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Our previous studies have suggested that dopamine and noradrenaline may be coreleased from noradrenergic nerve terminals in the cerebral cortex. To further clarify this issue, the effect of electrical stimulation of the locus coeruleus on extracellular noradrenaline, dopamine and DOPAC in the medial prefrontal cortex, parietal cortex and caudate nucleus was analysed by microdialysis in freely moving rats. Stimulation of the locus coeruleus for 20 min with evenly spaced pulses at 1 Hz failed to modify cortical catecholamines and DOPAC levels. Stimulation with bursts of pulses at 12 and 24 Hz increased, in a frequency-related manner, not only noradrenaline but also dopamine and DOPAC in the two cortices. In both cortices noradrenaline returned to baseline within 20 min of stimulation, irrespective of the stimulation frequency, whereas dopamine returned to normal within 20 and 60 min in the medial prefrontal cortex and within 60 and 80 min in the parietal cortex after 12 and 24 Hz stimulation, respectively. DOPAC remained elevated throughout the experimental period. Phasic stimulation of the locus coeruleus at 12 Hz increased noradrenaline in the caudate nucleus as in the cerebral cortices but was totally ineffective on dopamine and DOPAC. Tetrodotoxin perfusion into the medial prefrontal cortex dramatically reduced noradrenaline and dopamine levels and suppressed the effect of electrical stimulation. These results indicate that electrical stimulation-induced increase of dopamine is a nerve impulse exocytotic process and suggest that cortical dopamine and noradrenaline may be coreleased from noradrenergic terminals.

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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Summary Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25 mg/kg, SC) and d-amphetamine (AMPH, 2.5 mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10 μg/1 μl) and in the nucleus accumbens (NAc) shell and core (0.5 μg/0.5 μl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region.