Background-The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results-The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event (Pϭ0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96] Key Words: myocardial infarction Ⅲ lipoproteins Ⅲ coronary disease Ⅲ antioxidants P araoxonase (EC.3.1.8.1, aryldialkylphosphatase) (PON1) has been extensively studied in the field of toxicology because it hydrolyses organophosphate compounds, used as insecticides and nerve gases. 1,2 PON1 is synthesized in the liver and in serum is located on HDL. The serum HDL concentration is inversely correlated with atherosclerosis risk. 3 The mechanism for this continues to be the subject of considerable debate. The initial focus of attention was on the role of HDL in reverse-cholesterol transport. However, recent studies have suggested more diverse mechanisms. HDL protects against oxidative modification of LDL, 4 -6 which is believed to be central to the initiation and progression of atherosclerosis. 7 The antioxidant activity of HDL relates to its enzymes, primarily PON1, but also LCAT, 8 and these can prevent lipid-peroxide accumulation on LDL both in vitro and in vivo. 9 -14 PON1 activity is partly genetically determined. An amino acid substitution at position 192 (Q3 R) gives rise to 2 allozymes, 15,16 the relative activities of which are substrate dependent. Substrates, such as paraoxon and fenitroxon, are hydrolyzed faster by the R alloenzyme, whereas other substrates, such as phenyl acetate, are hydrolyzed at the same rate by both alloenzymes, and yet others, such as diazoxon and the nerve gases soman and sarin, are hydrolyzed more rapidly by the Q alloenzyme. 17 The Q alloenzyme in vitro provides greater protection against the accumulation of lipid peroxides on LDL than the R alloenzyme. 18,19 A second exonic polymorphism of the PON1 gene occurs at amino acid position 55 (L3 M). This polymorphism also affects PON1 activity, although less than that of the 192 polymorphism. 20 There have been many case-control studies to test the hypothesis that the 192R allele of the PON1 gene is associated with coronary heart disease (CHD). 21 A recent metaanalysis of these found that the PON1-192R allele was significantly related to the presence of CHD, but there was evidence of publication bias. 22 Furthermore, genetic casecontrol studies fail to test the hypothesis that serum PON1 activity protects against CHD, because the 192 polymorphism accounts for only a small part of the 40-fold individual variation in serum PON1 act...

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, we investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague-Dawley rats were exposed to repeated social defeat for five days while controls were placed into a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology.

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Serotonin is widely believed to exert inhibitory control over aggressive behavior and intent. In addition, a number of studies of fish, reptiles, and mammals, including the lizard Anolis carolinensis, have demonstrated that serotonergic activity is stimulated by aggressive social interaction in both dominant and subordinate males. As serotonergic activity does not appear to inhibit agonistic behavior during combative social interaction, we investigated the possibility that the negative correlation between serotonergic activity and aggression exists before aggressive behavior begins. To do this, putatively dominant and more aggressive males were determined by their speed overcoming stress (latency to feeding after capture) and their celerity to court females. Serotonergic activities before aggression are differentiated by social rank in a region-specific manner. Among aggressive males baseline serotonergic activity is lower in the septum, nucleus accumbens, striatum, medial amygdala, anterior hypothalamus, raphe, and locus ceruleus but not in the hippocampus, lateral amygdala, preoptic area, substantia nigra, or ventral tegmental area. However, in regions such as the nucleus accumbens, where low serotonergic activity may help promote aggression, agonistic behavior also stimulates the greatest rise in serotonergic activity among the most aggressive males, most likely as a result of the stress associated with social interaction.

Interactions between central corticotropin-releasing factor (CRF) and serotonergic systems are believed to be important for mediating fear and anxiety behaviors. Recently we demonstrated that infusions of CRF into the rat dorsal raphe nucleus result in a delayed increase in serotonin release within the medial prefrontal cortex that coincided with a reduction in fear behavior. The current studies were designed to study the CRF receptor mechanisms and pathways involved in this serotonergic response. Infusions of CRF (0.5 microg/0.5 microL) were made into the dorsal raphe nucleus of urethane-anesthetized rats following either inactivation of the median raphe nucleus by muscimol (25 ng/0.25 microL) or antagonism of CRF receptor type 1 or CRF receptor type 2 in the dorsal raphe nucleus with antalarmin (25-50 ng/0.5 microL) or antisauvagine-30 (2 microg/0.5 microL), respectively. Medial prefrontal cortex serotonin levels were measured using in-vivo microdialysis and high-performance liquid chromatography with electrochemical detection. Increased medial prefrontal cortex serotonin release elicited by CRF infusion into the dorsal raphe nucleus was abolished by inactivation of the median raphe nucleus. Furthermore, antagonism of CRF receptor type 2 but not CRF receptor type 1 in the dorsal raphe nucleus abolished CRF-induced increases in medial prefrontal cortex serotonin. Follow-up studies involved electrical stimulation of the central nucleus of the amygdala, a source of CRF afferents to the dorsal raphe nucleus. Activation of the central nucleus increased medial prefrontal cortex serotonin release. This response was blocked by CRF receptor type 2 antagonism in the dorsal raphe. Overall, these results highlight complex CRF modulation of medial prefrontal cortex serotonergic activity at the level of the raphe nuclei.

The mesocorticolimbic dopamine system, which governs components of reward and goal-directed behaviors, undergoes final maturation during adolescence. Adolescent social stress contributes to adult behavioral dysfunction, and is linked to adult psychiatric and addiction disorders. Here, behavioral, corticosterone, and limbic dopamine responses to amphetamine were examined in adult male rats previously exposed to repeated social defeat stress during mid-adolescence. Amphetamine (2.5 mg/kg, ip) was administered after a novel environment test, with behavior observed in the same context for 90 min thereafter. Adult rats that had been defeated in adolescence showed increased locomotion in the novel environment, but reduced amphetamineinduced locomotion relative to non-defeated age matched controls. Monoamine and corticosterone responses to amphetamine were examined following a second amphetamine injection 3 days later. In previously defeated rats, corticosterone and medial prefrontal cortex dopamine responses to amphetamine were blunted while dopamine responses in the nucleus accumbens core were elevated. Our results suggest that experience of social defeat stress during adolescent development can contribute to altered behavioral and endocrine responses to amphetamine in adulthood. Furthermore, these effects are paralleled by changes in amphetamine-induced dopamine responses in corticolimbic systems implicated in addiction disorders.