The compound N-piperidinyl-[8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide] (NESS 0327) was synthesized and evaluated for binding affinity toward cannabinoid CB 1 and CB 2 receptor. NESS 0327 exhibited a stronger selectivity for CB 1 receptor compared with, showing a much higher affinity for CB 1 receptor (K i ϭ 350 Ϯ 5 fM and 1.8 Ϯ 0.075 nM, respectively) and a higher affinity for the CB 2 receptor (K i ϭ 21 Ϯ 0.5 nM and 514 Ϯ 30 nM, respectively). Affinity ratios demonstrated that NESS 0327 was more than 60,000-fold selective for the CB 1 receptor, whereas SR 141716A only 285-fold. NESS 0327 alone did not produce concentration-dependent stimulation of guanosine 5Ј-O-(3-[ Interest in the pharmacology of cannabinoids (CBs) has rapidly increased after the cloning of cannabinoid receptors and the discovery of their endogenous ligand: arachidonylethanolamide (anandamide) (Devane et al., 1988(Devane et al., , 1992Munro et al., 1993). Two types of cannabinoid receptors, CB 1 and CB 2 , have been characterized, both of which have distinct anatomical distributions and ligand binding profiles. Cannabinoid CB 1 receptors are present in the central nervous system with the highest densities in the hippocampus, cerebellum, and striatum (Herkenham et al., 1990;Howlett, 1998), and to a lesser extent in several peripheral tissues. Cannabinoid CB 2 receptors seem to be predominantly located in peripheral tissues (Pertwee, 1997(Pertwee, , 1999Galiègue et al., 1995). Both receptors belong to the G protein-coupled family of receptors that negatively regulate adenylate cyclase and control the release of arachidonic acid (Howlett, 1995). Naturally occurring [⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) and ⌬ 8 -THC] and synthetic cannabinoid agonists CP 55,940, and WIN 55, produce a number of effects in mice (hypoactivity, catalepsy, hypothermia, and antinociception) that are collectively known as the tetrad of cannabinoidinduced behaviors (Abood and Martin, 1992;Compton et al., 1992Compton et al., , 1993. These behaviors are of a central origin and are thought to be mediated via the cannabinoid CB 1 receptor (Rinaldi-Carmona et al., 1994;Compton et al., 1996;Lichtman and Martin, 1997), whereas the CB 2 receptor may mediate some of the peripheral effects of ⌬ 9 -THC, such as immunosuppression (Martin, 1986).The cloning of CB 1 and CB 2 receptors and the subsequent development of selective tools have advanced the concept of Article, publication date, and citation information can be found at

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Clinically important differences exist between antipsychotic agents and formulations in terms of safety and tolerability. Features of the biochemical interaction between the antipsychotic and the D2-receptor may underlie these differences. This article reviews current information on the relationship between antipsychotic receptor occupancy and clinical response. A literature search was performed using the keywords 'antipsychotic or neuroleptic', 'receptor' and 'occupancy' and 'dopamine' and 'D2' supplemented by the authors' knowledge of the literature. Imaging and clinical data have generally supported the hypotheses that optimal D2-receptor occupancy in the striatum lies in a 'therapeutic window' between approximately 65 and approximately 80%, however, pharmacokinetic and pharmacodynamic properties of a drug should also be taken into account to fully evaluate its therapeutic effects. Additional research, perhaps in preclinical models, is needed to establish D2-receptor occupancy in various regions of the brain and the optimal duration of D2-receptor blockade in order to maximise efficacy and tolerability profiles of atypical antipsychotics and thereby improve treatment outcomes for patients with schizophrenia.

Objective: Previous reports have shown that the D 9 -tetrahydrocannabinol (D 9 TCH), the major psychoactive cannabinoid components of marijuana, is unable to inhibit thyroid hormonal activity. The aim of this study was to characterize the CB1 functional expression in the rat thyroid by a multi-methods approach. Methods and Results: RT-PCR was used to detect the mRNA expression of the CB1 cannabinoid receptor (17:8^4:0% of the normalizing reference gene b 2 microglobulin), as well as the expression of the endocannabinoid hydrolyzing enzyme, fatty acid amide hydrolase (46:9^4:3% of b 2 microglobulin), in the rat thyroid gland.The CB1-encoded protein was detected in its glycosylated form (63 kDa) by Western blot, employing a polyclonal antibody, while CB1 immunohistochemical localization showed an intracellular positive staining in both follicular and parafollicular cells. In addition, a 30% decrease in serum levels of both 3,5,3 0 tri-iodothyronine (T 3 ) and thyroxine (T 4 ) was detected 4 h after the administration of the synthetic cannabinoid receptor agonist, WIN 55,212-2 (10 mg/kg i.p.). These effects were antagonized by pretreatment with the CB1 antagonist SR 141716A (3 mg/kg i.p.); thyrotrophin levels were unaffected by both treatments. Conclusion: These data indicate that functional CB1 receptors which are able to modulate the release of T 3 and T 4 are expressed in the rat thyroid, and suggest a possible role of cannabinoids in the regulation of rat thyroid hormonal activity.

Reduction in both presynaptic and postsynaptic structures in the aging neocortex may significantly affect functional synaptic properties in this area. To directly address this issue, we combined whole-cell patch-clamp recording of spontaneously occurring postsynaptic currents (PSCs) with morphological analysis of layer V pyramidal neurons in the parietal cortex of young adult (1- to 2-month-old) and aged (28- to 37-month-old) BN x F344 F(1) hybrid rats. Analysis of spontaneous PSCs was used to contrast functional properties of basal synaptic input with structural alterations in the dendritic tree of pyramidal neurons and density of terminals in contact with these cells. We observed significant changes in a number of morphological parameters of pyramidal neurons in aged rats. These include smaller cell body size and fewer basal dendritic branches (but not of oblique dendrites and dendritic tufts) and spines. Ultrastructural analysis also revealed a lower density of presynaptic terminals per unit length of postsynaptic membrane of labeled pyramidal neurons in the aged brain. This reduction in both presynaptic and postsynaptic elements was paralleled by a significant decrease in frequency of tetrodotoxin-insensitive miniature (action potential-independent) PSCs (mPSCs). The frequency of excitatory and inhibitory mPSCs was reduced to the same extent. In contrast, no significant change was observed in the frequency of spontaneous PSCs recorded in absence of tetrodotoxin (sPSCs), indicating an increase in action potential-dependent (frequency(sPSCs) - frequency(mPSCs)) input to pyramidal neurons in the aged group. This functional compensation may explain the lack of drastic loss of spontaneous neuronal activity in normal aging.