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Background: Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported. Aims and Methods: We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX. Results: The comparison between the patients with dopamine supersensitivity psychosis (n = 44) and those without (n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching (n = 80) and those who failed (n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores. Conclusions: Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring. [ABSTRACT FROM AUTHOR]

Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

Background: Roughly 30% of schizophrenia patients fail to respond to at least two antipsychotic trials. Psychosis has been traditionally considered to be poorly sensitive to psychotherapy. Nevertheless, there is increasing evidence that psychological interventions could be considered in treatment-resistant psychosis (TRP). Despite the relevance of the issue and the emerging neurobiological underpinnings, no systematic reviews have been published. Here, we show a systematic review of psychotherapy interventions in TRP patients of the last 25 years.Methods: The MEDLINE/PubMed, ISI WEB of Knowledge, and Scopus databases were inquired from January 1, 1993, to August 1, 2018, for reports documenting augmentation or substitution with psychotherapy for treatment-resistant schizophrenia (TRS) and TRP patients. Quantitative data fetched by Randomized Controlled Trials (RCTs) were pooled for explorative meta-analysis.Results: Forty-two articles have been found. Cognitive behavioral therapy (CBT) was the most frequently recommended psychotherapy intervention for TRS (studies, n = 32, 76.2%), showing efficacy for general psychopathology and positive symptoms as documented by most of the studies, but with uncertain efficacy on negative symptoms. Other interventions showed similar results. The usefulness of group therapy was supported by the obtained evidence. Few studies focused on negative symptoms. Promising results were also reported for resistant early psychosis.Limitations: Measurement and publication bias due to the intrinsic limitations of the appraised original studies.Conclusions: CBT, psychosocial intervention, supportive counseling, psychodynamic psychotherapy, and other psychological interventions can be recommended for clinical practice. More studies are needed, especially for non-CBT interventions and for all psychotherapies on negative symptoms.

Background: Roughly 30% of schizophrenia patients fail to respond to at least two antipsychotic trials. Psychosis has been traditionally considered to be poorly sensitive to psychotherapy. Nevertheless, there is increasing evidence that psychological interventions could be considered in treatment-resistant psychosis (TRP). Despite the relevance of the issue and the emerging neurobiological underpinnings, no systematic reviews have been published. Here, we show a systematic review of psychotherapy interventions in TRP patients of the last 25 years. Methods: The MEDLINE/PubMed, ISI WEB of Knowledge, and Scopus databases were inquired from January 1, 1993, to August 1, 2018, for reports documenting augmentation or substitution with psychotherapy for treatment-resistant schizophrenia (TRS) and TRP patients. Quantitative data fetched by Randomized Controlled Trials (RCTs) were pooled for explorative meta-analysis. Results: Forty-two articles have been found. Cognitive behavioral therapy (CBT) was the most frequently recommended psychotherapy intervention for TRS (studies, n = 32, 76.2%), showing efficacy for general psychopathology and positive symptoms as documented by most of the studies, but with uncertain efficacy on negative symptoms. Other interventions showed similar results. The usefulness of group therapy was supported by the obtained evidence. Few studies focused on negative symptoms. Promising results were also reported for resistant early psychosis. Limitations: Measurement and publication bias due to the intrinsic limitations of the appraised original studies. Conclusions: CBT, psychosocial intervention, supportive counseling, psychodynamic psychotherapy, and other psychological interventions can be recommended for clinical practice. More studies are needed, especially for non-CBT interventions and for all psychotherapies on negative symptoms. [ABSTRACT FROM AUTHOR]

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 D 2 , D 3 and serotonin 2A 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 D 2 agonist quinpirole-induced hyperlocomotion test and a dopamine D 2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D 2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D 2 receptor density. Further, our results show that mRNA levels of dopamine D 2 and D 3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D 3 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 D 3 receptors than haloperidol, antagonism of blonanserin at dopamine D 3 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. [ABSTRACT FROM AUTHOR]

Dopamine supersensitivity psychosis (DSP) is observed in patients with schizophrenia under antipsychotic treatment, and it is characterized by rebound psychosis, an uncontrollable psychotic episode following a stable state and tardive dyskinesia. DSP, first described in patients taking typical antipsychotics in the late 1970s, sometimes appears even in patients who are treated with current atypical antipsychotics. It was recently demonstrated that DSP can have a negative impact on the long-term prognosis of schizophrenia patients and that DSP could be involved in the etiology of some cases of treatment-resistant schizophrenia. Accumulating evidence suggests that an up-regulation of dopamine D2 receptors (DRD2) in the brain caused by long-term exposure to antipsychotics is related to the DSP phenomenon. The present review describes the clinical characteristics and the etiology of DSP in the era of second-generation antipsychotics for patients with schizophrenia. Based on the mechanism of DSP, several potential treatments for patients presenting with a DSP episode or the dopamine supersensitivity state are also discussed. [ABSTRACT FROM AUTHOR]

Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16–17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity. [ABSTRACT FROM AUTHOR]

Elderly patients are vulnerable to the adverse neurological effects of antipsychotics, particularly Parkinsonian symptoms and tardive dyskinesia. This vulnerability in the elderly becomes complex and unpredictable when aripiprazole is prescribed to replace other second-generation or first-generation antipsychotics. This report describes a 69-year-old female schizophrenic patient, who received aripiprazole after using a few antipsychotics, including the first- and second-generation ones. The tardive dyskinesia developed 6 weeks after switching to aripiprazole but subsided 4 weeks later when stopping the concurrent amantadine and decreasing the dosage of trihexyphenidyl. However, Parkinsonian symptoms developed insidiously thereafter, which remitted after the dosage of trihexyphenidyl was increased again. The possible mechanisms of the alternated adverse neurological events after a switch to aripiprazole in the chronic elderly psychosis are discussed.

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-HT 2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT 2 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-HT 2 receptor antagonist (ritanserin; 0.01 and 0.1 mg/kg) and of a 5-HT 2A receptor antagonist (MDL100,907; 0.025–0.1 mg/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 (0.1 mg/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-HT 2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT 2A receptor density in the caudate-putamen. Thus, activation of either 5-HT 2 receptors or of 5-HT 2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT 2 /5-HT 2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT 2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT 2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity. [ABSTRACT FROM AUTHOR]

Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. [ABSTRACT FROM AUTHOR]

The administration of aripiprazole (ARI), a dopamine partial agonist, could provoke abrupt psychotic worsening in patients with schizophrenia. We explored the relationship between this psychotic worsening and dopamine supersensitivity psychosis (DSP), which is a clinically vulnerable state. We conducted a retrospective investigation for 264 patients whose treatment medication was switched to ARI from other antipsychotics. We divided the patients into the DSP(+) group with a history of DSP episode(s) (N = 70) and the DSP(–) group without such a history (N = 194), and then compared the clinical factors relevant to the success or failure of the switch to ARI between them. The results revealed that patients in the DSP(+) group experienced psychotic worsening following the switch to ARI with a significant higher rate compared to the DSP(–) group (23% vs. 8%, P < 0.01). Moreover, the dosages of the drugs before the ARI introduction in the patients experiencing the psychotic worsening in the DSP (-) group were higher than those in other patients of the group. Our findings suggest that patients who receive high dosages of antipsychotic drugs form overt or covert DSP and such state is highly associated with psychotic worsening following ARI treatment. [ABSTRACT FROM AUTHOR]

Background and objective Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal. Method This was a randomized, double-blind, placebo-controlled study of 48 patients who met criteria for DSM-IV(r) Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of ≥14. Half the participants received 0.25mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial. Results One week after stopping the medication, the HAMD ratings of the drug-treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64±0.18 units for the medication-treated patients, compared to 1.12±0.26 units for the placebo group (P=0.05). The regimen was well tolerated. Conclusions Seven days of an ultra-low dose of 0.25mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidol-induced behavioural supersensitivity to dopamine. Limitations The sample was small. More patients are needed in a future study. [ABSTRACT FROM AUTHOR]

Abstract: Individuals with schizophrenia are at very high risk for drug abuse and addiction. Patients with a coexisting drug problem fare worse than patients who do not use drugs, and are also more difficult to treat. Current hypotheses cannot adequately account for why patients with schizophrenia so often have a co-morbid drug problem. I present here a complementary hypothesis based on evidence showing that chronic exposure to antipsychotic medications can induce supersensitivity within the brain's dopamine systems, and that this in turn can enhance the rewarding and incentive motivational effects of drugs and reward cues. At the neurobiological level, these effects of antipsychotics are potentially linked to antipsychotic-induced increases in the striatal levels of dopamine D2 receptors and D2 receptors in a high-affinity state for dopamine, particularly at postsynaptic sites. Antipsychotic-induced dopamine supersensitivity and enhanced reward function are not inevitable consequences of prolonged antipsychotic treatment. At least two parameters appear to promote these effects; the use of antipsychotics of the typical class, and continuous rather than intermittent antipsychotic exposure, such that silencing of dopaminergic neurotransmission via D2/3 receptors is unremitting. Thus, by inducing forms of neural plasticity that facilitate the ability of drugs and reward cues to gain control over behaviour, some currently used treatment strategies with typical antipsychotics might contribute to compulsive drug seeking and drug taking behaviours in vulnerable schizophrenia patients. [Copyright &y& Elsevier]

Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABAA) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective. [ABSTRACT FROM PUBLISHER]

Abstract: It is known that schizophrenia patients are behaviorally supersensitive to dopamine-like drugs (amphetamine, methylphenidate). There is evidence for an increased release of dopamine, a slight increase of dopamine D2 receptors and an increase of dopamine D2High receptors in schizophrenia, all possibly explaining the clinical supersensitivity to dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in many animal models of psychosis. The increased amounts of D2High receptors in psychotic-like behavior in animals may result from a loss of control of D2 by various factors. These factors include the rate of phosphorylation and desensitization of D2 receptors by kinases, the attachment of arrestin to D2 receptors, internalization of D2 receptors, the rate of receptor de-phosphorylation, formation of D2 receptor dimers, and GTP regulation by various GTPases. While at present there are no statistically significant associations of any of these controlling factors and their genes with schizophrenia, investigation of D2High receptors in schizophrenia will require a new radioligand in order to selectively label D2High receptors in vivo in patients. Finally, haloperidol reduces the number of D2High receptors that are elevated by amphetamine, indicating that this therapeutic effect may occur clinically. [Copyright &y& Elsevier]

Abstract: Schizophrenia patients are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate, meaning that patients respond to such drugs with increased psychotic symptoms, as compared to control subjects. A basis of such supersensitivity may be an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of D2High receptors in active stages of schizophrenia. While the pre-synaptic release of dopamine is normal in stable patients with schizophrenia, brain imaging studies find that D2 receptors are increased by an average of 5.8% in antipsychotic-free schizophrenia patients. It is possible that the behavioral supersensitivity may stem from more D2High receptors in schizophrenia. Although the antipsychotic/dopamine D2 receptor can exist in vitro in a state of high affinity for dopamine (as D2High), or in a state of low affinity for dopamine (as D2Low), there is no clear evidence that D2High states can be selectively labeled or stably exist in vivo. Nevertheless, two studies revealed an 80% increase in apparent D2High receptors in schizophrenia patients after reducing endogenous dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in vitro in animal models of psychosis, including dopamine-supersensitive animals pretreated with amphetamine, marijuana, or phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including those for glutamate receptors. The elevation of D2High receptors in vitro and the increased apparent D2High receptors in vivo is consistent with behavioral dopamine supersensitivity in schizophrenia patients. [Copyright &y& Elsevier]

Abstract: The in vivo labeling and brain imaging of dopamine transporters measure the density of dopamine neuron terminals in the human caudate/putamen. A review of such studies shows that the long-term use of antipsychotics had no major effect on the density of the dopamine terminals in individuals who had no tardive dyskinesia, but had reduced the density in those patients with tardive dyskinesia. In addition, the normal loss of dopamine terminals in healthy individuals was approximately 5% per decade. However, this rate of cell loss was apparently increased by approximately three-fold, to about 15% per decade, in schizophrenia patients using antipsychotics on a long-term basis, as measured by the in vivo imaging of the dopamine transporters in the dopamine neuron terminals. While an apparent reduction in dopamine transporters may result from reduced expression of the transporters secondary to antipsychotic treatment, the seemingly increased loss rate is consistent with the accumulation of antipsychotics in the neuromelanin of the substantia nigra, subsequent injury to the dopamine-containing neurons, and the development of extrapyramidal motor disturbances such as tardive dyskinesia or Parkinson's disease. [Copyright &y& Elsevier]

Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain’s dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. [ABSTRACT FROM PUBLISHER]

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) that is nonselectively activated by endogenous metabolites of amino acids. TAAR1 is considered a promising drug target for the treatment of psychiatric and neurodegenerative disorders. However, no selective ligand to identify TAAR1-specific signaling mechanisms is available yet. Here we report a selective TAAR1 antagonist, EPPTB, and characterize its physiological effects at dopamine (DA) neurons of the ventral tegmental area (VTA). We show that EPPTB prevents the reduction of the firing frequency of DA neurons induced by p-tyramine (p-tyr), a nonselective TAAR1 agonist. When applied alone, EPPTB increases the firing frequency of DA neurons, suggesting that TAAR1 either exhibits constitutive activity or is tonically activated by ambient levels of endogenous agonist(s). We further show that EPPTB blocks the TAAR1- mediated activation of an inwardly rectifying K+ current. When applied alone, EPPTB induces an apparent inward current, suggest- ing the closure of tonically activated K+ channels. Importantly, these EPPTB effects were absent in Taar1 knockout mice, ruling out off-target effects. We additionally found that both the acute application of EPPTB and the constitutive genetic lack of TAAR1 increase the potency of DA at D2 receptors in DA neurons. In summary, our data support that TAAR1 tonically activates inwardly rectifying K+ channels, which reduces the basal firing frequency of DA neurons in the VTA. We hypothesize that the EPPTB-induced increase in the potency of DA at D2 receptors is part of a homeostatic feedback mechanism compensating for the lack of inhibitory TAAR1 tone. [ABSTRACT FROM AUTHOR]

This study deals with the possible inhibitory role played by acetyl-l-carnitine (ALC) against methamphetamine (METH)-induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH-mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH-mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH-induced sensitization. Another interesting observation was the significantly higher METH-induced hyperactivity at day 15 (after a 7- day drug-free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH-induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant-mediated neurotoxicity. By demonstrating an in vivo action against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior. [ABSTRACT FROM AUTHOR]

Rats received continuous or discontinuous administration of trifluoperazine or cis-flupenthixol in drinking water for up to 12 months. Continuous and discontinuous trifluoperazine administration had no consistent effect on apomorphine-induced stereotyped behaviour and there was no difference between drug treatments. Continuous and discontinuous cis-flupenthixol administration enhanced apomorphine-induced stereotypy, but there was no difference in the effect of the two drug treatments. Both continuous and discontinuous administration of trifluoperazine increased the number of specific striatal H-spiperone binding sites ( B). Over the period of treatment there was no difference in the effects of the different treatments. Continuous or discontinuous cis-flupenthixol intake did not increase B after 6 or 12 months intake. Continuous or discontinuous neuroleptic treatment produced no difference in functional striatal dopamine receptor activity as judged by apomorphine-induced stereotyped behaviour. Ligand binding studies also suggest that the overall change in striatal receptor function is not affected by the use of a discontinuous drug regime. [ABSTRACT FROM AUTHOR]

Some behavioral and biochemical effects of four dopaminergic agonists (apomorphine, piribedil, lergotrile, and bromocriptine) were determined in the mouse. As expected, all four drugs dose-dependently reversed the α-methyltyrosine-induced decline of fore-brain dopamine. All four compounds reduced locomotor activity at low doses, but only apomorphine and bromocriptine increased motor activity at higher doses. All four drugs caused some reversal of the baclofen-induced elevation in forebrain dopamine concentrations, but only apomorphine and bromocriptine completely reversed the effects of baclofen. After chronic treatment with haloperidol, the behavioral effects of lergotrile and bromocriptine were altered. Doses of those drugs reducing motor activity in normal animals were ineffective after chronic haloperidol. The latent stimulation induced by bromocriptine was enhanced, while a stimulatory effect of lergotrile emerged in these animals. These effects were noted in conjunction with an enhanced sensitivity to the drug-induced decrease in dopamine turnover. These results demonstrate that dopamine agonists may be differentiated on the basis of certain behavioral and biochemical tests and suggest an interaction of these drugs with two different populations of dopamine receptors. [ABSTRACT FROM AUTHOR]

The effects of long-term amphetamine treatment were evaluated on responding supported by self-stimulation of the substantia nigra. Rats repeatedly treated with d-amphetamine, and tested with a low dose of the drug that ordinarily has no behavioral effect, showed higher response rates than animals repeatedly treated with saline and tested with the same dose of amphetamine. In contrast, a depression in responding was observed among animals that received long-term amphetamine administration and were tested with saline. The effects of long-term amphetamine treatment on self-stimulation could not be explained by the intrusion of drug-induced competitive behaviors such as locomotor activity and stereotypy. The results were attributed to changes in dopamine neurotransmission following prolonged exposure to amphetamine and were also discussed in terms of an animal model for 'amphetamine psychosis' and 'postamphetamine depression' in man. [ABSTRACT FROM AUTHOR]

The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [ d-Ala, d-Leu]-enkephalin (DADL) were observed upon dopamine D and D binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The μ-agonist sufentanil (1 or 20 Erg/kg, i. p.), the κ-agonist U50,488H (10 mg/kg, i. p.) and DADL (1 μg/animal, i. c. v.) all significantly elevated D but not D binding site density in rat striatum. Pretreatment with sufentanil (1 μg/kg, i. p.) induced an elevation in apomorphine-induced sterotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i. p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 μg/animal, i. c. v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D sites to the exclusion of D sites. However, the precise mechanism by which this effect is elicited remains to be established. [ABSTRACT FROM AUTHOR]

Oculogyric crisis (OGC) is a type of acute dystonic reaction which is usually a side effect of an antipsychotic treatment. There are case reports on OCG with almost all antipsychotic drugs, especially with the highly potent ones. In psychotic patients, there are cases of OCG accompanied by psychotic exacerbation during antipsychotic treatment. Besides, there are cases of OCG after cessation of antipsychotic treatment. However, to our knowledge, there are no cases of OCG associated with psychotic exacerbation following antipsychotic drug withdrawal. We present a 26-year-old patient who had psychotic exacerbation accompanied by OCG after cessation of his 2-year amisulpiride treatment. He was in remission for two years before he developed auditory hallucinations, reference delusions and repetitious OCG just after stopping his medication. In this study, we investigated the possible reasons for these symptoms and we assume that they may be related to dopamine receptor supersensitivity which is the result of long-term antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Oculogyric crisis (OGC) is a type of acute dystonic reaction which is usually a side effect of an antipsychotic treatment. There are case reports on OCG with almost all antipsychotic drugs, especially with the highly potent ones. In psychotic patients, there are cases of OCG accompanied by psychotic exacerbation during antipsychotic treatment. Besides, there are cases of OCG after cessation of antipsychotic treatment. However, to our knowledge, there are no cases of OCG associated with psychotic exacerbation following antipsychotic drug withdrawal. We present a 26-year-old patient who had psychotic exacerbation accompanied by OCG after cessation of his 2-year amisulpiride treatment. He was in remission for two years before he developed auditory hallucinations, reference delusions and repetitious OCG just after stopping his medication. In this study, we investigated the possible reasons for these symptoms and we assume that they may be related to dopamine receptor supersensitivity which is the result of long-term antipsychotic treatment. (Archives of Neuropsychiatry 2013; 50: 186-188) [ABSTRACT FROM AUTHOR]

Summary: Elderly patients are vulnerable to the adverse neurological effects of antipsychotics, particularly Parkinsonian symptoms and tardive dyskinesia. This vulnerability in the elderly becomes complex and unpredictable when aripiprazole is prescribed to replace other second-generation or first-generation antipsychotics. This report describes a 69-year-old female schizophrenic patient, who received aripiprazole after using a few antipsychotics, including the first- and second-generation ones. The tardive dyskinesia developed 6 weeks after switching to aripiprazole but subsided 4 weeks later when stopping the concurrent amantadine and decreasing the dosage of trihexyphenidyl. However, Parkinsonian symptoms developed insidiously thereafter, which remitted after the dosage of trihexyphenidyl was increased again. The possible mechanisms of the alternated adverse neurological events after a switch to aripiprazole in the chronic elderly psychosis are discussed. [ABSTRACT FROM AUTHOR]

Introduction: Chronic treatment with dopamine D2 receptor antagonists has been proposed to lead to dopamine receptor supersensitivity. Frequently, this is conceptualized as upregulation or changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity are probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis.Hypothesis: Recent data suggest that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes.Discussion: Presynaptic increase in dopamine release occurs when super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated.Conclusion: TD likely develops due to changes across the synapse and terminology such as 'dopamine receptor supersensitivity' can be misleading. 'Synaptic upregulation' may be a more correct term. [ABSTRACT FROM AUTHOR]

All antipsychotic medications attenuate the symptoms of psychosis by interacting with dopamine D2 receptors and reducing dopamine-mediated neurotransmission. However, long-term antipsychotic treatment can produce neuroadaptations that are thought to lead to dopamine supersensitivity. In patients with schizophrenia, this dopamine supersensitivity could compromise treatment efficacy, promote relapse to psychosis and trigger movement disorders. Such effects have been seen in patients treated with either typical or atypical antipsychotics. In non-human animals, chronic exposure to antipsychotic medications, using clinically pertinent doses and modes of administration, can also evoke dopamine supersensitivity. This is indicated by an augmented behavioural response to dopamine agonists and tolerance to the antipsychotic-like effects of ongoing treatment. Here, we first describe antipsychotic-evoked dopamine supersensitivity in patients with schizophrenia and in laboratory animals. We then review approaches to prevent or reverse antipsychotic-evoked dopamine supersensitivity, based on preclinical animal studies. This evidence suggests that using atypical antipsychotics and regular but intermittent (versus continuous) antipsychotic dosing/D2 receptor occupancy is significantly less likely to produce dopamine supersensitivity. Lastly, we discuss potential neurobiological mechanisms. These include changes at the D2 receptor, but also other changes within and outside of the dopamine system. We conclude that in parallel to the search for new antipsychotic molecules, we need to better understand how different dosing regimens with currently used medications influence long-term outcome. There is also a pressing need to better characterize the development and expression of dopamine supersensitivity in humans. This will help determine the treatment strategies least likely to evoke dopamine supersensitivity. This article is part of the issue entitled 'Special Issue on Antipsychotics'. • Long-term antipsychotic treatment can evoke dopamine supersensitivity. • This might impair treatment efficacy and worsen psychosis in schizophrenia patients. • Dopamine supersensitivity is also linked to tolerance to antipsychotics in rats. • D2-related changes are seen but are not perfect dopamine supersensitivity markers. • Adequate dosing and treatment kinetics can prevent dopamine supersensitivity. [ABSTRACT FROM AUTHOR]

Dopamine supersensitivity is an important consideration for assessing treatment-resistant schizophrenia. The emergence of dopamine supersensitivity might be related to upregulation of dopamine D2 receptor, which engenders tolerance to antipsychotics, rebound psychosis, and tardive dyskinesia (TD). A 24-year-old man with a history of treatment-resistant schizophrenia was hospitalized for treatment of bone fracture sustained during a suicide attempt. After the operation, his clinical symptoms implied malignant catatonia. The patient discontinued antipsychotics without rebound psychosis under clonazepam treatment. His psychotic symptoms were controlled further with 24 mg/day aripiprazole without relapse or worsening. Clonazepam might be an effective option for the management of dopamine supersensitivity psychosis (DSP)., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.