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PubMed2000

Depressive characteristics of FSL rats: involvement of central nicotinic receptors.

Antidepressant effects of acute or chronic nicotine treatments in swim test immobility of Flinders sensitive line (FSL) rats, an animal model of depression, were recently demonstrated (Tizabi et al. Psychopharmacology 142:193, 1999). In the present study we sought to determine whether the antidepressant effects of nicotine could be blocked by the nicotinic antagonist, mecamylamine (MEC). Moreover, the effects of chronic nicotine treatment on [3H]cytisine binding in discrete brain regions of FSL and their control Flinders resistant line (FRL) rats were also evaluated. Adult male FSL rats were treated with MEC (0.5 mg/kg) 20 min prior to an acute or chronic nicotine administration. MEC by itself did not affect the immobility in swim test. However, it completely blocked the acute or chronic nicotine effects. Daily nicotine injection (0.4 mg/kg/day for 14 days) resulted in an increase in [3H]cytisine binding primarily in the FRL rats. An increase in nicotinic receptor binding following chronic nicotine administration is believed to reflect desensitization of these receptors. These findings, coupled with previous observation of higher basal nicotinic receptors in FSL rats, further support the involvement of central nicotinic receptors in depressive characteristics of these rats. Moreover, the data suggest therapeutic potential for selective nicotinic receptor agonists in depressive disorders.

Alkaloids↗
PubMed1999

GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue.

Identification of nicotinic receptor subtypes involved in nicotine dependence is required for guiding the design of more selective antagonists capable of blocking the nicotine cue and nicotine self-administration. Due to the multiplicity of nicotinic receptors in the mammalian brain, selective agonists and antagonists are needed to assess the functional involvement of a particular subtype in vivo. Only recently have a few nicotinic receptor subtype-selective antagonists and agonists been identified. GTS-21 (also known as DMBX-anabaseine) is the only agent so far reported that selectively stimulates the alpha7 nicotinic receptor. Here GTS-21 was used to assess the possible mediation of the nicotine cue by this receptor subtype. Long-Evans rats were trained to discriminate between presession administration of 0.10 or 0.40 mg/kg (-)-nicotine bitartrate and its vehicle. GTS-21 did not substitute for nicotine, as all subjects consistently chose the vehicle lever after GTS-21 substitution. In another experiment, different doses of GTS-21 were administered prior to nicotine administration to investigate whether GTS-21 would antagonize the nicotine cue. Such was not the case. The lack of effect of GTS-21 upon the nicotine cue is consistent with the notion that the cue is mediated by nicotinic receptors other than the alpha7 receptor.

Alkaloids↗
PubMed1998

Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord.

The development of nicotinic acetylcholine receptors (nAChRs) in brains from human fetuses of 4-12 weeks gestational age was studied. The expression of nAChR subunit mRNAs was analyzed using reverse transcriptase-polymerase chain reaction. Expression of alpha 3, alpha 4, alpha 5, alpha 7, beta 2, beta 3 and beta 4 mRNA were all detected in the prenatal spinal cord, medulla oblongata, pons, cerebellum, mesencephalon, subcortical forebrain and cortex during first trimester development. Relative quantification of mRNA showed that the highest levels for alpha 3, alpha 4 and alpha 7 were expressed in the spinal cord, alpha 5 was most abundant in the cortex and beta 3 was highest in the cerebellum. beta 4 seemed to be equally distributed in all regions whereas beta 2 was high in the cortex and cerebellum. A comparison of expression of nAChR subunit mRNAs in the cortex and cerebellum of prenatal and aged (54-81 years) brain showed that mRNA levels for alpha 4, alpha 5, alpha 7, beta 2 and beta 4 were significantly higher in the prenatal cortex and cerebellum than in aged brain, whereas the level of alpha 3 transcript was similar, and beta 3 significantly higher in aged cortex. Specific binding of [3H]-epibatidine to prenatal brain membranes was detected as early as 4-5 weeks of gestation in the spinal cord, medulla oblongata, pons and subcortical forebrain. A positive correlation between gestational age and [3H]-epibatidine and [3H]-cytisine binding was found in several brain regions. The highest specific binding of [3H]-epibatidine and [3H]-cytisine was detected in the spinal cord, pons and medulla oblongata and the lowest in the cortex. Saturation analysis of [3H]-cytisine binding in both prenatal and aged brain were best fit by a model for a single site, whereas binding data for [3H]-epibatidine revealed two classes of binding sites. The early presence of nAChR proteins and gene transcripts shown in the present study suggests an important role for nAChRs in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development.

Aged↗
PubMed2000

Genetic and pharmacological strategies identify a behavioral function of neuronal nicotinic receptors.

The studies outlined here used pharmacological and genetic approaches to attempt to identify the nicotinic receptors that modulate nicotine-induced seizures. Full-blown clonic-tonic seizures were induced by intracerebroventricular (i.c.v.) injection of nicotine, the alpha4beta2 selective agonist ABT-418 and the alpha7-selective GTS-21. Cytisine, which is a partial agonist at alpha4beta2-type receptors, produced partial seizures. DHbetaE and MLA did not block nicotine-induced seizures. Instead, both antagonists caused seizures. Restriction fragment length polymorphisms (RFLPs) for the alpha7 receptor were identified in two inbred strains (C3H and DBA) that differ in sensitivity to nicotine-induced seizures. F2 mice derived from a C3H x DBA cross that were homozygous for the C3H variant of the alpha7 RFLP were more sensitive to nicotine-induced seizures than were F2 mice that were homozygous for the DBA RFLP. In a study that used RI strains derived from two selectively bred mouse lines (LS and SS), an association between sensitivity to nicotine-induced seizures and an RFLP associated with the alpha4 gene was found. These data support the assertion that both alpha4 and alpha7 receptor types are involved in modulating convulsions produced by nicotine.

Alkaloids↗
PubMed1999

Nicotinic receptor binding sites in rat primary neuronal cells in culture: characterization and their regulation by chronic nicotine.

We have characterized high affinity neuronal nicotinic acetylcholine receptors labeled by [3H]cytisine in primary neuronal cell cultures from fetal rat brains. After 15 days in culture, the highest density of [3H]cytisine binding sites (Bmax approximately 57 fmol/mg protein) was found in cells from the brainstem, which includes the following subcortical brain areas: the septum, thalamus, hypothalamus, midbrain, pons and medulla. A lower density of sites was found in cells from the cerebral cortex, hippocampus, and caudate nucleus. [3H]Cytisine binds to receptors in primary cells from the brainstem and cerebral cortex with a Kd of approximately 0. 5 nM, and the binding is inhibited by the agonists nicotine, acetylcholine, and epibatidine with IC50 values of 1 to 20 nM, and by carbachol and the antagonist dihydro-beta-erythroidine with IC50 values of 0.5 to 1.5 microM. Chronic treatment of neuronal cultures with nicotine for 7 days differentially affected the number of nicotinic receptors in cells from different brain areas; it significantly increased the number of nicotinic binding sites in cells from the cerebral cortex, hippocampus, and caudate, but not in cells from the brainstem. The nicotine-induced increase of receptors in cerebral cortical cultures was not blocked by either mecamylamine or dihydro-beta-erythroidine. These results indicate that primary cultures of rat neuronal cells provide a good model system in which to study and compare the properties and regulation of native neuronal nicotinic acetylcholine receptors.

Acetylcholine↗
PubMed2003

An exploratory approach to modeling explosive compound persistence and flux using dissolution kinetics.

Recent advances in the description of aqueous dissolution rates for explosive compounds enhance the ability to describe these compounds as a contaminant source term and to model the behavior of these compounds in a field environment. The objective of this study is to make predictions concerning the persistence of 2,4,6-trinitrotoluene (TNT) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in solid form both as individual explosive compounds and components of octol, and the resultant concentrations of explosives in water as a result of dissolution using three exploratory modeling approaches. The selection of dissolution model and rate greatly affect not only the predicted persistence of explosive compound sources but also their resulting concentrations in solution. This study identifies the wide range in possible predictions using existing information and these modeling approaches to highlight the need for further research to ensure that risk assessment, remediation and predicted fate and transport are appropriately presented and interpreted.

Azocines↗
PubMed1984

Which opioid receptor mechanism modulates feeding?

There is substantial evidence for the role of endogenous opioid peptides in the regulation of appetite. This communication examines the possible opioid peptide mechanism(s) which are involved in appetite regulation. In the rat, activation of both the dynorphin-kappa opioid receptor and the beta-endorphin-epsilon opioid receptor appear to enhance feeding, most probably acting in different areas of the central nervous system. It also appears that rats may have a mu anorectic system. Too few studies have been undertaken to define whether the delta or sigma receptor systems are also involved in feeding responses. It is becoming apparent that a great deal of species diversity exists in the feeding responses to opiates, making it difficult to extrapolate the results obtained in rats to other species. In humans, studies with naloxone suggest an opioid sensitive feeding system which possibly is specifically involved in the regulation of carbohydrate uptake. In addition, we report here preliminary data suggesting the presence of a mu anorectic system in humans. Thus, analogous to the findings for the role of opioid receptors in analgesia, it appears that multiple opioid receptors may be involved in appetite regulation, each receptor relating to a different aspect of feeding.

Animals↗
PubMedDate not supplied

Interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with nicotinic acetylcholine receptor subtypes expressed in cell lines and rat cortex.

The interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with different nicotinic acetylcholine receptor (nAChR) subtypes was studied in cell lines and rat cortex. MPA showed an affinity (Ki = 1.21 nM) which was higher than anatoxin-a > (-)-nicotine > (+)-[R]nornicotine > (-)-[S]nornicotine > and (+)-nicotine, but lower than cytisine (Ki = 0.46 nM) in competing for (-)-[3H]nicotine binding in M10 cells, which stably express the recombinant alpha4beta2 nAChR subtype. A one-binding site model was observed in all competing experiments between (-)-[3H]nicotine binding and each of the agonists studied in M10 cells. MPA showed a 13-fold higher affinity for (-)-[3H]nicotine binding sites compared to the [3H]epibatidine binding sites in rat cortical membranes. In human neuroblastoma SH-SY5Y cells, which predominantly express the alpha3 nAChR subunit mRNA, MPA displaced [3H]epibatidine binding from a single population of the binding sites with an affinity in the same nM range as that observed MPA in displacing [3H]epibatidine binding in rat cortical membranes. Chronic treatment of M10 cells with MPA significantly up-regulated the number of (-)-[3H]nicotine binding sites in a concentration dependent manner. Thus MPA appears to have higher affinity to alpha4-subunit containing receptor subtype than alpha3-subunit containing receptor subtype of nAChRs. Furthermore MPA binds to alpha4beta2 receptor subtype with higher affinity than (-)-nicotine and behaves, opposite to cytisine, as a fult agonist in up-regulating the number of nAChRs.

Alkaloids↗
PubMed2001

Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands.

We have developed one-step syntheses of halogenated derivatives of (-)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen-sulphur exchange. The affinities of these pyridone-modified analogs of (-)-cytisine for (alpha 4)(2)(beta 2)(3) and alpha 7* nAChRs in rat forebrain membranes were determined by competition with (+/-)-[(3)H]epibatidine and [(3)H]MLA, respectively. The 3-halocytisines 7 possess subnanomolar affinities for (alpha 4)(2)(beta 2)(3) nAChRs, higher than those found for (-)-cytisine as well as for the 5-halocytisines 8 and 3,5-dihalocytisines 6. In contrast to the parent alkaloid the 3-halogenated species display much a higher affinity for the alpha 7* nAChR subtype. The most potent molecule was 3-bromocytisine (7b) with preferential selectivity (200-fold) for the (alpha 4)(2)(beta 2)(3) subtype [K(i)=10 pM (alpha 4 beta 2) and 2.0 nM (alpha 7*)]. Replacement of the lactam with a thiolactam pharmacophore to thiocytisine (12) resulted in a subnanomolar affinity for the (alpha 4)(2)(beta 2)(3) nAChR subtype (K(i)=0.832 nM), but in a drastic decrease of affinity for the alpha 7* subtype; thiocytisine (12) has a K(i) value of 4000 nM (alpha 7*), giving a selectivity of 4800-fold for the neuronal (alpha 4)(2)(beta 2)(3)-nAChR and thus displaying the best affinity-selectivity profile in the series under consideration.

Aconitine↗
PubMed2002

Synthesis and DNA interaction of a mixed proflavine-phenanthroline Tröger base.

We report the synthesis of an asymmetric Tröger base containing the two well characterised DNA binding chromophores, proflavine and phenanthroline. The mode of interaction of the hybrid molecule was investigated by circular and linear dichroism experiments and a biochemical assay using DNA topoisomerase I. The data are compatible with a model in which the proflavine moiety intercalates between DNA base pairs and the phenanthroline ring occupies the DNA groove. DNase I cleavage experiments were carried out to investigate the sequence preference of the hybrid ligand and a well resolved footprint was detected at a site encompassing two adjacent 5'-GTC.5-GAC triplets. The sequence preference of the asymmetric molecule is compared to that of the symmetric analogues.

Azocines↗
PubMed2001

Chronic toxicity of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in soil determined using the earthworm (Eisenia andrei) reproduction test.

The sublethal and chronic effects of the environmental contaminant and explosive octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in artificial soil were assessed using the earthworm (Eisenia andrei). Based on various reproduction parameters (total and hatched number of cocoons, number of juveniles and their biomass), fecundity was reduced at the different concentrations of HMX tested (from 280.0 +/- 12.3 to 2502.9 +/- 230.0 mg kg-1 dry soil) in spiked artificial soil (LOEC: 280.0 +/- 12.3 mg kg-1 dry soil). The growth of adult E. andrei was also reduced at the different concentrations tested, though no mortality occurred, even at the highest tested concentrations. The number of juveniles produced was correlated with the number of total and hatched cocoons, and the biomass of juveniles was correlated with the number of cocoons. Pooled results of these and earlier studies on explosives (TNT, RDX) using the E. andrei reproduction test confirm that effects of HMX on cocoon production are indicative of some reproductive consequences (number of juvenile and their biomass), whereas adult growth, in general, does not correlate strongly with change in reproduction capacity.

Animals↗
PubMed2000

Human post-mortem striatal alpha4beta2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson's syndrome.

The density of nicotinic alpha4beta2 receptors, which are believed to largely mediate nicotine's effects, has been reported to be decreased in post-mortem hippocampus of patients with schizophrenia. In the present study, using [(3)H]cytisine as a radioligand, we observed a significant 30% decrease in post-mortem striatum of patients with schizophrenia (n=12) as compared to controls (n=12). A 25% decrease of striatal alpha4beta2 receptor density in patients with Parkinson's syndrome (n=12) was not significant. As an upregulation of alpha4beta2 receptors has been observed due to nicotine consumption, the beneficial effects of nicotine described in patients with schizophrenia may be partly due to a compensation for a decrease in alpha4beta2 nicotinic acetylcholine receptors.

Aged↗
PubMed2001

Endogenous adrenergic control of reflexes evoked by mechanical stimulation of the heel in the decerebrated rabbit.

In decerebrated rabbits, reflexes were evoked in medial gastrocnemius motoneurones by mechanical stimulation of the heel, using four pinch strengths from 183 (innocuous) to 4577 (noxious) mN. The alpha(2)-adrenoceptor antagonist idazoxan (1-156 microg intrathecal (i.th.) significantly increased responses to pinch strengths of 607 mN and above. Subsequent administration of the alpha(1) adrenoceptor selective antagonist prazosin (200 microg i.th.) decreased reflexes to 4577 mN pinches but had no other significant effects. The opioid antagonist (-)-quadazocine (25 microg i.th.) caused no further changes in reflexes. Spinal section at L1 in the presence of this drug combination enhanced gastrocnemius responses to 183 and 607 mN stimuli, had no effect on reflexes to 1866 mN and significantly decreased responses to 4577 mN pinches. These data confirm that reflexes evoked by 'natural' stimulation of heel mechanoreceptors are subject to powerful tonic descending inhibition mediated by alpha(2)-adrenoceptors. For the highest strength stimulus, the results of alpha(2) blockade involved enabling of descending facilitation as well as reduction of descending inhibition.

Adrenergic alpha-Antagonists↗
PubMed2003

Modulation of inhibitory synaptic activity by a non-alpha4beta2, non-alpha7 subtype of nicotinic receptors in the substantia gelatinosa of adult rat spinal cord.

The GABA/glycine-mediated inhibitory activity in the substantia gelatinosa (SG) of the spinal cord is critical in the control of nociceptive transmission. We examined whether and how SG inhibitory activity might be regulated by neuronal nicotinic receptors (nAChRs). Patch-clamp recordings were performed in SG neurons of spinal slice preparations from adult rats. We provided electrophysiological evidence that inhibitory presynaptic terminals in the SG expressed nAChRs and their activation resulted in large increases in the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in over 90% SG neurons tested. The enhancement of inhibitory activity was mediated by increases in the release of GABA/glycine, and direct Ca(2+) entry through SG presynaptic nAChRs appeared to be involved. Miniature IPSC frequency could be enhanced by the nAChR agonists nicotine or cytisine. Nicotine could still elicit large increases in mIPSC frequency in the presence of the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (5 microM) and the alpha7 nAChR-selective antagonist methyllycaconitine (40 nM). However, nicotine did not produce a significant enhancement of mIPSC frequency in the presence of the broad spectrum nAChR antagonist mecamylamine (5 microM). Nicotinic agonist-evoked whole-cell currents from SG neurons and the antagonist profiles also indicated the presence of a subtype of nAChRs, which were different from the major central nervous system nAChR subtypes, i.e. alpha4beta2* or alpha7 nAChRs. Together, our results suggest that a subtype of nAChR, possibly alpha3beta4* nAChR or a new nAChR type, is highly expressed at the inhibitory presynaptic terminals in SG of adult rats and play a role in the control of inhibitory activity in SG.

2-Amino-5-phosphonovalerate↗
PubMed1999

Effects of chronic treatment with (+)-nicotine on the stress-induced hypertension and downregulation of central nicotinic receptors in rats: comparative study with (-)-nicotine.

The effects of chronic treatment with (+)-nicotine on the immobilization stress-induced changes in blood pressure, body weight, and [3H]cytisine binding to brain nicotinic receptors were examined in rats and were compared with those of (-)-nicotine. Immobilization stress (2 hr/day(-1), for 2 weeks) induced a moderate elevation of blood pressure, loss of body weight gain, and downregulation of [3H]cytisine binding sites in cerebral cortex and midbrain. Chronic treatment with (+)- or (-)-nicotine inhibited the stress-induced hypertension but did not suppress the inhibition of body weight gain by stress. Body weight before stress load was also reduced by (-)-nicotine but not (+)-nicotine treatment. Treatment with each isomer increased the maximum number of [3H]cytisine binding sites (Bmax) of brain stem, cerebral cortex, and hippocampus. The Bmax in midbrain was also increased by (+)-nicotine but not by (-)-nicotine. Stress-induced downregulation in cerebral cortex was inhibited by both isomers. These results suggest that (+)- and (-)-nicotine cause various effects, including anti-stress effect, on the central nervous system in rats, which are slightly different between the isomers.

Alkaloids↗
PubMed2001

Nicotine-induced alterations in the expression of nicotinic receptors in primary cultures from human prenatal brain.

The nicotinic receptor proteins and gene transcripts for the different nicotinic receptor subunits exist in human prenatal brain already at 4-5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [(3)H]epibatidine (labelling both the alpha3 and alpha4 subtype) and [(3)H]cytisine (labelling the alpha4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5-11 weeks of gestation), the highest specific binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The effects of nicotine exposure were studied in primary cultures of prenatal brain (7.5-11 weeks of gestation). Treatment with nicotine (1-100 microM) for 3 days significantly increased the specific binding of [(3)H]epibatidine and [(3)H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-specific differences in the sensitivity to nicotine exposure. Relative quantification of mRNA showed that the expression of the nicotinic receptor subunits alpha3 and alpha7, but not alpha4, was increased in cortical cells after nicotine treatment. These findings support the assumption of a potential risk of disturbance in the functional role of nicotinic receptors during brain development as a consequence of maternal smoking during pregnancy.

Alkaloids↗
PubMed2002

Differential nicotinic receptor expression in monkey basal ganglia: effects of nigrostriatal damage.

Our previous work showed that there were marked declines in (125)I-alpha-conotoxin MII labeled nicotinic receptors in monkey basal ganglia after nigrostriatal damage, findings that suggest alpha3/alpha6 containing nicotinic receptors sites may be of relevance to Parkinson's disease. We now investigate whether there are differential changes in the distribution pattern of nicotinic receptor subtypes in the basal ganglia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals compared to controls to better understand the changes occurring with nigrostriatal damage. To approach this we used (125)I-alpha-conotoxin MII, a marker for alpha3/alpha6 nicotinic receptors, and (125)I-epibatidine, a ligand that labels multiple nicotinic subtypes. The results demonstrate that there were medial to lateral gradients in nicotinic receptor distribution in control striatum, as well as ventromedial to dorsolateral gradients in the substantia nigra, which resembled those of the dopamine transporter in these same brain regions. Treatment with MPTP, a neurotoxin that selectively destroys dopaminergic nigrostriatal neurons, led to a relatively uniform decrease in nicotinic receptor sites in the striatum, but a differential effect in the substantia nigra with significantly greater declines in the ventrolateral portion. Competition analysis in the striatum showed that alpha-conotoxin MII sensitive sites were primarily affected after lesioning, whereas multiple nicotinic receptor populations were decreased in the substantia nigra. From these data we suggest that in the striatum alpha3/alpha6 nicotinic receptors are primarily localized on dopaminergic nerve terminals, while multiple nicotinic receptor subtypes are present on dopaminergic cell bodies in the substantia nigra. Thus, if activation of striatal nicotinic receptors is key in the regulation of basal ganglia function, alpha3/alpha6-directed nicotinic receptor ligands may be more relevant for Parkinson's disease therapy. However, nicotinic receptor ligands with a broader specificity may be more important if receptors in the substantia nigra play a dominant role in controlling nigrostriatal activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Laminar distribution of nicotinic receptor subtypes in human cerebral cortex as determined by [3H](-)nicotine, [3H]cytisine and [3H]epibatidine in vitro autoradiography.

The subregional localization of different nicotinic acetylcholine receptor subtypes in human cerebral cortex was estimated by quantitative in vitro autoradiography using the nicotinic ligands [3H](-)nicotine, [3H]cytisine and [3H]epibatidine in large whole human forebrain hemispheres. Saturation experiments in frontal cortex revealed for [3H](-)nicotine two binding sites with affinity constants (Kd) of 0.45 and 6.3 nM and binding site densities (Bmax) of 3.0 and 14.2 pmol/g, for [3H]cytisine one binding site with Kd of 0.19 nM and Bmax of 21.8 pmol/g, and for [3H]epibatidine one binding site with Kd of 0.011 nM and Bmax of 20.0 pmol/g. The laminar binding distributions of the three ligands were compared in different cortical areas by creating binding profiles perpendicular to the entire cortical depth. The regional autoradiographic binding patterns of the three ligands were essentially similar, with higher receptor binding in cortical layers I, III and V. In the primary sensory cortex and inferior frontal sulcus, marked binding of all ligands was observed in layer III. [3H]Cytisine showed the lowest difference between maximal and minimal binding within the gray tissue in all other areas. In the primary motor cortex, [3H]epibatidine and [3H](-)nicotine showed high binding in layers III and V. The [3H](-)nicotine binding was higher than that of the other ligands in layers I and VI of the primary motor cortex, the deeper layer V of the primary sensory cortex, layer III of the superior temporal sulcus and layer VI of the parietal cortex. A distinct band of binding of [3H](-)nicotine and [3H]epibatidine but not of [3H]cytisine was found in layer IIlb of the occipital cortex and layer V of the superior temporal sulcus. [3H]Epibatidine showed higher binding than the other ligands in all layers of the medial frontal, superior frontal and superior temporal sulcus. The findings with the three nicotinic ligands suggest three binding sites in the cortex with different laminar distributions. All three ligands bound to an identical receptor site, most likely the alpha4 nicotinic receptor subunit. The morphological distribution of [3H]epibatidine and [3H](-)nicotine binding indicate that they bind to an additional site, especially in the primary motor cortex, in layer IIIb of the occipital cortex and layer V of the superior temporal sulcus. High binding of [3H](-)nicotine in layers I and VI of the primary motor cortex, the deeper layer V of the primary sensory cortex, layer III of the superior temporal sulcus and layer VI of the parietal cortex may indicate a third binding site.

Aged↗