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A variety of studies indicate that CART in the nucleus accumbens (NAcc) is involved in the action of psychostimulants. In order to understand in more detail if and how dopamine is involved in the regulation of CART mRNA in the NAcc, the present studies of individual receptors were performed. The D1 agonist, dihydrexidine, and the D1 antagonist, SCH23,390, were administered separately and in combination to adult male rats; however, no changes were found in CART mRNA as measured by in situ hybridization. The D2/3 agonist, quinpirole, was administered either separately or in combination with the D2 selective antagonist, L741,626, or the D3 selective antagonist, GR103,691. Quinpirole produced a decrease in CART mRNA of up to 43%. This effect was blocked by pretreatment with the D3 antagonist GR103, 691, but not by the D2 antagonist, L741,626. CART peptide levels showed a similar decrement after acute quinpirole. CART mRNA levels in the NAcc of D3 mutant mice were found to be higher than that in wild-type animals, but treating the mutants with quinpirole failed to produce a decrease in CART expression like that observed in wild-type rodents. These findings demonstrate that CART is regulated by dopamine in the NAcc, at least partly by D3 dopamine receptors.

Intracerebroventricular injections of the irreversible dopamine transporter (DAT) inhibitor, RTI-76 [3beta-(3-p-chlorophenyl) tropan-2beta-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride], decreased DAT binding in both the striatum and nucleus accumbens as measured by both [3H]GBR12935 and by [3H]WIN35,428. This decrease was dose-related, with 100 nmol RTI-76 producing approximately a 50% decrease in both regions. The maximal inhibition of DAT binding was observed 24 h after RTI-76 injection, and binding was fully restored 7 days after injection. The DAT protein half-life determined under these conditions was about 2 days. [3H]Nisoxetine binding at norepinephrine transporters in the cortex was not altered by RTI-76 administration at any time point or dose examined.

PCP and related compounds inhibit 3 H-mazindol binding to the cocaine receptor on dopamine transporters. The relative potencies of these compounds are such that some of the behavioral effects of PCP could be related to its action at the cocaine receptor; however, the affinity of PCP at the cocaine site (K i = 1.59 μM) is less than its affinity at its own receptor (K i about 0.12 μM). More data will be needed to conclusively implicate the cocaine receptor in the action of PCP.

The objective of this study was to examine the effect of neuronal impulse flow on the acetylcholine-dcpleting action of hemicholinium-3 (HC-3). We utilized electrolytic interruption of cholinergic axons and administration of pentobarbital as means to stop or slow impulse flow or release in cholinergic scptal-hippocampal neurones. It has been reported previously that placement of lesions in the septum results in a large rise in acetylcholine (ACh) levels in the hippocampus at short times post-lesion (0.5 3 hr). Administration of pentobarbital has a similar effect. When HC-3 was injected immediately prior to the placement of septal lesion, the post-lesion increase in ACh levels in the hippocampus were blocked. However, if HC-3 was administered 30 min after the placement of lesion, a time at which the post-lesion increases have already occurred, then HC-3 appeared to have no effect. In the striatum, a region which does not receive the cholinergic input from the septum and which should not be effected by placement of septal lesions, there was a depletion of acetylcholine caused by the administration of HC-3. The finding that HC-3 administration blocks the post-lesion rise in ACh levels, suggests that this post-lesion rise requires new synthesis of ACh and hence a supply of extracellular choline which is blocked by HC-3. Our finding that the HC-3 depleting effect was blocked 30 min after lesion, is consistent with the notion that the action of HC-3 is dependent on neuronal impulse flow. However it can be more broadly stated that HC-3 will have a reduced depleting action after any treatment resulting in a depression of acetylcholine synthesis rate.

The regional distribution of choline and acetylcholine was examined in rat brain. Choline was found to have a distribution similar to that of acetylcholine. With the exception of the cerebellum the ratio of choline to acetylcholine in different brain regions ranged between 2.5 and 3.6. When the majority of the cholinergic nerve endings in the hippocampus were destroyed by placement of a lesion in the medial septal area the concentrations of acetylcholine and choline in the hippocampus were reduced by 70–74 and 20–32 %, respectively. These results suggest that a significant portion of the free choline in brain is associated with cholinergic neurones.

Various biochemical and autoradiographic studies suggest a close association of opiate receptors with certain groups of primary sensory nerve fibres in the spinal cord and brainstem. The effect of deafferentation on autoradiographically-determined. stereospecific 3 H-diprenorphine binding sites, in two afferent systems, the vagus nerve and the accessory optic system, was investigated in the rat. Vagotomies appreciably decreased the density of opiate receptors associated with the intramedullary portion of the vagus nerve, the solitary tract and its nucleus and nucleus ambiguus. Enucleation reduced the density of opiate receptors associated with the midbrain accessory optic tract and its nuclei. These results, plus other autoradiographic and biochemical evidence, suggest a rather specific presynaptic localization of some opiate receptors to small calibre and unmyelinated sensory fibres in some areas of the CNS.

Over the past ten to fifteen years, receptor mapping has expanded from a very minor technique, beseiged by problems and limited in its approach, to one that is widespread, extended beyond receptors and applied to clinical problems and populations with modern imaging and scanning techniques.

The effects of buspirone on benzodiazepine receptors labelled in vivo with [3H]Ro 15-1788 were investigated. While buspirone did not affect the binding of benzodiazepine receptors in vitro, significant dose-related increases were observed in the in vivo labelling of benzodiazepine receptors in mice. However, similar results were also obtained with various neuroleptic agents and apomorphine. Potential mechanisms that may account for these results are discussed, but the data suggest caution in the use of [11C]Ro 15-1788 in positron emission tomography scanning in humans, since labelling by Ro 15-1788 may be affected by factors unrelated to direct changes at the benzodiazepine receptor site.