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The effects of nonselective nitric-oxide synthase (NOS) inhibitors [N--nitro-L-arginine methyl ester (L-NAME) and N--nitro-L-arginine (L-NNA)] and specific neuronal NOS (nNOSon adrenergic nerve-mediated vasoconstriction were studied in rat perfused mesenteric vascular beds without endothelium. Perfusion of L-NAME, L-NNA, or L-VNIO markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS; 2-8 Hz) without affecting vasoconstriction induced by exogenously injected norepinephrine (NE). Addition of L-arginine, a precursor for the synthesis of nitric oxide (NO), reversed the augmentation of the PNS response by L-NAME. The PNS (8 Hz)-evoked NE release in the perfusate was increased by L-NAME perfusion. In preparations treated with capsaicin [a depleter of calcitonin gene-related peptide (CGRP)-containing nerves], L-NAME did not augment vasoconstrictor responses to PNS or NE injection. Combined perfusion of CGRP(8-37) (a CGRP receptor antagonist) and L-NAME induced additive augmentation of the vasoconstrictor response to PNS but did not affect the response to NE injection. In preparations with active tone produced by methoxamine and in the presence of guanethidine, L-NAME perfusion did not affect the vasodilator response induced by PNS. Immunostaining of the mesenteric artery showed the presence of nNOS-like immunopositive nerve fibers, which were absent in arteries pretreated with capsaicin. These findings suggest that NO, which is released from perivascular capsaicin-sensitive nerves, presynaptically inhibits neurogenic NE release to modulate adrenergic neurotransmission.

Using [14C]-2-deoxyglucose autoradiography, we determined which forebrain and diencephalic areas showed metabolic alterations in response to unilateral electrical stimulation of the posterior medial forebrain bundle at parameters chosen to produce a just-submaximal rewarding effect. At these parameters, only a few areas were activated. There was no detectable activation anterior or dorsal to the genu of the corpus callosum. Just anterior to the anterior commissure, there was strong activation of the vertical limb of the diagonal band of Broca, with a focus in the nucleus of the diagonal band. Just posterior to the anterior commissure, there was strong activation of compartment "c" of the medial forebrain bundle (MFB), with weaker activation of the bed nucleus of the stria terminalis and the medial preoptic area. At midhypothalamic levels, the dorsolateral, dorsomedial, and ventral MFB all showed activation. There was bilateral suppression of activity in the lateral habenula. Activation appeared to end in the anterior ventral tegmental area of Tsai. Reward-blocking doses of the neuroleptic pimozide activated the caudate and the lateral habenula but did not alter any of the unilateral effects of stimulation. Using longer pulse durations and/or shifting the site of stimulation to the substantia nigra activated many of the systems not activated in the first experiment, including all of the major dopaminergic projection systems, proving the capacity of the technique to reveal activation of these systems. The results permit one to define a discrete projection system that merits electrophysiological investigation as a likely substrate for the rewarding effect of MFB stimulation. They also suggest that dopaminergic projection systems may not form part of the reward pathway itself.

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