Endogenous cannabinoid receptor ligands (endocannabinoids) may rescue neurons from glutamate excitotoxicity. As these substances also accumulate in cultured immature neurons following neuronal damage, elevated endocannabinoid concentrations may be interpreted as a putative neuroprotective response. However, it is not known how glutamatergic insults affect in vivo endocannabinoid homeostasis, i.e. N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as other constituents of their lipid families, N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs), respectively. Here we employed three in vivo neonatal rat models characterized by widespread neurodegeneration as a consequence of altered glutamatergic neurotransmission and assessed changes in endocannabinoid homeostasis. A 46-fold increase of cortical NAE concentrations (anandamide, 13-fold) was noted 24 h after intracerebral NMDA injection, while less severe insults triggered by mild concussive head trauma or NMDA receptor blockade produced a less pronounced NAE accumulation. By contrast, levels of 2-AG and other 2-MAGs were virtually unaffected by the insults employed, rendering it likely that key enzymes in biosynthetic pathways of the two different endocannabinoid structures are not equally associated to intracellular events that cause neuronal damage in vivo. Analysis of cannabinoid CB 1 receptor mRNA expression and binding capacity revealed that cortical sub®elds exhibited an up-regulation of these parameters following mild concussive head trauma and exposure to NMDA receptor blockade. This may suggest that mild to moderate brain injury may trigger elevated endocannabinoid activity via concomitant increase of anandamide levels, but not 2-AG, and CB 1 receptor density.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudateputamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to selfadminister cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine selfadministration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in eachCocaine abuse and dependence remain major public health and social problems. Cocaine abuse results from a complex interplay of behavioral, pharmacological, and neurobiological determinants. The main pharmacological effect of cocaine is to inhibit the reuptake of monoamines dopamine, norepinephrine, and serotonin at presynaptic terminals. As a consequence of these ac- (Hadfield et al. 1980;Heikkila et al. 1975;Ross and Renyi 1969). The major behavioral effect of cocaine is a psychomotor stimulant action with reinforcing addictive properties. This behavioral effect is produced primarily by inhibition of dopamine uptake, thereby increasing extracellular concentrations of released dopamine (Ritz et al. 1987; for a review see Kuhar et al. 1991;Spanagel and Weiss 1999). However, a recent study using mice lacking dopamine transporter proposed other mechanisms, such as increases in serotonin transmission, may mediate the reinforcing effects of cocaine (Rocha et al. 1998).Several studies have shown that cocaine also affects the expression of opioid peptides and opioid receptors. For example, chronic cocaine administration leads to increases in circulating ␤ -endorphin levels (Moldow and Fischman 1987), striatal preprodynorphin mRNA levels (Hurd et al. 1992;Daunais et al. 1993;Daunais and McGinty, 1995;Spangler et al. 1993Spangler et al. , 1996Spangler et al. , 1997, and striatonigral dynorphin content (Sivam 1989;Smiley et al. 1990) in rats and to decreases in preproenkephalin mRNA levels in rhesus monkeys (Daunais et al. 1997) and humans (Hurd and Herkenham 1993). Repeated administration of cocaine can also regulate the activity of opioid receptors in discrete brain regions of rats. Indeed, it has been shown that 2 weeks of either continuous administration of cocaine via subcutaneously implanted osmotic...

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