A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

Background:

Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown.

Methods:

In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal.

Results:

Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor.

Conclusions:

Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal.     

UPLC-MS/MS测定复方甘草口服溶液中4种生物碱含量

目的 采用超高效液相色谱-质谱联用方法同时测定复方甘草口服溶液中吗啡、可待因、罂粟碱和可卡因的含量。方法 采用Waters BEH C₁₈(50 mm×2.1 mm,1.7 μm)色谱柱,流动相为含0.1%甲酸的0.02 mol·L^-1乙酸铵溶液(A)-甲醇(B),梯度洗脱(0~1.5 min,92%A;1.5~2.0 min,92%A→60%A;2.0~4.5 min,60%A;4.5~4.6 min,60%A→92%A;4.6~5.0 min,92%A),流速为0.2 mL·min^-1,柱温为35 ℃;质谱采用电喷雾离子源,多反应监测模式(正离子)。结果 吗啡、可待因、罂粟碱和可卡因浓度分别在5.68~113.4,1.04~20.85,0.53~10.58和0.16~3.13 μg·L^-1内线性关系良好,r值为0.998 4~0.999 9,平均回收率为98.8%~100.3%,定量下限分别为0.5,0.5,0.05,0.01 μg·L^-1,检测限为0.2,0.2,0.02,0.005 μg·L^-1。结论 该方法分析速度快,灵敏度高,结果准确可靠,是复方甘草口服溶液质量控制的一种可行方法。     

Gender Differences in Condom Usage Among Rural Crack-Using Men and Women

SUMMARY

Consistent condom use is an important aspect of decreasing HIV transmission risk in heterosexual crack cocaine using populations. This study explores gender differences in attitudes and motivations to use condoms within a rural, economically disadvantaged sample. Qualitative data analysis identified recurrent themes regarding condom use and assessed how themes varied among men and women. Analyses showed that men and women exhibit different rationales for condom use, while both reported inconsistencies between their knowledge about safe sex, receptivity to condom use, and applications in practice. The findings suggest that prevention programs should be tailored to increase consistent condom use among main partners of crack smokers at risk for HIV.     

Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons

Serotonin 5-HT(1B) receptors modulate behavioral responses to cocaine, but the effects of cocaine on endogenous 5-HT(1B) receptor expression are not known. Therefore, we examined the effect of binge cocaine administration on 5-HT1B mRNA expression in rat brain. We found that chronic, but not acute, binge cocaine exposure increased 5-HT(1B) mRNA by approximately 80% in nucleus accumbens shell and dorsal striatum. Surprisingly, 5-HT(1B) mRNA was increased in nucleus accumbens shell after chronic vehicle treatment as well, but this effect was driven by animals that were housed with cocaine-treated animals. Thus, 5-HT(1B) mRNA is upregulated by repeated exposure to cocaine and perhaps by social stress as well; both of these factors are relevant to the risk for relapse in cocaine addiction.     

Contemporary cocaine use patterns and associated harms in Melbourne and Sydney, Australia

The aim of this paper was to explore the nature of cocaine use and harms through a cross-sectional survey of cocaine users interviewed in the two largest Australian cities of Sydney (n = 88) and Melbourne (n = 77) between October 2004 and January 2005. The study supported previous findings that Australian cocaine users could be classified broadly into two types. The majority of cocaine users interviewed were classified as socially and economically integrated. They were young, employed, well-educated people who generally snorted cocaine on a recreational basis, typically in conjunction with other illicit and licit drugs. A second group of socially and economically marginalised users, residing mainly in Sydney, injected cocaine often in conjunction with heroin. This group reported significantly higher levels of cocaine use, cocaine dependence, criminal behaviour and human immunodeficiency virus (HIV) risk-taking behaviour. Heroin use was found to predict independently higher levels of cocaine use, criminal behaviour, needle sharing and physical problems in this sample, suggesting that increased resources and coverage for combined heroin/cocaine users may have scope for reducing cocaine-related problems in the Australian community.     

Behavioral response to buspirone in cocaine and phencyclidine withdrawal

The effects of buspirone in treating cocaine and phencyclidine (PCP) withdrawal were studied. Withdrawal symptoms of these two street-drugs are thought to be due to norepinephrine, dopamine and possibly serotonin depletion. Buspirone acts by enhancing dopaminergic and noradrenergic firing as well by suppressing serotonergic activity. Thirty-two cocaine abusers and 24 PCP abusers were withdrawn over a 30-day period. Half of each group received buspirone 10 mg t.i.d. and the other half 10 mg placebo t.i.d. In the cocaine group, buspirone was significantly more effective from the fifth day onward. In the PCP group, significant improvement was seen on the thirtieth day. Delayed effectiveness in PCP is thought due to its actions at other neurotransmitter sites.     

DIFFERENTIAL ACTIVATION OF ADRENOCEPTOR SUBTYPES BY NORADRENALINE APPLIED FROM THE INTIMAL OR ADVENTITIAL SURFACES OF RAT ISOLATED TAIL ARTERY

• 1 The vasoconstrictor effects of noradrenaline applied to the intimal and adventitial surfaces of perfused segments of rat tail artery in the presence and absence of endothelium were studied.
• 2 Noradrenaline was about six times more potent as a vasoconstrictor when applied to the intimal than to the adventitial surface. Cocaine (25 μmol/L) enhanced responses to adventitial noradrenaline to a greater extent than those to intimal noradrenaline. A high concentration of propranolol (1 μmol/L) had a similar effect.
• 3 The vasoconstriction elicited by adventitial noradrenaline declined from a peak whereas that to intimal noradrenaline remained steady. A low concentration of propranolol (0.1 μmol/L) abolished the decline in the response to adventitial noradrenaline.
• 4 The α₁- and α₂-adrenoceptor antagonists prazosin (1 nmol/L) and idazoxan (100 nmol/L) significantly reduced responses to intimal and adventitial noradrenaline in the presence or absence of endothelium.
• 5 Removal of endothelium enhanced responses to intimal but not adventitial noradrenaline. Idazoxan produced a significantly greater reduction of responses to noradrenaline in the absence than in the presence of endothelium, and was more effective against intimal than adventitial noradrenaline. Similar effects were produced by the nitric oxide synthase inhibitor l-NAME (30 μmol/L).
• 6 It was concluded that noradrenaline acts on both α₁- and α₂-adrenoceptors to produce vasoconstriction: the α₁-adrenoceptors appear to be uniformly distributed, whereas α₂-adrenoceptors are located nearer the intima. Intimal noradrenaline also acts on endothelial α₂-adrenoceptors to release EDRF which counteracts the vasoconstrictor action of noradrenaline. Adventitial noradrenaline also acts on β-adrenoceptors located near the adventitia to counteract the vasoconstriction produced by activation of α-adrenoceptors and its action is reduced by neuronal uptake.

     

Determination of cocaine and heroin with their respective metabolites in meconium by gas chromatography-mass spectrometry

The analysis of meconium specimens is a relatively accurate method for the detection of fetal exposure to drugs. The purpose of this study was to develop and validate a method for meconium sample preparation for a gas chromatography-mass spectrometry (GC-MS) confirmation of meconium extracts for cocaine, benzoylecgonine, codeine, morphine and 6-monoacetylmorphine. The analytes were initially extracted from the matrix by methanol. Subsequently a solid-phase extraction with Waters Oasis HLB cartridges was applied. Analytes were determined in GC-MS single monitoring mode. The method was validated in the range 40-2000 ng g(-1) using 0.5 g of meconium per assay. The detector response was linear over the studied range, and limits of quantitation and detection were found to be acceptable. Intra- and inter-batch coefficients of variation oscillated between 2.54% and 20.5%, and mean relative errors were in the range 0.79%-19.9%. The recoveries were higher than 42.1% in all cases. Finally the method was applied to analysis of meconium in newborns to assess fetal exposure to cocaine and opiates.     

Gender Differences in Treatment-Seeking Brazilian Drug-Dependent Individuals

The authors compared 66 women and 66 men entering an outpatient treatment for drug dependence, focussing on demographics, progression of dependence, and other associated clinical features. Most of the subjects were dependent on cocaine (75%). Women, as compared with men, had a higher level of education, were more likely to have migrated from other places to the city of Sao Paulo, to report past suicide attempts, and to have first-degree relatives with alcohol problems. There were no gender differences regarding the total time of drug use, baseline severity of dependence, and rates of concurrent psychiatric comorbidity. Clinicians working with drug-dependent women should note the high rates of suicidal behavior in this population, and should explore, besides psychiatric status, risk factors such as impulsive temperament traits. It should also be noted that higher rates of alcohol problems in women's family background pose challenges for the development of effective preventive and treatment strategies.     

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Changes in the brain''s cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer''s disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.