Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia.
ABSTRACT: 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 We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive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.
Project description:Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.
Project description:Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'
Project description:<h4>Background</h4>One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear.<h4>Method</h4>We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group.<h4>Results</h4>Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes.<h4>Conclusions</h4>Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.
Project description:Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson's disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors. The D2 dopamine receptor (DRD2) is the primary target for both typical and atypical antipsychotic drugs, and for drugs used to treat Parkinson's disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.
Project description:When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes.This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time.Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS).Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy.clinicaltrials.gov identifier NCT00088049; NCT00036088.
Project description: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 ?5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (?5PAM), 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, 0.6 mg/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 ?5PAM 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 ?5PAM 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.
Project description:Reward modulates the saliency of a specific drug exposure and is essential for the transition to addiction. Numerous human PET-fMRI studies establish a link between midbrain dopamine (DA) release, DA transporter (DAT) availability, and reward responses. However, how and whether DAT function and regulation directly participate in reward processes remains elusive. Here, we developed a novel experimental paradigm in Drosophila melanogaster to study the mechanisms underlying the psychomotor and rewarding properties of amphetamine (AMPH). AMPH principally mediates its pharmacological and behavioral effects by increasing DA availability through the reversal of DAT function (DA efflux). We have previously shown that the phospholipid, phosphatidylinositol (4, 5)-bisphosphate (PIP<sub>2</sub>), directly interacts with the DAT N-terminus to support DA efflux in response to AMPH. In this study, we demonstrate that the interaction of PIP<sub>2</sub> with the DAT N-terminus is critical for AMPH-induced DAT phosphorylation, a process required for DA efflux. We showed that PIP<sub>2</sub> also interacts with intracellular loop 4 at R443. Further, we identified that R443 electrostatically regulates DA efflux as part of a coordinated interaction with the phosphorylated N-terminus. In Drosophila, we determined that a neutralizing substitution at R443 inhibited the psychomotor actions of AMPH. We associated this inhibition with a decrease in AMPH-induced DA efflux in isolated fly brains. Notably, we showed that the electrostatic interactions of R443 specifically regulate the rewarding properties of AMPH without affecting AMPH aversion. We present the first evidence linking PIP<sub>2</sub>, DAT, DA efflux, and phosphorylation processes with AMPH reward.
Project description:Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca<sup>2+</sup>-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.
Project description:Schizophrenia (SCZ) treatment is essentially limited to the use of typical or atypical antipsychotic drugs, which suppress the main symptoms of this mental disorder. Metabolic syndrome is often reported in patients with SCZ under long-term drug treatment, but little is known about the alteration of lipid metabolism induced by antipsychotic use. In this study, we evaluated the blood serum lipids of a validated animal model for SCZ (Spontaneously Hypertensive Rat, SHR), and a normal control rat strain (Normotensive Wistar Rat, NWR), after long-term treatment (30 days) with typical haloperidol (HAL) or atypical clozapine (CLZ) antipsychotics. Moreover, psychostimulants, amphetamine (AMPH) or lisdexamfetamine (LSDX), were administered to NWR animals aiming to mimic the human first episode of psychosis, and the effects on serum lipids were also evaluated. Discrepancies in lipids between SHR and NWR animals, which included increased total lipids and decreased phospholipids in SHR compared with NWR, were similar to the differences previously reported for SCZ patients relative to healthy controls. Administration of psychostimulants in NWR decreased omega-3, which was also decreased in the first episode of psychosis of SCZ. Moreover, choline glycerophospholipids allowed us to distinguish the effects of CLZ in SHR. Thus, changes in the lipid metabolism in SHR seem to be reversed by the long-term treatment with the atypical antipsychotic CLZ, which was under the same condition described to reverse the SCZ-like endophenotypes of this validated animal model for SCZ. These data open new insights for understanding the potential influence of the treatment with typical or atypical antipsychotics on circulating lipids. This may represent an outcome effect from metabolic pathways that regulate lipids synthesis and breakdown, which may be reflecting a cell lipids dysfunction in SCZ.
Project description:Disruption of conditioned avoidance response (CAR) in rodents is one trademark feature of many antipsychotic drugs. In adult rats, repeated olanzapine (OLZ) treatment causes an enhanced disruption of avoidance response (sensitization), whereas repeated clozapine (CLZ) treatment causes a decreased disruption (tolerance). The present study addressed (1) whether OLZ sensitization and CLZ tolerance can be induced in adolescent rats, and (2) the extent to which OLZ sensitization and CLZ tolerance induced in adolescence persists into adulthood. Male adolescent Sprague-Dawley rats (approximate postnatal days (?P) 43-47) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 mg/kg, sc) daily for 5 consecutive days in the CAR model. They were then tested for the expression of OLZ sensitization or CLZ tolerance either in adolescence (?P 50) or after they matured into adults (?P 76 and 92) in a challenge test during which all rats were injected with either a lower dose of OLZ (0.5 mg/kg) or CLZ (5.0 mg/kg). When tested in adolescence, rats previously treated with OLZ showed a stronger inhibition of CAR than those previously treated with vehicle (ie, sensitization). In contrast, rats previously treated with CLZ showed a weaker inhibition of CAR than those previously treated with vehicle (ie, tolerance). When tested in adulthood, the OLZ sensitization was still detectable at both time points (?P 76 and 92), whereas the CLZ tolerance was only detectable on ?P 76, and only manifested in the intertrial crossing. Performance in the prepulse inhibition and fear-induced 22 kHz ultrasonic vocalizations in adulthood were not altered by adolescence drug treatment. Collectively, these findings suggest that atypical antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation. As antipsychotic drugs are being increasingly used in children and adolescents in the past two decades, findings from this study are important for understanding the impacts of adolescent antipsychotic treatment on the brain and behavioral developments. This work also has implications for clinical practice involving adolescence antipsychotic treatments in terms of drug choice, drug dose, and schedule.