotion, and coordination. This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats. Secondly, there are L-NG-nitro arginine methyl ester (L-NAME)- and haloperidol-induced catalepsy as well as the rat acute and chronic models of ‘positive-like’ schizophrenia symptoms, that BPC 157 counteracted, and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine (dopamine agents application), MK-801 (non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration (to induce sensitivity). Thirdly, after rat spinal cord compression, there were advanced healing and functional recovery (counteracted tail paralysis). Likewise, in BPC 157 therapy, there is specific support for each of these topics: counteracted encephalopathies; alleviated vascular occlusion disturbances (stroke); counteracted dopamine disturbances (dopamine receptors blockade, receptors super sensitivity development, or receptor activation, over-release, nigrostriatal damage, vesicles depletion), and nitric oxide-system disturbances (“L-NAME non-responsive, L-arginine responsive,” and “L-NAME responsive, L-arginine responsive”) (schizophrenia therapy); inflammation reduction, nerve recovery in addition to alleviated hemostasis and vessels function after compression (spinal cord injury therapy). Thus, these disturbances may be all resolved within the same agent’s beneficial activity, i.e., the stable gastric pentadecapeptide BPC 157.

Plasma monoamines change under dopamine supersensitivity psychosis in patients with schizophrenia: A comparison with first-episode psychosis.

Patients with first-episode psychosis respond well to initial antipsychotic treatment, but among patients experiencing a relapse of psychosis, the response rate falls to approximately 30%. The mechanism of this discrepancy has not been clarified, but the development of dopamine supersensitivity psychosis with the underlying up-regulation of post-synaptic dopamine D2 receptors could be involved in this lesser response. It is uncertain whether elevated dopamine synthesis and release occurs in patients with dopamine supersensitivity psychosis, in contrast to those with first-episode psychosis. We examined a first-episode psychosis group (n=6) and a chronic schizophrenia group, i.e. patients experiencing relapse (n=23) including those who relapsed due to dopamine supersensitivity psychosis (n=18). Following the initiation of treatment, we measured the patients' blood concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol at two weeks and four weeks after the baseline measurements. The first-episode psychosis group tended to show decreased homovanillic acid, accompanied by an improvement of symptoms. The chronic schizophrenia group showed no alteration of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol over the treatment period. These results were the same in the dopamine supersensitivity psychosis patients alone. Our findings suggest that unlike first-episode psychosis, the release of dopamine from presynaptic neurons did not increase in relapse episodes in the patients with dopamine supersensitivity psychosis. This indirectly indicates that the development of supersensitivity of post-synapse dopamine D2 receptor is involved in relapse in dopamine supersensitivity psychosis patients.

Dopamine D1 receptor antagonist reduces stimulant-induced conditioned place preferences and dopamine receptor supersensitivity.

Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals; however, dopamine receptor subtypes associated with the development of supersensitivity in CPP animals are largely unknown. The present preclinical study aimed to examine whether dopamine D1 or D2 receptor antagonists exert inhibitory effects on stimulant-induced psychological behaviors. Additionally, the authors aimed to elucidate the role of dopamine receptor supersensitivity on the development of reward-related behavior. Sprague Dawley rats subjected to methamphetamine- and cocaine-induced CPP tests were treated with dopamine D1 (SCH23390) or D2 (sulpiride) receptor antagonists. Following the CPP experiment, rats were challenged with apomorphine (dopamine receptor agonist), and locomotor activity was measured. Methamphetamine- and cocaine-induced CPP was reduced with the administration of SCH23390, but not sulpiride. In addition, the apomorphine challenge evoked an increase in locomotor activity in stimulant-pre-treated rats, reflecting dopamine receptor supersensitivity. SCH23390 pre-treatment inhibited the development of dopamine receptor supersensitivity, while sulpiride demonstrated no inhibitory effects. These results suggest that the dopamine D1 receptor antagonist SCH23390 inhibits the development of dopamine receptor supersensitivity which is associated with the development of CPP.

Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D2, D3 and serotonin2A receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D2 agonist quinpirole-induced hyperlocomotion test and a dopamine D2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D2 receptor density. Further, our results show that mRNA levels of dopamine D2 and D3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D3 receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D3 receptors than haloperidol, antagonism of blonanserin at dopamine D3 receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity.

Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?

Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

Dopamine receptor changes after long-term haloperidol treatment in rats.

Abstract Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits & Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans & Rubovits 1972; Moore & Thornburg 1975; Sayers et al 1975; Tarsy & Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H-neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.

Enhancement of Phosphatidylinositol Turnover and Cyclic Nucleotide Accumulation by Chronic Anethole Trithione Treatment in Rat Submaxillary Glands

The effect of chronic treatment with anethole trithione (ANTT) on the phosphatidylinositol (PI) turnover and cyclic (c)AMP and cGMP accumulation in rat submaxillary glands (SMG) has been compared with the effect of chronic treatment with atropine and a cholinesterase inhibitor, diisopropylfluorophosphate (dyflos, DFP). Experiments were performed 24, 48 and 24 h after the last dose of ANTT, atropine and dyflos, respectively. ANTT and atropine enhanced carbachol-stimulated [32P] incorporation into phosphatidic acid in the SMG slices, while dyflos showed no effect. Pilocarpine-stimulated in-vivo incorporation of [3H]myoinositol into inositol phosphates was significantly enhanced by ANTT, but not by atropine or by dyflos. Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by ANTT and atropine, but not by dyflos. Pilocarpine-stimulated in-vivo accumulation of cAMP and cGMP was enhanced by ANTT and atropine, but dyflos reduced cAMP accumulation without affecting cGMP accumulation. The enhancement of PI turnover and cyclic nucleotide accumulation seems to contribute to the development of supersensitivity of the salivary gland caused by chronic treatment with ANTT and atropine, while reduction of cAMP accumulation may be responsible for the subsensitivity caused by dyflos.

Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis

Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia.

Involvement of Ca 2+-dependent PKCs in the adaptive changes of μ-opioid pathways to sympathetic denervation in the guinea pig colon

In the guinea pig colon, chronic sympathetic denervation entails supersensitivity to inhibitory μ-opioid agents modulating cholinergic neurons. The mechanism underlying such adaptive change has not yet been unravelled, although protein kinase C (PKC) may be involved. A previous study indirectly demonstrated that activation of μ-opioid receptors on myenteric neurons facilitates PKC activity. Such coupling may counteract the inhibitory action of μ-opioid agents on acetylcholine overflow, since PKC, per se, increases this parameter. After chronic sympathetic denervation such restraint abates, representing a possible mechanism for development of supersensitivity to μ-opioid agents. In the present study, this hypothesis was further investigated. After chronic sympathetic denervation, Ca 2+-dependent PKC activity was reduced in colonic myenteric plexus synaptosomes. The μ-opioid agent, DAMGO, increased Ca 2+-dependent PKC activity in synaptosomes obtained from normal, but not from denervated animals. In myenteric synaptosomes obtained from this experimental group, protein levels of Ca 2+-dependent PKC isoforms βI, βII and γ decreased, whereas α levels increased. In whole-mount preparations, the four Ca 2+-dependent PKC isoforms co-localized with μ-opioid receptors on subpopulations of colonic myenteric neurons. The percentage of neurons staining for PKCβII, as well as the number of μ-opioid receptor-positive neurons staining for PKCβII, decreased in denervated preparations. The same parameters related to PKCα, βI or γ remained unchanged. Overall, the present data strengthen the concept that μ-opioid receptors located on myenteric neurons are coupled to Ca 2+-dependent PKCs. After chronic sympathetic denervation, a reduced efficiency of this coupling may predominantly involve PKCβII, although also PKCβI and γ, but not PKCα, may be implicated.

Role of Endogenous Release of Norepinephrine in Muscle Spasms After Chronic Spinal Cord Injury

The recovery of persistent inward currents (PICs) and motoneuron excitability after chronic spinal cord transection is mediated, in part, by the development of supersensitivity to residual serotonin (5HT) below the lesion. The purpose of this paper is to investigate if, like 5HT, endogenous sources of norepinephrine (NE) facilitate motoneuron PICs after chronic spinal transection. Cutaneous-evoked reflex responses in tail muscles of awake chronic spinal rats were measured after increasing presynaptic release of NE by administration of amphetamine. An increase in long-lasting reflexes, known to be mediated by the calcium component of the PIC (CaPIC), was observed even at low doses (0.1-0.2 mg/kg) of amphetamine. These findings were repeated in a reduced S2 in vitro preparation, demonstrating that the increased long-lasting reflexes by amphetamine were neural. Under intracellular voltage clamp, amphetamine application led to a large facilitation of the motoneuron CaPIC. This indicates that the increases in long-lasting reflexes induced by amphetamine in the awake animal were, in part, due to actions directly on the motoneuron. Reflex responses in acutely spinal animals were facilitated by amphetamine similar to chronic animals but only at doses that were ten times greater than that required in chronic animals (0.2 mg/kg chronic vs. 2.0 mg/kg acute), pointing to a development of supersensitivity to endogenous NE in chronic animals. In summary, the increases in long-lasting reflexes and associated motoneuron CaPICs by amphetamine are likely due to an increased release of endogenous NE, which motoneurons become supersensitive to in the chronic stages of spinal cord injury.

Development of Naltrexone Supersensitivity During Food‐Maintained Responding Enhances Naltrexone's Ability to Reduce Ethanol‐Maintained Responding

Similar doses of the opiate antagonist naltrexone (NTX) reduce responding maintained by food and ethanol. In animals responding for food, repeated administration of NTX produces supersensitivity to NTX. The purpose of this study was to determine whether the factors that produce enhanced sensitivity to NTX during food-maintained responding also contribute to NTX's ability to reduce ethanol-maintained responding. Rats (n=12) were trained to lever press using food reinforcement. After responding stabilized, the rats were trained to respond for 10% ethanol. Before ethanol sessions, injections of 30 mg/kg NTX were given. Subsequently, weekly cumulative NTX dose-effect curves (1, 3, 10, 30, and 100 mg/kg), known to produce NTX supersensitivity, were determined during food-maintained responding in half the rats for 8 weeks while the other half of the rats received saline vehicle injections instead. To determine whether NTX supersensitivity would transfer to ethanol self-administration, ethanol-maintained responding was re-established and 30 mg/kg NTX was administered again. Initially, 30 mg/kg NTX had little effect on ethanol-maintained responding. During food-maintained responding, supersensitivity developed in rats receiving weekly cumulative NTX injections. After development of supersensitivity, 30 mg/kg decreased ethanol-maintained responding. Naltrexone's potency to reduce ethanol-maintained responding was unchanged in rats that received only vehicle injections for 8 weeks. The mechanisms that produce NTX supersensitivity during food-maintained responding may play a role in NTX's effect on ethanol consumption. Naltrexone's effect on responding for ethanol was much smaller than that reported in other studies. Further exploration may lead to techniques that maximize NTX's effect on ethanol while minimizing its effect on other behaviors.

Functional interaction between α 2-adrenoceptors, μ- and κ-opioid receptors in the guinea pig myenteric plexus: Effect of chronic desipramine treatment

The existence of a functional interplay between α 2-adrenoceptor and opioid receptor inhibitory pathways modulating neurotransmitter release has been demonstrated in the enteric nervous system by development of sensitivity changes to α 2-adrenoceptor, μ- and κ-opioid receptor agents on enteric cholinergic neurons after chronic sympathetic denervation. In the present study, to further examine this hypothesis we evaluated whether manipulation of α 2-adrenoceptor pathways by chronic treatment with the antidepressant drug, desipramine (10 mg/kg i.p. daily, for 21 days), could entail changes in enteric μ- and κ-opioid receptor pathways in the myenteric plexus of the guinea pig distal colon. In this region, subsensitivity to the inhibitory effect of both UK14,304 and U69,593, respectively α 2A-adrenoceptor and κ-opioid receptor agonist, on the peristaltic reflex developed after chronic desipramine treatment. On opposite, in these experimental conditions, supersensitivity developed to the inhibitory effect of [D-Ala, N-Me-Phe4-Gly-ol5]-enkephalin (DAMGO), μ-opioid receptor agonist, on propulsion velocity. Immunoreactive expression levels of α 2A-adrenoceptors, μ- and κ-opioid receptors significantly decreased in the myenteric plexus of the guinea pig colon after chronic desipramine treatment. In these experimental conditions, mRNA levels of α 2A-adrenoceptors, μ- and κ-opioid receptors significantly increased, excluding a direct involvement of transcription mechanisms in the regulation of receptor expression. Levels of G protein-coupled receptor kinase 2/3 and of inhibitory G i/o proteins were significantly reduced in the myenteric plexus after chronic treatment with desipramine. Such changes might represent possible molecular mechanisms involved in the development of subsensitivity to UK14,304 and U69,593 on the efficiency of peristalsis. Alternative molecular mechanisms, including a higher efficiency in the coupling between receptor activation and downstream intracellular effector systems, possibly independent from inhibitory G i/o proteins, may be accounted for the development of supersensitivity to DAMGO. Increased sensitivity to the μ-opioid agonist might compensate for the development of α 2A-adrenoceptor and κ-opioid receptor subsensitivity. On the whole, the present data further strengthen the concept that, manipulation of α 2-adrenergic inhibitory receptor pathways in the enteric nervous system entails changes in opioid inhibitory receptor pathways, which might be involved in maintaining homeostasis as suggested for μ-opioid, but not for κ-opioid receptors.

Carbamazepine prevents imipramine-induced behavioural sensitization to the dopamine D 2-like receptor agonist quinpirole

Chronic treatment with antidepressants potentiates the behavioural sensitivity to the administration of dopamine receptor agonists. Such supersensitivity might be involved in the mechanism of action of antidepressant drugs, but it has also been suggested to play a role in the mechanisms underlying antidepressant treatment-related mania (i.e. antidepressant-induced mood switch and rapid cycling). Consistently to this hypothesis, we have recently shown that lithium salts, which are poorly effective in antidepressant-related mania, fail to prevent the development of imipramine-induced supersensitivity to the locomotor effect of the dopamine D 2-like receptor agonist quinpirole. In the present paper, we report the ability of carbamazepine, an anticonvulsant with antimanic and mood stabiliser properties, to prevent the development of supersensitivity to the locomotor response to quinpirole induced by chronic treatment with imipramine. The present results, together with the results of our previous study, might contribute to explain the different responsiveness to lithium and carbamazepine observed in some manic patients, and are consistent with the clinical data suggesting that carbamazepine might be more effective than lithium in antidepressant-related mania.

Chronic lithium chloride fails to prevent imipramine-induced sensitization to the dopamine D 2-like receptor agonist quinpirole

Lithium salts, an effective antimanic treatment, are able to prevent the development of the dopaminergic behavioural supersensitivity induced by chronic treatment with neuroleptics, by denervation of the dopaminergic terminal fields and by rapid eye movements (REM) sleep deprivation, which is considered a model of mania. We have studied the effect of a lithium (LiCl) diet, inducing a lithium serum level in the range of therapeutic efficacy, on the development of the supersensitivity to the locomotor effect of the dopamine D 2-like receptor agonist, quinpirole, induced by chronic treatment with the antidepressant drug, imipramine. The results show that lithium is not able to prevent the development of such behavioural supersensitivity. The present data suggest that antidepressant-induced dopaminergic supersensitivity might provide a useful model of those manic states induced by (or subsequent to) antidepressant treatments. Moreover, the finding is consistent with the view that antidepressant-induced dopaminergic supersensitivity might play a role in the therapeutic effect of these drugs (which is known to be augmented by lithium, and not antagonised). Finally, the results show that the dopaminergic supersensitivity induced by imipramine is qualitatively different from that induced by neuroleptics or denervation of the dopaminergic terminal fields.

Does postsynaptic alpha 1-adrenergic receptor supersensitivity contribute to autonomic dysreflexia?

Quadriplegics often experience periods of severe hypertension known as autonomic dysreflexia. Clinically, these events have been well documented, but the mechanisms for mediating autonomic dysreflexia remain unclear. We used a chronic rat model to investigate the potential development of supersensitivity at postsynaptic alpha 1-adrenergic receptors as a contributing factor to the exaggerated sympathetic response characteristic of autonomic dysreflexia. Adult male Wistar and Sprague-Dawley rats were anesthetized and given spinal transection at T5. After 30 days, rats were reanesthetized and arterial and venous catheters implanted. Twenty-four hours later, colorectal distension (CRD) was used to evoke autonomic dysreflexia in conscious, spinalized rats. To gauge changes in alpha 1-receptor sensitivity, we assessed mean arterial pressure (MAP) in response to intravenous phenylephrine (PE) infusions. No consistent differences were observed between intact and spinalized rats. Therefore, supersensitivity of alpha 1-receptors cannot completely account for the hypertensive bouts associated with autonomic dysreflexia. In addition, while attempting to develop an appropriate model for autonomic dysreflexia, we discovered that spinalized Wistar rats exhibited MAP responses characteristic of autonomic dysreflexia, whereas lesioned Sprague-Dawley rats did not, when subjected to CRD. Thus Wistar rats provide a better animal model for autonomic dysreflexia.

Dizocilpine prevents the enhanced locomotor response to quinpirole induced by repeated electroconvulsive shock

Repeated administration of electroconvulsive shock, as expected, potentiated the locomotor stimulant response to quinpirole (0.3 mg/kg s.c.), a dopamine D 2-like receptor agonist. Chronic, but not acute, treatment with the NMDA receptor non-competitive antagonist dizocilpine (0.3 mg/kg i.p.) prevented electroconvulsive shock-induced potentiation of quinpirole locomotor response. These results suggest that NMDA receptor activation is necessary for the development of supersensitivity to dopamine receptor agonists produced by repeated electroconvulsive shock. The relevance of this observation in regard to the mechanism of electroconvulsive shock therapeutic effect is discussed.

Diminished noradrenergic stimulation reduces the activity of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase in rat cerebral cortex.

The present study examined the in vivo regulation of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase (PDE4) in rat cerebral cortex. The hydrolysis of cyclic AMP, formed by stimulation of beta-adrenergic receptors, was measured in cerebral cortical slices. Hydrolysis of cyclic AMP formed under these conditions was inhibited by the PDE4-selective inhibitor rolipram but not by selective inhibitors of other PDE families. Intraventricular infusion of 6-hydroxydopamine (6-OHDA; 200 micrograms) decreased the rate constant of cyclic AMP hydrolysis and increased the cyclic AMP half-life 17 days, but not 1 or 7 days, following the treatment. A reduction in norepinephrine (NE) content occurred first; the NE level was reduced to 42, 24, and 6% of control at 1, 7, and 17 days after 6-OHDA infusion, respectively. This was followed by the development of supersensitivity of beta-adrenergic receptor-linked adenylyl cyclase, which occurred 7 days after the infusion. The reduction in PDE4 activity occurred last. When a higher dose of 6-OHDA (300 micrograms) was used, the reduction in the rate constant of cyclic AMP hydrolysis occurred by 7 days; at this time NE content was depleted to 6% of control. Similar to 6-OHDA treatment, continuous blockade of beta-adrenergic receptors, produced by chronic propranolol infusion, decreased the rate constant of cyclic AMP hydrolysis. Therefore, the current results indicate that diminished stimulation of beta-adrenergic receptors, either by loss of noradrenergic innervation or by receptor blockade, reduces the activity of PDE4. This suggests that PDE4 regulation may contribute in the homeostasis of the noradrenergic receptor-effector system in the brain.

Previous dopaminergic innervation is not necessary for the development of dopamine supersensitivity in rat striatal neurons

The development of supersensitivity to dopamine by striatal neurons is widely considered to be a response to interruption of dopaminergic synaptic function. However, it is not clear whether pre-existing dopaminergic innervation is in fact necessary for supersensitivity to develop. In this study, rat foetal striatal cells were obtained prior to their innervation by dopaminergic fibres, and grafted into the cortex or thalamus of adult rats. In the absence of dopaminergic innervation, the grafts developed and became organized into striatum-like and non-striatum-like patches. Both in animals with intrathalamic and in animals with intracortical grafts, systemic administration of a low dose of apomorphine (0.25 mg/kg) induced intense fos expression in striatum-like patches not innervated by dopaminergic fibres. These results indicate that pre-existing dopaminergic innervation is not required for the development of supersensitivity, and that dopaminergic innervation is necessary to develop an adequate synergistic interaction between D 1 and D 2 receptors.

Effects of chronic methamphetamine on SCH23390- or haloperidol-induced catalepsy, and effects of coadministration of SCH23390 or haloperidol in Mice

The influence of chronic treatment of mice with methamphetamine, an indirect dopamine agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7ol hydrochloride (SCH23390), a D 1 receptor agonist, or haloperidol, a mainly D 2 antagonist, was investigated. Once every other day treatment with 3 mg/kg SC methamphetamine for 15 days resulted in an increase in the catalepsy produced by haloperidol (0.3 mg/kg IP) (haloperidol catalepsy), but in a decrease in the catalepsy produced by SCH23390 (0.3 mg/kg IP) (SCH23390 catalepsy), 24 h and 7 days after withdrawal of methamphetamine. These effects of chronic methamphetamine were antagonized by coadministration of either SCH23390 (0.5 mg/kg SC) or haloperidol (1.0 mg/kg SC). These results suggest that the decreased responsiveness to SCH23390 in chronic methamphetamine-pretreated mice results from a supersensitivity of D 1 receptors, and that the increased responsiveness to haloperidol catalepsy results from a subsensitivity of D 2 receptors. The attenuated response to SCH23390 may be interpreted as an example of sensitization to methamphetamine, and the enhanced haloperidol response as an example of tolerance to methamphetamine, based on the development of supersensitivity and subsensitivity of D 1 and D 2 receptors, respectively, after chronic methamphetamine administration. Furthermore, it is suggested that coadministration of either SCH23390 or haloperidol could prevent the development of D 1 receptor supersensitivity and D 2 receptor subsensitivity induced by chronic methamphetamine.

Effects of nitric oxide (NO) synthesis inhibition on the development of supersensitivity to stereotypy and locomotion stimulating effects of methamphetamine

The present study examined the effects of nitric oxide (NO) synthase inhibitor, Nω-nitro- l-arginine methyl ester (LNAME; 30 and 60 mg/kg, i.p.) on the development of supersensitivity to stereotypy as well as locomotion stimulating effects of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c., respectively). Rats treated with MA for 10 days showed enhancement in MA-induced stereotypy and locomotor activity. Rats pretreated with LNAME prior to MA also showed enhancement in the two types of behavior, also they showed significantly reduced stereotypy scores compared to those treated with MA alone. The results suggest that NO synthesis is not critically involved in the development of behavioral supersensitivity to stereotypy stimulating as well as locomotion stimulating effect of MA. However, NO synthesis may have a modulatory role in behavioral sensitization in stereotypy.