Parkinson Drug Research Articles

Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease.

At present, treatment for Parkinson's disease (PD) is only symptomatic; therefore, it is important to identify new targets tackling the molecular causes of the disease. We previously found that lymphoblasts from sporadic PD patients display increased activity of the cyclin D3/CDK6/pRb pathway and higher proliferation than control cells. These features were considered systemic manifestations of the disease, as aberrant activation of the cell cycle is involved in neuronal apoptosis. The main goal of this work was to elucidate whether the inhibition of cyclin D3/CDK6-associated kinase activity could be useful in PD treatment. For this purpose, we investigated the effects of two histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic (SAHA) acid and sodium butyrate (NaB), and the m-TOR inhibitor rapamycin on cell viability and cyclin D3/CDK6 activity. Moreover, the potential neuroprotective action of these drugs was evaluated in 6-hydroxy-dopamine (6-OHDA) treated dopaminergic SH-SY5Y cells and primary rat mesencephalic cultures. Here, we report that both compounds normalized the proliferative activity of PD lymphoblasts and reduced the 6-OHDA-induced cell death in neuronal cells by preventing the over-activation of the cyclin D3/CDK6/pRb cascade. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it is plausible that they may serve as novel therapeutic drugs for PD. We report here that peripheral cells from Parkinson's disease (PD) patients show an enhanced proliferative activity due to the activation of cyclin D3/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). Treatment of PD lymphoblasts with inhibitors of histone deacetylases like suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), or with rapamycin, inhibitor of mechanistic target of rapamycin (mTOR) normalized the proliferation of PD lymphoblasts by preventing the over-activation of the cyclin D3/CDK6/pRb cascade. These drugs were shown to have neuroprotective effects in both human neuroblastoma SH-SY5Y cells and primary rat mid-brain dopaminergic neuronal cultures toxicity induced by 6-hidroxydopamine. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it seems reasonable to believe that the repositioning of these drugs toward PD holds promise as a novel therapeutic strategy.

A proposal to prevent omissions and delays of antiparkinsonian drug administration in hospitals.

A prospective study carried out in the Netherlands showed that the most important risk factor for motor function deterioration in Parkinson's disease (PD) during hospital admission was medication error, including both incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs.1 Indeed, one of the reported reasons for omitting or delaying levodopa administration has been medication unavailability on time where needed, that is, in medical wards where the patient is admitted. Skelly et al in a recent study carried out in Derby Hospital (National Parkinson Foundation Centre of Excellence for Parkinson’s Disease) report that even in a ward specially designed to treat patients with PD, with an enhanced stock of anti-PD medications, 2.5% of all doses were not administered because the drug was not available on time.2 It is likely this problem is compounded in other nonspecialized wards and especially in smaller hospitals. To counteract this problem, Parkinson's United Kingdom “Get it on time campaign,”3 among others, has suggested that all commercially available antiparkinsonian drugs should be available in all hospital wards and on time. Given the data described previously, this seems unfeasible, especially in small hospitals where having available all the anti-PD drugs would certainly result in the expiration of many of these drugs before they are used. We think a possible solution can be found in Skelly et al’s reflections: “The available stock was not used as flexibly as we had hoped: e.g. doses of modified release medications were omitted rather than a temporary switch to available standard release drugs.”2 (p. 1246) We agree and propose a therapeutic interchange protocol (Figure 1) where the unavailable PD drug is first converted to the equivalent levodopa dose according to published dose equivalency.4 Then an immediate release levodopa dose could be administered until the original drug is available. Immediate release levodopa is cheap. Thus, having it in each hospital ward is a realistic approach. Figure 1. An example of applying the proposed protocol to prevent Parkinson’s disease (PD) drug omissions. It has to be kept in mind that dose equivalencies proposed by Tomlinson et al were developed to compare dose intensities of antiparkinsonian drugs in clinical trials rather than to use them in clinical practice and were catalogued by the authors as mere approximations. Paraphrasing Magdalinou et al5: “PD medications should be regarded as important as insulin is for diabetics.” (p. 540) Using short-acting insulin instead of the patient’s chronic insulin treatment is now routine clinical practice in hospitals. Although there may be some limitations to this approach, we think changing to an equivalent dose of immediate release levodopa could help to prevent PD drug omissions and delays.

Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.

G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders.

Meta-analysis of Placebo-controlled Clinical Trials of Safinamide and Entacapone as Add-on Therapy to Levodopa in the Treatment of Parkinson’s Disease

Chronic levodopa (L-dopa) treatment of Parkinson’s disease (PD) patients is sooner or later associated with the onset of motor complications, for example wearing off and dyskinesia. PD patients with motor complications usually require the addition of further PD drugs to reduce these L-dopa side effects and enhance its efficacy. Entacapone is an available catechol-O-methyltransferase (COMT) inhibitor, which was extensively investigated as add-on to L-dopa/dopadecarboxylase inhibitor (DDCI) application in PD patients. Safinamide, a watersoluble, orally active a-aminoamide derivative, which modulates dopaminergic and glutamatergic neurotransmission with a unique dual mechanism of action, has been studied in two placebo-controlled clinical trials as add-on therapy to L-dopa in fluctuating PD patients. To date, there are no head-to-head clinical trials comparing the efficacy of safinamide and entacapone in the clinic. The aim of this meta-analysis was to determine effect sizes of safinamide and entacapone as add-on treatment to L-dopa in fluctuating PD patients. A systematic search of the literature on entacapone trials up to the end of September 2014 was first conducted on the MEDLINE and EMBASE databases in order to identify appropriate studies. Definition criteria for inclusion were prospective, randomised, placebocontrolled and double-blinded trials on the efficacy and safety of entacapone or safinamide in fluctuating L-dopa-treated PD patients. Four studies for entacapone and two trials on safinamide were considered. Data from the safinamide trials were provided by Zambon and therefore ‘safinamide’ was not used as a search term. Safinamide and entacapone treatment was comparable in terms of the main efficacy variables (offtime, percentageontime, Unified Parkinson’s Disease Rating Scale). Significant advantages in favour of safinamide were shown in terms of the total incidence of adverse events (AEs) in comparison to placebo, the study discontinuation due to AEs and deaths and in the risk differences of the AEs versus placebo, particularly for nausea, vomiting, diarrhoea, dizziness, urine abnormality and shortness of breath. The odds ratio (OR) of 0.907 for any AE corresponds to an overall AE rate of 68.7 % for safinamide whereas the OR of 2.089 to an overall AE rate of 84.4 % for entacapone.

Anti-fibrillation potency of caffeic acid against an antidepressant induced fibrillogenesis of human α-synuclein: Implications for Parkinson's disease.

Alpha synuclein is a 14 kDa intrinsically disordered, presynaptic protein whose fibrillation is a critical step in the pathogenesis of Parkinson's disease (PD). A structural investigation of the effect of escitalopram (a selective serotonin reuptake inhibitor) on α-synuclein was performed using ANS and ThT assays, CD, turbidity and Rayleigh scattering measurements as well as atomic force and transmission electron microscopy. Analysing the mechanism of α-synuclein fibril formation, helped us in elucidating the passage of an intermediate at 75 μM concentration of escitalopram. Fibrils of α-synuclein were obtained at 100 μM concentration of escitalopram. Inhibition of α-synuclein fibrillation was brought about by a polyphenolic acid known as caffeic acid which acted in a concentration dependent manner ranging from 10 to 60 μM. Maximum inhibition was achieved at a concentration of 60 μM. Fibrillation of α-synuclein in presence of escitalopram gives us clue for the negative effects of antidepressant. Inhibitory activity of caffeic acid against α-synuclein fibrillation may guide us in designing novel therapeutic drugs for PD.

The α7 nAChR selective agonists as drug candidates for Alzheimer's disease.

The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the α7 nAChR is one of the most abundant subtypes in the brain. The α7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the Aβ amyloid. Aβ amyloid is co-localized with α7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the α7 nAChR expression. Treatment with α7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the α7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the α7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab.

Does a specialist unit improve outcomes for hospitalized patients with Parkinson's disease?

ObjectiveSuboptimal management of Parkinson's disease (PD) medication in hospital may lead to avoidable complications. We introduced an in-patient PD unit for those admitted urgently with general medical problems. We explored the effect of the unit on medication management, length of stay and patient experience.MethodsWe conducted a single-center prospective feasibility study. The unit's core features were defined following consultation with patients and professionals: specially trained staff, ready availability of PD drugs, guidelines, and care led by a geriatrician with specialty PD training. Mandatory staff training comprised four 1 h sessions: PD symptoms; medications; therapy; communication and swallowing. Most medication was prescribed using an electronic Prescribing and Administration system (iSOFT) which provided accurate data on time of administration. We compared patient outcomes before and after introduction of the unit.ResultsThe general ward care (n = 20) and the Specialist Parkinson's Unit care (n = 24) groups had similar baseline characteristics. On the specialist unit: less Parkinson's medication was omitted (13% vs 20%, p < 0.001); of the medication that was given, more was given on time (64% vs 50%, p < 0.001); median length of stay was shorter (9 days vs 13 days, p = 0.043) and patients' experience of care was better (p = 0.01).DiscussionIf replicated and generalizable to other hospitals, reductions in length of stay would lead to significant cost savings. The apparent improved outcomes with Parkinson's unit care merit further investigation. We hope to test the hypothesis that specialized units are cost-effective and improve patient care using a randomized controlled trial design.

Body &amp; Brain: Early Parkinson's drug use may be OK: Taking levodopa long‐term doesn't increase side effects

Body &amp; Brain: Early Parkinson's drug use may be OK: Taking levodopa long‐term doesn't increase side effects

Nicotinamide mononucleotide improves energy activity and survival rate in an in vitro model of Parkinson's disease.

Nicotinamide adenine dinucleotide (NAD+) repletion has been shown to provide marked neuroprotection from genotoxic agent-induced neuronal and astrocyte cell death. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN). Therefore, it was hypothesized that NMN may attenuate apoptosis and improve energy metabolism in Parkinson’s disease (PD)-like behavioral and neuropathological changes, and produce significant beneficial effects. In this study, a cellular model of PD, using rotenone-treated PC12 cells, was established to test the hypothesis that NMN may decrease PD-like pathological changes. Experiments were carried out to investigate cell survival, including an intracellular lactate dehydrogenase (LDH) assay. Apoptotic and necrotic cell death, NAD+ levels and ATP levels were also evaluated. It was observed that NMN was able to significantly attenuate the rotenone-induced reduction in the survival rate of PC12 cells, as assessed by MTT and LDH assays. NMN treatment also significantly reduced the rotenone-induced apoptosis of the cells, as assessed by flow cytometry-based Annexin V/7-aminoactinomycin D staining. Furthermore, NMN restored intracellular levels of NAD+ and ATP in the rotenone-treated cells, thus demonstrating the capacity of NMN to ameliorate mitochondrial inhibitor-induced impairments of energy metabolism. The present study indicates that NMN produces significant beneficial effects by attenuating apoptosis and improving energy metabolism in a cellular model of PD. These results suggest that NMN may become a promising therapeutic drug for PD.

Novel and functional ABCB1 gene variant in sporadic Parkinson’s disease

Parkinson’s disease (PD) is a common progressive neurodegenerative disease. Most cases of PD are sporadic, which is caused by interaction of genetic and environmental factors. To date, genetic causes for sporadic PD remain largely unknown. ATP-binding cassette sub-family B member 1 (ABCB1) is a membrane-associated protein that acts as an efflux transporter for many substrates, including chemotherapeutic agents, anti-epilepsy medicine, antibiotics and drugs for PD. ABCB1 gene is widely expressed in human tissues, including endothelial cells of capillary blood vessels at blood–brain barrier sites. In PD patients, decreased ABCB1 levels have been reported. We speculated that misregulation of ABCB1 gene expression, caused by DNA sequence variants (DSVs) within its regulatory regions, may be involved in PD development. In this study, we genetically and functionally analyzed the proximal promoter of the human ABCB1 gene, which is required for constitutive expression, in sporadic PD patients and healthy controls. The results showed that a novel and heterozygous DSV g.117077G>A was identified in one PD patient, but in none of the controls. This DSV significantly altered the transcriptional activity of the ABCB1 gene promoter in transiently transfected HEK-293 cells. A heterozygous DSV g.116347T>C was only found in one control. Four single-nucleotide polymorphisms, g.116154T>C (rs28746504), g.117130A>G (rs2188524), g.117356C>G (rs34976462) and g.117372T>C (rs3213619), and one heterozygous deletion DSV g.116039del were found in PD patients and controls with similar frequencies. Therefore, our findings suggest that ABCB1 gene promoter DSVs may contribute to PD development as a rare risk factor.

Parkinson's drug could treat diabetic retinopathy

Parkinson's drug could treat diabetic retinopathy

A Critical Evaluation of Behavioral Rodent Models of Motor Impairment Used for Screening of Antiparkinsonian Activity: The Case of Adenosine A2A Receptor Antagonists

Animal models of motor dysfunction constitute the basis for the screening of new drugs with potential efficacy in diseases characterized by motor impairment, such as Parkinson's Disease (PD). Taking adenosine A(2A) receptor antagonists as an example of a new class of drugs for PD, the review will examine the most utilized rodent models of motor impairment and the results reported in the literature with this class of drugs. The results obtained so far in rodent models of PD suggested that A(2A) receptor antagonists might have symptomatic therapeutic efficacy in PD. They may ameliorate initiation of movement, gait and muscle rigidity, sensorimotor integration deficits, and tremor. Moreover, A(2A) receptor antagonists when administered with a low sub-threshold dose of L-DOPA potentiated its efficacy. However, the clinical trials so far performed have evaluated their efficacy in the "ON/OFF" of PD patients with motor complications, showing a limited efficacy of this class of drug. Therefore, on one hand, animal models of PD might have a limited validity; on the other hand, clinical trials should explore the efficacy of A(2A) receptor antagonists on a broader range of parkinsonian conditions.

Parkinson's drug promotes myelin repair

Parkinson's drug promotes myelin repair

PND59 - Drug Compliance and Persistence in Patients with Parkinson’s Disease Treated in Primary Care in the United Kingdom: A CPRD-Based Study

Differences in compliance and persistence between Parkinson’s disease (PD) drugs were found in a previous US claim database analysis. The objective was to apply the same methodology in another setting using the Clinical Practice Research Datalink (CPRD) in the UK. A retrospective analysis of patients starting a new PD drug (rasagiline, selegiline, pramipexole, ropinirole, entacapone, tolcapone, levodopa) between January 2009 and January 2012 was conducted using CPRD. Patients were categorized as naive to PD therapy (NT) or having prior PD therapy (PT), depending on the prescription of other PD drugs within a 12-month look-back period. The observation period was 12 months. Compliance was measured using the medication possession ratio (MPR) and non-compliance was defined as an MPR≤80%. Persistence was measured as the duration (days) of uninterrupted therapy without gap higher than 45 days. Of the 4,784 patients included in the compliance analysis, 3,675 patients (76.8%) had compliance rates >80%. Mean MPRs were generally comparable across PD products (range:84%-90%, all pairwise p=NS). Percentage of patients with MPR>80% was significantly greater with rasagiline (85.6%, all p<0.05 except vs. ropinirole p=NS). Of the 5,266 patients included in the persistence analysis, the highest mean number of persistent days of treatment was reported for rasagiline (284 days; all p<0.05 vs others, except vs. ropinirole p=0.14 and levodopa p=0.06). Patient persistence at 12 months was significantly greater with rasagiline compared with others in NT patients (66.5%, all p<0.05) and with levodopa in PT patients (72.7%, all p<0.05). A high and comparable level of compliance was observed across PD drugs. Persistence was significantly higher than other drugs with rasagiline in treatment-naïve patients and with levodopa in previously treated patients.

AN AUDIT OF INPATIENT PARKINSON'S DISEASE MANAGEMENT AT BARNET AND CHASE FARM HOSPITALS

BackgroundAs a chronic disorder Parkinson's disease (PD) is mostly managed in outpatient clinics and primary care. Admission of PD patients is often the result of complications or associated comorbid disease.A...

Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G protein-coupled receptor field.

There is serious interest in understanding the dynamics of the receptor-receptor and receptor-protein interactions in space and time and their integration in GPCR heteroreceptor complexes of the CNS. Moonlighting proteins are special multifunctional proteins because they perform multiple autonomous, often unrelated, functions without partitioning into different protein domains. Moonlighting through receptor oligomerization can be operationally defined as an allosteric receptor-receptor interaction, which leads to novel functions of at least one receptor protomer. GPCR-mediated signaling is a more complicated process than previously described as every GPCR and GPCR heteroreceptor complex requires a set of G protein interacting proteins, which interacts with the receptor in an orchestrated spatio-temporal fashion. GPCR heteroreceptor complexes with allosteric receptor-receptor interactions operating through the receptor interface have become major integrative centers at the molecular level and their receptor protomers act as moonlighting proteins. The GPCR heteroreceptor complexes in the CNS have become exciting new targets for neurotherapeutics in Parkinson's disease, schizophrenia, drug addiction, and anxiety and depression opening a new field in neuropsychopharmacology.

Targeting Striatal Metabotropic Glutamate Receptor Type 5 in Parkinson`s Disease: Bridging Molecular Studies and Clinical Trials

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced dyskinesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Non-dopaminergic Treatments for Motor Control in Parkinson’s Disease

The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.

Levodopa Incorporation in Alginate Membranes for Drug Delivery Studies

Parkinsons Disease (PD) is the second most common progressive neurodegenerative disorder and is referred as a leading cause of neurologic disability. The symptoms and signs of PD result from a decrease of dopamines level in the basal ganglia. Accordingly to this, exogenous substitution with dopamine agonists like levodopa, is used to correct the mechanical disorders at the early stages of the disease. Levodopa is referred as a standard in the treatment of PD. The modern studies of PD drug development and experimental therapeutics focuses on the concept of slowing and targeting the release of levodopa to prolong the therapeutic effect and reduce the number of administrations. The transdermal route was thought to be the best route for providing a progressive supply of levodopa to the systemic circulation. Alginate was chosen as a drug carrier because of its biocompatible and biodegradable properties and also because it has been widely used in drug delivery systems (DDS). The aim of this research work was to produce alginate membranes with and without levodopa. A solvent casting based methodology was used. Calcium chloride was assayed as crosslinking agent. Membranes were characterized using Differential Scanning Calorimetry (DSC) techniques. Drug release was evaluated using UV Spectrophotometry.

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence.