强啡肽对纹状体内D_1多巴胺受体反应的调节

用6-羟多巴胺破坏黑质纹状体通路,使大鼠多巴胺耗竭后,应用原位杂交组织化学方法测量D1多巴胺受体对即早基因c－fos和zif268诱导反应,分析强啡肽对突触前、后调节作用。先用D1多巴胺受体激动剂SKF－38393反复处理动物,促进纹状体内强啡肽表达,在伏隔核强啡肽表达增加,同时伴随着即早基因c-fos和zif268的减少．在纹状体的背部和两侧,强啡肽表达虽大量增加,而D1多巴胺受体反应仍然维持原水平．在中央纹状体区,即早基因的表达处于中间水平。结果提示,纹状体内强啡肽起着调节多巴胺输入到纹状体黑质神经元的作用,包括突触前、后位置;并且调节作用在纹状体的腹、背侧区是不同的     

Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin

Posterior pituitary hormone secretion and central neural expression of the immediate-early gene product c-Fos was examined in adult ferrets after intravenous administration of CCK octapeptide. Pharmacological doses of CCK (1, 5, 10, or 50 microg/kg) did not induce emesis, but elicited behavioral signs of nausea and dose-related increases in plasma vasopressin (AVP) levels without significant increases in plasma oxytocin (OT) levels. CCK activated neuronal c-Fos expression in several brain stem viscerosensory regions, including a dose-related activation of neurons in the dorsal vagal complex (DVC). Activated brain stem neurons included catecholaminergic and glucagon-like peptide-1-positive cells in the DVC and ventrolateral medulla. In the forebrain, activated neurons were prevalent in the paraventricular and supraoptic nuclei of the hypothalamus and also were observed in the central nucleus of the amygdala and bed nucleus of the stria terminalis. Activated hypothalamic neurons included cells that were immunoreactive for AVP, OT, and corticotropin-releasing factor. Comparable patterns of brain stem and forebrain c-Fos activation were observed in ferrets after intraperitoneal injection of lithium chloride (LiCl; 86 mg/kg), a classic emetic agent. However, LiCl activated more neurons in the area postrema and fewer neurons in the nucleus of the solitary tract compared with CCK. Together with results from previous studies in rodents, our findings support the view that nauseogenic treatments activate similar central neural circuits in emetic and nonemetic species, despite differences in treatment-induced emesis and pituitary hormone secretion.     

Stress interacts with peripheral cholinesterase inhibitors to cause central nervous system effects

Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to have central cholinesterase inhibition properties under certain conditions (such as when ingested with other chemical compounds or following a high level of stress). Here we tested if stressing rats, using an intermittent 1 hr tailshock protocol, affected the degree of brain acetylcholinesterase (AChE) inhibition caused by a subsequent single injection of PB (2.0 mg/kg) or neostigmine bromide (NB, 0.32 mg/kg), another peripheral carbamate cholinesterase inhibitor. Stressed rats treated with PB had lower levels of AChE activity in the basal forebrain/striatum, but not in other brain areas. Stressed rats treated with NB did not show basal forebrain/striatum AChE activity changes but did show minor reductions of AChE activity in the cortex and cerebellum. These results confirm that prior stress can change the characteristic actions of certain peripherally acting drugs, thus possibly leading to unexpected central nervous system effects. Possible causes for these effects are discussed.     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

Brain regional differences in CB1 receptor adaptation and regulation of transcription

Cannabinoid CB₁ receptors (CB₁Rs) are expressed throughout the brain and mediate the central effects of cannabinoids, including Δ⁹-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana. Repeated THC administration produces tolerance to cannabinoid-mediated effects, although the magnitude of tolerance varies by effect. Consistent with this observation, CB₁R desensitization and downregulation, as well as induction of immediate early genes (IEGs), vary by brain region. Zif268 and c-Fos are induced in the forebrain after acute THC administration. Phosphorylation of the cAMP response-element binding protein (CREB) is increased in a region-specific manner after THC administration. Results differ between acute versus repeated THC injection, and suggest that tolerance to IEG activation might develop in some regions. Repeated THC treatment produces CB₁R desensitization and downregulation in the brain, although less adaption occurs in the striatum as compared to regions such as the hippocampus. Repeated THC treatment also induces expression of ΔFosB, a very stable isoform of FosB, in the striatum. Transgenic expression of ?FosB in the striatum enhances the rewarding effects of several drugs, but its role in THC-mediated effects is not known. The inverse regional relationship between CB₁R desensitization and ?FosB induction suggests that these adaptations might inhibit each other, although this possibility has not been investigated. The differential regional expression of individual IEGs by acute or repeated THC administration suggests that regulation of target genes and effects on CB₁R signaling will contribute to the behavioral effects of THC.     

Associative and sensorimotor cortico‐basal ganglia circuit roles in effects of abused drugs

The mammalian forebrain is characterized by the presence of several parallel cortico‐basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal‐directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico‐basal ganglia circuits become involved in drug‐related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use.     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

Review. Neurobiological mechanisms for opponent motivational processes in addiction

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.     

Enhanced muscarinic M1 receptor gene expression in the corpus striatum of streptozotocin-induced diabetic rats

Acetylcholine (ACh), the first neurotransmitter to be identified, regulate the activities of central and peripheral functions through interactions with muscarinic receptors. Changes in muscarinic acetylcholine receptor (mAChR) have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). Previous reports from our laboratory on streptozotocin (STZ) induced diabetic rats showed down regulation of muscarinic M1 receptors in the brainstem, hypothalamus, cerebral cortex and pancreatic islets. In this study, we have investigated the changes of acetylcholine esterase (AChE) enzyme activity, total muscarinic and muscarinic M1 receptor binding and gene expression in the corpus striatum of STZ – diabetic rats and the insulin treated diabetic rats. The striatum, a neuronal nucleus intimately involved in motor behaviour, is one of the brain regions with the highest acetylcholine content. ACh has complex and clinically important actions in the striatum that are mediated predominantly by muscarinic receptors. We observed that insulin treatment brought back the decreased maximal velocity (V_max) of acetylcholine esterase in the corpus striatum during diabetes to near control state. In diabetic rats there was a decrease in maximal number (B_max) and affinity (K_d) of total muscarinic receptors whereas muscarinic M1 receptors were increased with decrease in affinity in diabetic rats. We observed that, in all cases, the binding parameters were reversed to near control by the treatment of diabetic rats with insulin. Real-time PCR experiment confirmed the increase in muscarinic M1 receptor gene expression and a similar reversal with insulin treatment. These results suggest the diabetes-induced changes of the cholinergic activity in the corpus striatum and the regulatory role of insulin on binding parameters and gene expression of total and muscarinic M1 receptors.     

Estrogen Rapidly Induces c-jun Immunoreactivity in Rat Striatum

Estrogen has been reported to exert rapid effects on the function of neurons located in various brain regions, including those where classical estrogen receptors are not abundant, such as the striatum. The mechanism underlying these actions is not well understood, but does not appear to involve classical estrogen receptor-mediated genomic mechanisms. Estrogen has also been shown to regulate expression of immediate-early gene products in many tissues. In the present study, immunohistochemical methods were used to determine whether estrogen modulates the appearance of e-jun immunoreactivity (IR) in the striatum of rats. Administration of estradiol (100 μg/rat) to ovariectomized rats for 15 min induced a rapid and transient increase in c-jun-IR in the dorsomedial striatum and the core region of the nucleus accumbens. These data suggest that c-jun may serve as one of the rapidly responding mediators of estrogen action in the striatum and nucleus accumbens.     

Estradiol: A key biological substrate mediating the response to cocaine in female rats

A consistent finding in drug abuse research is that males and females show differences in their response to drugs of abuse. In women, increased plasma estradiol is associated with increased vulnerability to the psychostimulant and reinforcing effects of drugs of abuse. Our laboratory has focused on the role of estradiol in modulating the response to cocaine. We have seen that ovariectomy increases the locomotor response to a single cocaine injection, whereas estradiol exacerbates the locomotor response to repeated cocaine administration. Cocaine-induced sensitization of brain activity, as measured by fMRI, is also dependent on plasma estradiol. Moreover, we observed that although all ovariectomized rats show conditioned place preference to cocaine, it is more robust in ovariectomized rats with estradiol.Opioid receptors are enriched in brain regions associated with pleasure and reward. We find that in females, the effectiveness of kappa opioid agonists in decreasing the locomotor response to repeated cocaine varies with plasma estradiol. We also find that estradiol regulates the density of mu opioid receptors in brains areas associated with reward. These data hint that in females, estradiol modulates the behavioral effects of cocaine by regulating mu and kappa opioid signaling in mesocorticolimbic brain structures. Identifying the mechanisms that mediate differences in vulnerability to drugs of abuse may lead to effective therapeutic strategies for the treatment and prevention of addiction and relapse. We encourage health practitioners treating persons addicted to drugs to consider gender differences in response to particular pharmacotherapies, as well the sex steroid milieu of the patient.     

Expression and localization of Parkinson's disease-associated leucine-rich repeat kinase 2 in the mouse brain

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been identified as the cause of familial Parkinson's disease (PD) at the PARK8 locus. To begin to understand the physiological role of LRRK2 and its involvement in PD, we have investigated the distribution of LRRK2 mRNA and protein in the adult mouse brain. In situ hybridization studies indicate sites of mRNA expression throughout the mouse brain, with highest levels of expression detected in forebrain regions, including the cerebral cortex and striatum, intermediate levels observed in the hippocampus and cerebellum, and low levels in the thalamus, hypothalamus and substantia nigra. Immunohistochemical studies demonstrate localization of LRRK2 protein to neurones in the cerebral cortex and striatum, and to a variety of interneuronal subtypes in these regions. Furthermore, expression of LRRK2 mRNA in the striatum of VMAT2-deficient mice is unaltered relative to wild-type littermate controls despite extensive dopamine depletion in this mouse model of parkinsonism. Collectively, our results demonstrate that LRRK2 is present in anatomical brain regions of direct relevance to the pathogenesis of PD, including the nigrostriatal dopaminergic pathway, in addition to other regions unrelated to PD pathology, and is likely to play an important role in the normal function of telencephalic forebrain neurones and other neuronal populations.