SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation.

(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]pyrano[2,3-d]azepine (SSR591813) is a novel compound that binds with high affinity to the rat and human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the alpha4beta2 nAChR (Ki, human alpha3beta4 > 1000, alpha3beta2 = 116; alpha1beta1deltagamma > 6000 nM and rat alpha7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human alpha4beta2 nAChR subtype (EC50 = 1.3 micro M, IA =19% compared with the full agonist 1,1-dimethyl-4-phenyl-piperazinium). In vivo findings from microdialysis and drug discrimination studies confirm the partial intrinsic activity of SSR591813. The drug increases dopamine release in the nucleus accumbens shell (30 mg/kg i.p.) and generalizes to nicotine or amphetamine (10-20 mg/kg i.p.) in rats, with an efficacy approximately 2-fold lower than that of nicotine. Pretreatment with SSR591813 (10 mg/kg i.p.) reduces the dopamine-releasing and discriminative effects of nicotine. SSR591813 shows activity in animal models of nicotine dependence at doses devoid of unwanted side effects typically observed with nicotine (hypothermia and cardiovascular effects). The compound (10 mg/kg i.p.) also prevents withdrawal signs precipitated by mecamylamine in nicotine-dependent rats and partially blocks the discriminative cue of an acute precipitated withdrawal. SSR591813 (20 mg/kg i.p.) reduces i.v. nicotine self-administration and antagonizes nicotine-induced behavioral sensitization in rats. The present results confirm important role for alpha4beta2 nAChRs in mediating nicotine dependence and suggest that SSR591813, a partial agonist at this particular nAChR subtype, may have therapeutic potential in the clinical management of smoking cessation.

The preclinical pharmacologic profile of tiapride.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D(2) (IC(50) = 110-320 nM) and D(3) (IC(50) = 180 nM) receptors in vitro but lacks affinity for dopamine D(1) and D(4) receptors and for non-dopaminergic receptors including H(1), alpha(1), alpha(2)-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED(50) approximately 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10-30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas. In behavioral experiments in rats, lower doses of tiapride (ED(50) = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED(50) = 60 mg/kg, ip) were required to block stereotyped movements. In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED(50) = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED(50) = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3-30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance. The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D(2) and D(3) receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors.

SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one] is a novel pyridoindole derivative that displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha2 (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these data (K(i), alpha1beta2gamma2 = 17, alpha2beta2gamma2 = 73, alpha5beta3gamma2 = 215 nM) and indicate intermediate affinity for the alpha3beta2gamma2 subtype (K(i) = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha2 and alpha3 subunits and as a partial agonist at recombinant GABA(A) receptors expressing alpha1 and alpha5 subunits. SL651498 elicited anxiolytic-like activity similar to that of diazepam [minimal effective dose (MED): 1-10 mg/kg, i.p.] in three conflict models, in the elevated plus-maze, the light/dark test, and the defense test battery in rats and mice. Results from activity tests and electroencephalogram analysis indicated that SL651498 induced muscle weakness, ataxia, or sedation at doses much higher than those producing anxiolytic-like activity (MED > or = 30 mg/kg, i.p.). Repeated treatment for 10 days with SL651498 (30 mg/kg, i.p., b.i.d.) in mice was not associated with the development of tolerance to its anticonvulsant effects or physical dependence. Furthermore, SL651498 was much less active than diazepam in potentiating the depressant effects of ethanol in mice. The "anxioselective" profile of SL651498 points to a major role for GABA(A) alpha2 subtype in regulating anxiety and suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity.

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice.

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.

Amisulpride: from animal pharmacology to therapeutic action.

Amisulpride is a benzamide derivative with a unique neurochemical and psychopharmacological profile. This compound has selective affinity for human dopamine D3 and D2 receptor subtypes in vitro (binding constant, K approximately 3 nmol/l) and blocks functional responses mediated by these receptors. In ex vivo binding studies, amisulpride is twice as selective for D3 as for D2 receptors. At low doses, it preferentially blocks presynaptic dopamine autoreceptors (increase in dopamine release in vivo in the rat olfactory tubercle, 50% effective dose, ED50 3.7 mg/kg), while postsynaptic dopamine receptor antagonism is apparent at higher doses (decrease in striatal acetylcholine levels, ED50 approximately 60 mg/kg). Anisulpride preferentially stimulates dopamine synthesis and displaces 3H-raclopride binding in vivo in the limbic system rather than the striatum. It antagonizes apomorphine-induced hypothermia in mice and amphetamine-induced hypermotility in rats at low doses (ED50 2-3 mg/kg), blocks apomorphine-induced climbing and spontaneous grooming in mice, blocks apomorphine-induced gnawing in rats at higher doses (ED50 19-115 mg/kg) and does not induce catalepsy at 100 mg/kg. The preferential antagonism by amisulpride of presynaptic D2/D3 receptors is reflected behaviourally in the potent blockade of apomorphine-induced effects mediated by dopamine autoreceptors (yawning and hypomotility: ED50 0.2 and 0.3 mg/kg, respectively) compared with those medicated by postsynaptic D2 receptors (e.g. gnawing: ED50 115 mg/kg). Moreover, low doses of amisulpride induce prohedonic (potentiation of food-induced place preference) effects in rats. The atypical neurochemical and psychopharmacological profiles of amisulpride may explain its therapeutic efficacy on both positive and negative symptoms of schizophrenia.

Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.

The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D3 and both pre- and postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D2/D3 antagonist [3H]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [3H]raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D2 and D3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors. This atypical profile may explain the therapeutic efficacy of amisulpride in the treatment of both positive and negative symptoms of schizophrenia.

Complex allosteric modulation of the binding of the NMDA receptor antagonist [3H]CGP39653.

7-Chlorokynurenate, an antagonist at the glycine recognition site of the NMDA receptor complex, increases the binding of the competitive NMDA receptor antagonist [3H]CGP39653 ([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to well washed rat brain membranes but only in the presence of 100 microM spermine. Conversely, spermine only increases [3H]CGP39653 binding in the presence of 10 microM 7-chlorokynurenate, through a mechanism insensitive to the putative polyamine antagonists ifenprodil, arcaine or putrescine. Thus, the effects of glycine antagonists and polyamines on the binding of competitive NMDA receptor antagonists may depend on the residual glycine and polyamine content of the membrane preparation or the state of the glycine recognition site. These data further attest to the complexity of interactions between spermine and the glycine and glutamate recognition sites of the NMDA receptor.

Inhibition of insulin release induced by galanin in the dog is not exclusively mediated by activation of ATP-sensitive K+ channels.

Exogenous galanin (9 pmol/min during 20 min i.a.) decreased insulin levels in the plasma sampled from the pancreatic vein of the blood-perfused pancreas of dogs in which ganglionic transmission and beta-adrenoceptors had been blocked. This effect was not modified by idazoxan (1 mg/kg followed by 0.02 mg/kg/min i.v.) but was partially reduced (50%) by glibenclamide (1 mg/kg followed by 0.02 mg/kg/min i.v.). This dose of glibenclamide blocked entirely the hypoinsulinemic activity of diazoxide, an activator of pancreatic ATP-modulated K+ channels, whereas the dose of idazoxan prevented the effect of the alpha 2-adrenoceptor agonist UK-14,304. Therefore, in dogs, the decrease in insulin secretion produced by exogenous galanin is only partially mediated by activation of glibenclamide-sensitive ATP-gated K+ channels and is independent of alpha 2-adrenoceptor stimulation.

Adrenergic and nonadrenergic cotransmitters inhibit insulin secretion during sympathetic stimulation in dogs.

Vascular and biochemical responses to pancreatic sympathetic nerve stimulation were investigated in the blood-perfused pancreas of anesthetized dogs. During sympathetic nerve stimulation, pancreatic perfusion pressure and norepinephrine release increased, whereas insulin secretion decreased. The latter effect did not occur after pretreatment with the alpha 2-adrenoceptor antagonist idazoxan. However, after beta-adrenoceptor blockade with propranolol, neither single administration of idazoxan nor the alpha 1-adrenoceptor antagonist prazosin or glibenclamide, a blocker of ATP-modulated K+ channels, affected the decrease in insulin secretion induced by sympathetic nerve stimulation. In contrast, the combination of glibenclamide with idazoxan markedly antagonised the decrease in insulin release evoked by the latter procedure. After depletion of catecholamines with syrosingopine, the stimulation-induced inhibition of insulin secretion remained unchanged even though no increases in pancreas perfusion pressure or norepinephrine release were observed. In this preparation, glibenclamide inhibited the decrease in insulin release by 50%. In animals pretreated with the neuronal blocking agent bretylium, all of the responses to sympathetic nerve stimulation were abolished. These results indicate that the inhibitory effects exerted by the sympathetic nervous system on insulin secretion are mediated not only by the classical neurotransmitter norepinephrine acting on alpha 2-adrenoceptors but also by a nonadrenergic cotransmitter that can maintain transmission under conditions of catecholamine deficiency. The postulated nonadrenergic cotransmitter(s) acts, at least partly, via the opening of ATP-modulated K+ channels blockable by glibenclamide, and its release can be prevented by the neuronal blocking agent bretylium.

Tachykinins in the rat substantia nigra: effects of selective dopamine receptor antagonists.

The effects of sustained blockade of dopamine receptors by selective dopamine antagonists on the tachykinin (substance P and neurokinin A) content in the substantia nigra were examined. The treatment of rats for 14 days with D-1/D-2 dopamine receptor antagonist haloperidol (2 mg/kg) or selective D-2 antagonist sulpiride (100 mg/kg) produced a similar and significant decrease in nigral substance P and neurokinin A-like immunoreactivity content, about 32-36% and 27-28% of control respectively. In contrast, administration of SCH 23390 (1 mg/kg), a selective and potent D-1 dopamine receptor antagonist, failed to affect the levels of substance P and neurokinin A in the substantia nigra and did not change the sulpiride-induced reduction of the nigral tachykinin peptides. These results indicate that the D-1 dopamine receptors are not involved in the modulation of nigral substance P and neurokinin A content and suggest that the blockade of the D-2 dopamine receptor subtype exerts the same regulation of the tachykinin gene expression, in spite of the existence of three mRNAs encoding substance P and neurokinin A.

Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibit prostaglandin biosynthesis in-vitro.

Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin greater than LC1261. The oral LD50 in mice was 25 mg kg-1 for indomethacin and greater than 1 g kg-1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents.

Metalloendopeptidase (EC 3.4.24.11) but not angiotensin converting enzyme is involved in the inactivation of substance P by synaptic membranes of the rat substantia nigra.

Substance P is a neuropeptide released in vivo from the substantia nigra, the principal substance P nerve terminal region in the rat brain. Its inactivation was investigated in a purified nigral synaptic membrane preparation. The membrane-bound enzyme shares many features with the endopeptidase 24-11 (EC 3.4.24.11): 1) hydrolysis of peptide bonds Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10, 2) sensitivity to the inhibition by phosphoramidon and 3) relative affinity for substance P. Bestatine and captopril inhibit only the hydrolysis of the metabolites. These results suggest that substance P is inactivated in substantia nigra by endopeptidase 24-11 and that a bestatin-sensitive aminopeptidase and angiotensin converting enzyme may play a role in subsequent degradation of the substance P metabolites.

Serotonergic projections to the spinal cord but not those to the olfactory bulb also contain substance P. A combined immunocytochemical and autoradiographic study following retrograde axonal transport of [3H]serotonin labeled products.

Co-localization of substance P with serotonin in raphe projection neurons was studied by combining substance P immunocytochemistry and autoradiography following uptake and retrograde axonal transport of [3H]serotonin and/or its products from target areas. In this study, two central pathways in the rat were investigated: the serotonergic projections of the midbrain raphe to the olfactory bulb and those of the medullary raphe that innervate the thoracic spinal cord. Two hours after pargyline pretreatment, injections of 10(-4) M [3H]serotonin were made either into the olfactory bulb or into the spinal cord and respectively 24 or 60 h thereafter, rats were administered with colchicine. After a 24 h survival time, the paraformaldehyde fixed brains were investigated for substance P immunocytochemistry and then treated for light and electron microscopy autoradiography. Combining both methods, we can define on the same tissue sections at least three labeled neuronal populations: substance P immunolabeled neurons, radiolabeled neurons and doubly immuno-radiolabeled neurons. In the midbrain raphe cells as well as in the olfactory bulb nerve terminals, two kinds of labeled profiles were detected: substance P immunoreactive profiles and radiolabeled ones. The radiolabeled cell bodies of the midbrain raphe (403 counted cells) were never reactive to substance P antibodies. Moreover, they were distributed caudally to substance P stained perikarya. In contrast, in the medullary raphe, of the 336 radiolabeled cell bodies 162 were stained after substance P antibody treatment. They represent about 48% of the serotonin radiolabeled neurons projecting to the thoracic spinal cord, where a great number of varicosities were observed immunolabeled, radiolabeled and doubly immuno-radiolabeled in the dorsal horn. At the ultrastructural level, cell bodies and dendritic processes were also doubly labeled. Both labelings were observed over the cytoplasm and some organelles or perikarya. These observations provide a morphological basis to support the hypothesis that substance P can occur within some but not all serotonergic neurons and raise questions about the expression of this peptide in these systems as well as the modes of interaction of these transmitter molecules.

Degradation of substance P by membrane peptidases in the rat substantia nigra: effect of selective inhibitors.

The hydrolysis of substance P by membrane peptidases prepared from the rat substantia nigra was studied in the presence of selective inhibitors. Substance P degradation by synaptic and mitochondrial membranes was completely inhibited by 1,10-phenanthroline (1 mM), a non-specific metallopeptidase inhibitor. Captopril and bestatine, selective inhibitors of angiotensin converting enzyme and aminopeptidases respectively, were without effects. However, phosphoramidon (1 microM), a putative 'enkephalinase' inhibitor, selectively inhibited substance P degradation by synaptic membranes. These results suggest that a phosphoramidon-sensitive endopeptidase may be the principal enzyme responsible for substance P degradation in substantia nigra.

Selective antagonists of dopamine receptor subtypes differentially affect substance P levels in the striatum and substantia nigra.

Repeated administration to rats of SCH 23390, a specific antagonist of the D-1 dopamine receptor, produced an increase in the substance P immunoreactivity in the striatum but not in the substantia nigra, whereas similar treatment with sulpiride, a specific D-2 dopamine receptor antagonist, reduced the nigral but not the striatal content of the peptide. When the two antagonists were given together, the SCH 23390-induced increase in striatal substance P was significantly reduced. The SCH 23390-induced increase in striatal substance P was curtailed by concomitant administration of progabide, a selective gamma-aminobutyric acid (GABA) receptor agonist. These results suggest the existence in the nigro-striatal complex of two different substance P-containing neurons which are differentially regulated by the dopamine receptor subtypes and indicate a role of GABA in the action of SCH 23390.

Concentrations of putative neurovascular transmitters in major cerebral arteries and small pial vessels of various species.

The levels of noradrenaline, neuropeptide Y, 5-hydroxytryptamine, and substance P were measured and compared between the large arteries of the circle of Willis and the small cerebral vessels of the pia mater in the rat, rabbit, cat, and monkey. In all species, noradrenaline and neuropeptide Y concentrations were greater in the larger arteries than in small pial vessels. Noradrenaline concentrations were dramatically reduced following cervical sympathectomy, with the extent of diminution differing greatly in the various species; the effects of cervical ganglionectomy on neuropeptide Y concentrations were less pronounced. 5-Hydroxytryptamine concentrations in rats, cats, and rabbits were significantly greater in the small pial vessels, although measurable concentrations existed in the circle of Willis. In cats and monkeys, substance P was found in major arteries, but was not detectable at the level of the small pial vessels. The differences in the regional distribution of the various neurotransmitter candidates in the cerebrovascular bed may reflect their physiological significance.

Inter- and intracellular relationship of substance P-containing neurons with serotonin and GABA in the dorsal raphe nucleus: combination of autoradiographic and immunocytochemical techniques.

Double-labeling experiments were performed at the electron microscopic level in the dorsal raphe nucleus of rat, in order to study the inter- and intracellular relationship of substance P with gamma-aminobutyric acid (GABA) and serotonin. Autoradiography for either [3H]serotonin or [3H]GABA was coupled, on the same tissue section, with peroxidase-antiperoxidase immunocytochemistry for substance P in colchicine-treated animals. Intercellular relationships were represented by synaptic contacts made by [3H]serotonin-labeled terminals on substance P-containing somata and dendrites, and by substance P-containing terminals on [3H]GABA-labeled cells. Intracellular relationships were suggested by the occurrence of the peptide within [3H]serotonin-containing and [3H]GABA-containing cell bodies and fibers. Doubly labeled varicosities of the two kinds were also observed in the supraependymal plexus adjacent to the dorsal raphe nucleus. The results demonstrated that, in addition to reciprocal synaptic interactions made by substance P with serotonin and GABA, the dorsal raphe nucleus is the site of intracellular relationships between the peptide and either the amine or the amino acid.

Progabide reverses the nigral substance P reduction induced by chronic impairment of dopaminergic transmission.

Repeated treatment with haloperidol or lesion of nigrostriatal dopaminergic neurons with 6-hydroxydopamine produced a reduction in substance P immunoreactivity in the rat substantia nigra. This reduction was reversed by the repeated administration of progabide, a selective GABA receptor agonist. As GABA inhibits substance P release, these results suggest that the reduction in nigral substance P levels was due to an increased liberation of the peptide probably related to deficient GABAergic function induced by impairment of striatal dopaminergic transmission.

Influence of GABA mimetics and lithium on biochemical manifestations of striatal dopamine target cell hypersensitivity.

The potential mechanisms whereby GABA mimetics and the antimanic agent lithium stabilize dopaminergic transmission are discussed. Evidence is presented that GABA mimetics, and in particular progabide, affect dopamine-mediated events in the basal ganglia on at least three levels. First, they reduce dopamine neuron activity in both the basal and the activated states. Secondly, on a long-term basis, they antagonize the proliferation of striatal dopamine receptors subsequent to chronic neuroleptic treatment. Thirdly, they modulate the expression of dopamine receptor activation by acting distally to the dopaminergic synapse. Lithium and GABA mimetics have the last two properties in common. These effects may represent the biochemical basis for the therapeutic action of GABA mimetics in iatrogenic dyskinesias. Moreover, the similarity between the biochemical effects of GABA mimetics and lithium suggest that the former drugs may have a therapeutic potential in mania.

Involvement of the D-2 dopamine receptor in the neuroleptic-induced decrease in nigral substance P.

Repeated treatment with, but not single administration of drugs which impair dopaminergic transmission produced a consistent reduction in substance P immunoreactivity in the rat substantia nigra. This effect appears to be related to the D-2 dopamine receptor function as the blockade of this receptor subtype by selective antagonists produced effects qualitatively similar to those produced by drugs lacking selectivity for different subclasses of dopamine receptors.