RESUMO
A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.
Assuntos
Discinesia Induzida por Medicamentos , Levodopa , Humanos , Levodopa/efeitos adversos , Diester Fosfórico Hidrolases , Ácido Glutâmico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Nucleotídeos CíclicosRESUMO
Behavioral flexibility-that is, the ability to deviate from established behavioral sequences-is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)âOFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFCâdorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA-OFC-DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLAâOFC inputs, represented within OFC ensembles and retrieved via OFCâDMS outputs during future choice.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Aprendizagem , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Corpo Estriado , Aprendizagem/fisiologia , Camundongos , Córtex Pré-Frontal/fisiologia , RecompensaRESUMO
Phosphodiesterase 9 (PDE9) degrades selectively the second messenger cGMP, which is an important molecule of dopamine signaling pathways in striatal projection neurons (SPNs). In this study, we assessed the effects of a selective PDE9 inhibitor (PDE9i) in the primate model of Parkinson's disease (PD). Six macaques with advanced parkinsonism were used in the study. PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects. While PDE9i was ineffective as monotherapy, 2.5 and 5 mg/kg (s.c.) of PDE9i significantly potentiated the antiparkinsonian effects of l-DOPA with a clear prolongation of the "on" state (p < 0.01) induced by either the suboptimal or threshold l-DOPA dose. Co-administration of PDE9i had no interaction with l-DOPA pharmacokinetics. PDE9i did not affect the intensity of LID. These results indicate that cGMP upregulation interacts with dopamine signaling to enhance the l-DOPA reversal of parkinsonian motor disability. Therefore, striatal PDE9 inhibition may be further explored as a strategy to improve motor responses to l-DOPA in PD.
Assuntos
Pessoas com Deficiência , Discinesia Induzida por Medicamentos , Transtornos Motores , Doença de Parkinson , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Dopamina , Discinesia Induzida por Medicamentos/tratamento farmacológico , Humanos , Levodopa/uso terapêutico , Transtornos Motores/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Diester Fosfórico Hidrolases , PrimatasRESUMO
RATIONALE: It is critical to identify potential risk factors, such as a history of early life stress (ELS), that may confer specific vulnerabilities to increased drug intake. OBJECTIVE: In this study, we examined whether male and female rhesus monkeys with a history of ELS (infant maltreatment; MALT) demonstrated significantly greater cocaine intake compared with controls. METHODS: Monkeys were trained to self-administer cocaine during 4-h sessions at a peak dose (0.003-0.1 mg/kg/infusion; extended access, "EA peak") and a dose of 0.1 mg/kg/infusion (EA 0.1) of cocaine. These data were compared with data obtained previously in monkeys trained during 1-h limited access (LA) sessions at the same peak dose of cocaine used here (Wakeford et al. Psychopharmacology, 236:2785-2796, 2019). RESULTS: Monkeys significantly increased total number of infusions earned in EA compared with LA, but total session response rates significantly decreased in EA compared with LA. There was no evidence of escalation in drug intake when we compared response rates to obtain the first 20 cocaine infusions between LA and EA peak conditions. Moreover, there was no evidence of escalation in drug intake during an additional 7 weeks of self-administration at 0.1 mg/kg/injection. CONCLUSIONS: The current study expands on previous reports demonstrating that rhesus macaques did not escalate cocaine intake under the experimental conditions employed and extended these findings by using a unique population of nonhuman primates with a history of infant MALT to test the hypothesis that ELS is a risk factor for escalation of cocaine intake in nonhuman primates. There was no clear evidence of escalation in cocaine intake as a consequence of ELS.