Neuroscience
-
The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. ⋯ Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.
-
Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD(+)) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. ⋯ CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
-
Neuroadaptations in the prefrontal cortex (PFC) are hypothesized to play an important role in the behavioral changes associated with repeated psychostimulant exposure, but there are few published studies that measure neuronal activity during the development and expression of sensitization. To address this, we recorded single neuron activity in the medial PFC (mPFC) of male rats that were exposed for 5 days to saline or amphetamine (AMPH; 1.0 mg/kg i.p.) and then given saline or AMPH challenges following a three-day withdrawal. We found that rats exposed to AMPH developed locomotor sensitization to the drug that emerged on the fifth treatment session and became statistically significant at AMPH challenge. ⋯ Furthermore, these units increased firing during a saline challenge that was given to assess associative conditioning. These results suggest that AMPH-induced adaptations in mPFC function are not as apparent as AMPH-induced adaptations in behavior. When mPFC adaptations do occur, they appear limited to the population of neurons that increase their firing in response to AMPH.
-
Stress activates multiple neural systems that suppress pain sensation. This adaptive phenomenon referred as stress-induced analgesia (SIA) is mediated by the activation of endogenous pain inhibitory systems. Both opioid and non-opioid forms of SIA have been elicited in rodents according to stressor parameters and duration. ⋯ In sum, by using genetic and pharmacological approaches, we demonstrated here that NTS2 receptors mediate non-opioid SIA. Our results also revealed that the release of endogenous NT in response to stress requires the presence of NTS2 to stimulate corticotropin-releasing factor (CRF)-induced elevation of plasma corticosterone, and that NTS2 receptors localized at the lumbar spinal cord participate to the disinhibition of descending pain control pathways. Therefore, these data highlight the significance of NTS2 as a novel target for the treatment of pain and stress-related disorders.
-
Clinically relevant concentrations of isoflurane or sevoflurane sensitize transient receptor potential vanilloid type 1 to several of its activators, including capsaicin. It has, moreover, been suggested these volatile general anaesthetics may augment nociceptive signalling arising from surgical procedures and thereby contribute to post-operative pain. To investigate this suggestion, we have studied intraplantar capsaicin injection-induced phosphorylation of extracellular signal-regulated kinase 1/2 in spinal dorsal horn neurons (which is a recognized marker of spinal nociceptive processing) in rat during isoflurane or sevoflurane anaesthesia after 60 min under anaesthesia. ⋯ The total number of spinal dorsal horn neurons labelled on the ipliateral side following capsaicin injection into the isoflurane-, or sevoflurane-, anaesthetized animals was significantly less than that produced by capsaicin alone. Further, capsaicin injection into isoflurane-, or sevoflurane-, anaesthetized animals reduced extracellular signal-regulated kinase 1/2 phosphorylation induced by the gases alone on both sides. These findings do not support the suggestion that isoflurane-, or sevoflurane-, induced sensitization of transient receptor potential vanilloid type 1 by capsaicin, or other agonist, is translated into induction of spinal nociceptive processing and consequential pain sensation.