S 14297, a novel selective ligand at cloned human dopamine D3 receptors, blocks 7-OH-DPAT-induced hypothermia in rats

The selective dopamine D₃ receptor agonist, 7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and the novel naphthofurane, S 14297 ((+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho,2,3-furanel]) bound with high affinity and selectivity to recombinant, human dopamine D₃ versus D₂ receptors stably transfected into Chinese hamster ovary cells: K_i values = 2 versus 103 nM for 7-OH-DPAT and 13 versus 297 nM for S 14297. In contrast, the putative dopamine D₃ receptor antagonist, AJ 76 (cis-(+)-5-methoxyl-1-methyl-2- (n-propylamino)tetralin), displayed low affinity and selectivity for dopamine D₃ versus D₂ sites (70 versus 154 nM). 7-OH-DPAT (0.01–0.16 mg/kg s.c.) provoked hypothermia in rats, and action abolished by S 14297 (0.04–0.63 mg/kg s.c.) and, less potently, by AJ 76 (0.16–2.5 mg/kg s.c.) S 14297 (20.0 mg/kg s.c.) did not modify prolactin secretion. These data suggest that dopamine D₃ receptors mediate hypothermia in the rat and that S 14297 acts as a selective antagonist at these sites.     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat

The effects of 5-HT₂ receptor blockade on the ability of a dopamine (DA) D₂ receptor antagonist to produce suppression of conditioned avoidance response (CAR) and to produce catalepsy in rats were examined. It was found that ritanserin (2 mg kg⁻¹ s.c.) enhanced the raclopride (0.1 mg kg⁻¹ s.c.)-induced suppression of CAR without affecting raclopride-induced catalepsy at either maximal (4 mg kg⁻¹ s.c.) or submaximal (0.2 mg kg⁻¹ s.c.) doses. Considering the CAR performance as an index of mesocorticolimbic dopaminergic functions, it is concluded that 5-HT₂ receptor blockade confers a limbic profile on the DA D₂ receptor antagonist.     

Is the potent 5-HT1A receptor agonist, alnespirone (S-20499), affecting dopaminergic systems in the rat brain?

The effects of the new methoxy-chroman 5-HT_1A receptor agonist, alnespirone (S-20499), on the dopamine systems in the rat brain were assessed in vivo by means of electrophysiological and neurochemical techniques. Cumulative doses of alnespirone (0.032–4.1 mg kg⁻¹, i.v.) did not modify the spontaneous firing rate of dopamine neurons in the substantia nigra as well as in the ventral tegmental area. The local application of alnespirone (0.1–10 μM) by reverse microdialysis into the dorsal striatum did not affect the dopamine output but induced a moderate, although dose-independent, increase of 5-HT (5-hydroxytryptamine, serotonin) concentrations in the dialysate. As expected of a 5-HT_1A receptor agonist, intraperitoneal (i.p.) administration of alnespirone at 2–32 mg kg⁻¹ markedly decreased 5-HT turnover in the striatum. Parallel measurements of dopamine turnover showed that alnespirone exerted no effect except at the highest dose (32 mg kg⁻¹, i.p.) for which a significant increase was observed. Interestingly, both alnespirone-induced reduction in 5-HT turnover and increase in dopamine turnover could be prevented by pretreatment with the selective 5-HT_1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]–N-(2-pyridinyl)cyclohexane carboxamide). Altogether, these data indicate that alnespirone does not exert any direct influence on central dopamine systems. The enhanced dopamine turnover due to alnespirone at high dose appeared to result from 5-HT_1A receptor stimulation, further supporting the idea that this receptor type may play a key role in 5-HT-dopamine interactions in brain.     

Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during the preweaning period

The effect of cocaine exposure during the preweaning period on the function of the central dopaminergic systems was determined in adult rats. The present study investigated the alterations in dopamine receptors in 93-day-old male and female rats treated with cocaine (50 mg kg⁻¹ day⁻¹), 1-[2-[bis(4-fluorophenyl)methoxyl]-4-[3-phenylpropyl]piperazine (GBR 12909) (50 mg kg⁻¹ every other day) or water during postnatal days 11–20. Haloperidol (2 mg kg⁻¹ day) or saline was injected during postnatal days 76–90 and the rats were killed on postnatal day 93. Quantitative receptor autoradiography with [³H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ([³H]SCH 23390) for the dopamine D₁ receptor and [³H]raclopride for the dopamine D₂ receptor was carried out. The results show that haloperidol increased [³H]raclopride binding in many forebrain regions. Preweaning cocaine treatment in males increased the area showing this effect. Males generally were more responsive to haloperidol than females. However, in GBR 12909-treated females, raclopride binding showed widespread increases following haloperidol injection. For SCH 23390 binding, most regions showed a significant interaction between haloperidol, sex and preweaning treatment group. This was due primarily to the GBR 12909-treated males, which showed elevated basal dopamine D₁ receptor binding levels and a haloperidol-induced reduction in dopamine D₁ receptor binding in most regions evaluated. These data suggest that inhibition of the dopamine transporter during ontogeny produces long-term alterations in dopamine receptor regulation but that selective inhibitors of the dopamine transporter produced greater effects than cocaine on both raclopride and SCH 23390 binding following chronic haloperidol injection.     

A comparison of the selectivities of SCH 23390 with BW737C89 for D1, D2 and 5-HT2 binding sites both in vitro and in vivo

The in vitro affinities (K_Is) for SCH 23390 in D₁, D₂ and 5-HT₂ binding assays were 0.4, 631 and 20 nM as compared with 0.3, 79 and 79 nM for BW737C89. The K_B values, derived from their abilities to right-shift dopamine-mediated dose-dependent increases in striatal adenylyl cyclase activity, were 0.8 and 0.5 nM for SCH 23390 and BW737C89, respectively. Thus, BW737C89 was a highly potent dopamine D₁ receptor antagonist and, although it was less D₁/D₂-selective than SCH 23390, it was more D₁/5-HT₂-selective. Both SCH 23390 and BW737C89 (0.1–100 μmol/kg s.c.) exhibited a selective dose-dependent protection of D₁, but not D₂, binding, from inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 8 mg/kg s.c.) as measure by [³H]SCH 23390 (D₁) and [³H]spiperone (D₂) binding. The ED₅₀ values for this selective protection of D₁ binding were similar and were between 1 and 3 μmol/kg s.c. BW737C89 showed no protective effect at all on the inactivation of [³H]ketanserin (5-HT₂) binding by EEDQ whereas SCH 23390 started to show protection at doses of 10 μmol/kg. s.c. and above. A direct comparison of the time course of the effects of pretreatment of a dose of 30 μmol/kg s.c. of both compounds to protect 5-HT₂ binding was carried out. This study confirmed the complete lack of protective effect of BW737C89 from 1 to 4 h of pretreatment whereas SCH 23390 exhibited 62, 29 and 28% protection at 1,2 and 4 h pretreatment respectively. Thus, these data clearly show that BW737C89 is a potent and selective D₁ antagonist which is more selective for D₁ receptors in vivo than is SCH 23390.     

Ganglion-blocking agents enhance neurally mediated bronchoconstriction in the guinea-pig: possible role of sensory neuropeptides

The effect of ganglion blockade by hexamethonium bromide (0.1–100 μmol · kg⁻¹) and pentolinium tartrate (0.01–3 μmol · kg⁻¹) on the bronchoconstriction induced by vagal nerve stimulation (15 HZ, 0.2 ms, 3 s, 7–20 V) was evaluated in the anaesthetized guinea-pig. Both ganglion-blocking agents potentiated this response dose dependently. When the neural bronchoconstriction was suppressed by atropine, hexamethonium restored this response dose dependently. Hexamethonium produced inhibitory effects on vagally induced bronchoconstriction in capsaicin-desensitized and in propranolol- or reserpine-pretreated guinea-pigs. Propranolol (0.03–3 μmol · kg⁻¹) produced a marked dose-dependent increase of neural bronchoconstriction (which was markedly reduced, about 10 times) in capsaicin-desensitized animals. Our results show that ganglion-blocking agents potentiate neural bronchoconstriction in the guinea-pig and that sensory neuropeptides may have a role in this effect. Moreover, β-adrenergic modulation of the release of neuropeptides from vagal sensory fibers is suggested.     

Behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor

The antimicrobial agent oxolinic acid, injected i.p. in mice, induced a dose dependent increase in locomotor activity. This stimulation culminated at the 32 mg/kg dose and became smaller for higher doses (64–128 mg/kg). When opposed to increasing doses (50–100–200 μg/kg i.p.) of haloperidol (D2 dopamine receptor antagonist), the stimulant locomotor effect of 32 mg/kg oxolinic acid was not significantly reversed. On the contrary increasing doses (7.5–15–30 μg/kg s.c.) of SCH 23390 (D1 dopamine receptor antagonist) inhibited the stimulant locomotor effect. In mice made completely akinetic by a pretreatment with reserpine (4 mg/kg s.c., 18 h before testing), dexamphetamine (2 mg/kg s.c.) reversed this akinesia and even displayed a stimulant activity, similar to that observed in mice not treated by reserpine. On the contrary, oxolinic acid (32 mg/kg) did not reverse the reserpine induced akinesia and even opposed the reversion induced by dexamphetamine. In a synaptosomal fraction prepared from striatum of rats, oxolinic acid inhibited the ³H dopamine uptake with an IC₅₀=4.3±0.6×10⁻⁶ M. Finally, in mice injected i.v. with a tracer dose of ³H WIN 35428 (1 μCi) (a dopamine uptake blocker), 32 mg/kg oxolinic acid, i.p. administered, reduced by about 50% the specific binding of the radioligand to striatal dopamine carriers. It is concluded that the stimulant locomotor effect of oxolinic acid depends on the blockade of the neuronal dopamine uptake complex.     

Discriminative stimulus effects of (-)-ephedrine in rats: analysis with catecholamine transporter and receptor ligands

A drug discrimination procedure was used to examine the neuropharmacology of (−)-ephedrine (5 mg/kg), a sympathomimetic amine found in a variety of dietary supplements. (−)-Ephedrine has caused concern because of its use as a precursor in the manufacture of street drugs (e.g. methamphetamine) and its potential for abuse and toxicity. In the present study, the catecholamine reuptake inhibitors mazindol and nomifensine, the norepinephrine (NE) reuptake inhibitor desipramine, and the dopamine D₂-like (e.g. D₂, D₃ and D₄) agonist quinpirole substituted for (−)-ephedrine (80% (−)-ephedrine-lever responding). The NE reuptake inhibitor nisoxetine, the D₁-like (e.g. D₁ and D₅) agonists (±)-SKF 38393 and SKF 82958, and the mixed D₁-/D₂-like agonist apomorphine occasioned intermediate levels of responding (50–79% (−)-ephedrine-lever responding). The (−)-ephedrine cue was antagonized by the D₁-like antagonist SCH 23390 and the ₁-adrenoceptor antagonist prazosin as well as the D₂-like antagonists (−)-eticlopride and haloperidol, although only at doses that disrupted responding in some rats. The discriminative stimulus effects of a small dose of (−)-ephedrine (1.25 mg/kg) were enhanced by the ₂-adrenoceptor antagonist idazoxan and to a lesser extent by the β-adrenoceptor antagonist (−)-propranolol. However, the ₂-adrenoceptor agonist clonidine (0.04 mg/kg) did not attenuate the (−)-ephedrine stimulus. These results suggest that D₁-, D₂-like, and ₁-adrenergic receptors mediate the discriminative stimulus effects of (−)-ephedrine. Substitution of desipramine for (−)-ephedrine and not for some other stimulants suggests that NE transmission is a prominent feature of the (−)-ephedrine discriminative stimulus, and that NE underlies therapeutic and abuse-related effects of (−)-ephedrine that diverge from those of other stimulants.     

Selective tolerance of group III and IV somatosympathetic reflexes to the effects of alfentanil

The effect of alfentanil on responses in renal sympathetic nerves evoked by supramaximal electrical stimulation of the radial nerve, has been observed in 6 dogs anaesthesised with -chloralose, paralysed with suxamethonium and ventilated artificially. During an initial infusion of alfentanil the responses of the late group IV (C fibre) and early group III (Aδ) were abolished by mean doses of 68 μg kg⁻¹ (SEM 3.2 μg kg⁻¹) and 797 μg kg⁻¹ (SEM 120 μg kg⁻¹), respectively. Recovery was allowed to occur to approximately 50% of control values (mean time 76 ± 14.3 min). The preparations were then conditioned with 7 incremental doses from 7.5 to 120 μg kg⁻¹ (i.v.) (total dose 308.5 μg kg⁻¹), administered at intervals of 10 min, and subsequently tested with large bolus doses (up to 2000 μg kg⁻¹) of alfentanil. In two preparations, the responses of both group IV and group III became completely tolerant to the effects of alfentanil while in the other four the response of the group IV was still eliminated by the drug and the response of group III showed selective tolerance. The heart rate and arterial pressure were reduced by 45 and 29%, respectively during the initial infusion of alfentanil. Thereafter there were no further significant changes in the circulation until the administration of naloxone (2 mg i.v.), which restored the sympathetic responses, heart rate and arterial pressure to control values.     

Effects of adenosine A2 receptor agonists on the excitation of capsaicin-sensitive afferent sensory nerves in airway tissues

We examined the effects of adenosine analogues on the asthmatic reactions induced by the stimulation of capsaicin-sensitive afferent sensory nerves. Intravenous (i.v.) injection of adenosine A₂ receptor agonists, 5′-(N-ethylcarboxamido)-adenosine (NECA) and 2-[p-(carboxyethyl)-phenylethylamino]-5′-N-ethylcarboxamido-adenosine (CGS 21680), dose dependently inhibited capsaicin-induced guinea-pig bronchoconstriction (1–1000 nmol kg⁻¹), whereas i.v. administration of the adenosine A₁ receptor agonist, N⁶-cyclo-hexyladenosine (CHA), did not affect it (1000 nmol kg⁻¹). Intratracheal injection of NECA (0.05–5 nmol site⁻¹) and CGA 21 680 (0.05−5 nmol site⁻¹) also reduced capsaicin-induced constriction in a dose-dependent manner. However, NECA (1000 nmol kg⁻¹) failed to inhibit substance P-induced guinea-pig bronchoconstriction. NECA (1–1000 nmol kg⁻¹) dose-dependently inhibited cigarette smoke-induced rat tracheal plasma extravasation, but not substance P-induced reaction. NECA (0.1–10 μM) and CGS 21 680 (10 μM) significantly blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea-pig lung, whereas CHA (10 μM) had no effect. This evidence suggests that adenosine A₂ receptors modulate negatively the excitation of capsaicin-sensitive afferent sensory nerves and substance P release from their endings in airway tissues.     

Comparative effects of opiate agonists on proximal and distal colonic motility in dogs

The colonic motility index was measured in dogs, by using strain-gauge transducers, before and after administration of opiate agonists. Fentanyl, a μ-compound, ethylketazocine (EKC), a κ-compound, [D-Ala²,Leu⁵]enkephalin (DADLE), a δ-agonist, were administered by intravenous (i.v.) or intrathecal (i.t.) routes. Fentanyl (2–10 nmol · kg⁻¹ i.v.) induced a dose-related period of hyperactivity characterized by an increase in both tone and frequency of contractions in the distal portion of the colon, whereas a period of hypomotility following a short-lived period of increased activity was elicited on the proximal colon. Fentanyl (0.1, 0.2 nmol · kg⁻¹ i.t.) had inhibitory effects on both proximal and distal colon. Small doses of EKC (2–4 nmol · kg⁻¹) administered i.t. or larger doses (20–40 nmol · kg⁻¹ i.v.) inhibited colonic motility for a dose-related duration, the effects of EKC being more marked on the distal colon than on the proximal colon. The administration of DADLE, 1–2 nmol · kg⁻¹ i.t., and 40-20 nmol · kg⁻¹ i.v., inhibited and stimulated the colonic contractions, respectively, in both proximal and distal colon. The results demonstrated that the colonic opiate-mediated responses may vary according to the route of administration, the portion of the colon studied and the opioid agonist used. Opiate agonists when administered centrally show a tendency to modulate colonic activity in a similar way whatever the type of agonist.     

Effect of fluoxetine on the spontaneous electrical activity of fronto-cortical neurons

The effect of fluoxetine on spontaneous extracellular activity of fronto-cortical neurons of chloral hydrate-anesthetized rats was investigated. Fluoxetine significantly increased the basal firing rate of cortical neurons in a dose-dependent manner (0.1–1000 μg kg⁻¹ i.v.), with a maximum excitatory effect of 53% at 1000 μg kg⁻¹. Selective destruction of ascending serotoninergic pathways induced by intracerebroventricular injections of 150 μg 5,7-dihydroxytryptamine, in desipramine-pretreated rats, antagonized the excitatory effect of fluoxetine. The present results suggest that fluoxetine significantly increases the electrical activity of the fronto-cortical neurons acting on serotoninergic uptake mechanisms localized at the level of raphe nuclei.     

Effects of avermectin B1a and picrotoxin on striatal release of dopamine with reference to replacement of extracellular chloride with nitrate

The present study was an attempt to elucidate the effects of avermectin B₁a (AVM) and picrotoxin, an anion channel opener and blocker, respectively, on the release of endogenous dopamine from the slices of caudate nucleus of the rat, using a superfusion method in order to determine the interaction between these agents with the γ-aminobutyric acid (GABA) receptor-anion channel complex. Avermectin (1.14–11.4 μM) reduced the Ca²⁺-dependent release of dopamine stimulated by 40 mM KCl without affecting the basal release of dopamine. In contrast, picrotoxin in doses larger than 20 μM facilitated the K⁺-stimulated release of dopamine. The inhibitory effect of avermectin was completely antagonized by 10 μM picrotoxin and 0.1 mM bicuculline; these doses of both agents did not change the K⁺-stimulated release of dopamine. Replacement of chloride (Cl⁻) in the superfusion medium with nitrate (NO⁻₃) markedly facilitated the K⁺-stimuIated release of dopamine and the increase was antagonized by verapamil (10 μM) and tetrodotoxin (1μM). In the nitrate medium, avermectin reduced the K⁺-stimulated release of dopamine and the inhibitory effect was antagonized by bicuculline. However, picrotoxin up to 100 μM did not affect the K⁺-stimulated release of dopamine either in the presence or absence of bicuculline. These results suggest that the dopaminergic nerve terminals in the caudate nucleus receive inhibitory regulation through the facilitation of anion channels. This regulation is apparently altered depending on the main anion in the extracellular fluid.     

Contribution of the serotonin 5-HT1A receptor agonism of 8-OH-DPAT and EMD 128130 to the regulation of haloperidol-induced muscle rigidity in rats

The aim of the present study was to find out whether (±)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT_1A agonist, and (R)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT_1A-agonist and dopamine D₂-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat’s hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125–0.5 mg/kg i.p.) and EMD 128130 (1–10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities.

Provided these results can be extrapolated to humans, the efficacy of EMD 128130 in relieving the haloperidol-induced muscle rigidity supports the concept that novel antipsychotics with 5-HT_1A agonist and dopamine D₂ antagonist activities should have a favourable extrapyramidal side-effect profile.     

Microcalorimetric investigation of the toxic action of ammonium ferric(III) sulfate on the metabolic activity of pure microbes

A series of calorimetric experiments were performed to investigate toxic action of ammonium ferric sulfate (AFS) on Bacillus subtilis, Pseudomonas putida and Candida humicola. The power–time curves of micro-organism metabolism were obtained, and the action of them by addition of AFS was studied. C. humicola, B. subtilis and P. putida were inhibited completely when the concentrations were up to 320.0, 160.0 and 160.0 μg mL⁻¹, respectively. The relationships between growth rate constant (k) and doses of AFS were approximately linear for three microbes, P. putida for 10.0–160.0 μg mL⁻¹ (R = −0.9746), B. subtilis for 0–160.0 μg mL⁻¹ (R = −0.9868) and C. humicola for 10.0–320.0 μg mL⁻¹ (R = −0.9955). The total heat dissipated per milliliter (Q_T) for three microbes remained balance approximately during the lower doses, P. putida and B. subtilis less than the dose of 20.0 μg mL⁻¹, 0.56 ± 0.01 and 0.26 ± 0.01 J mL⁻¹, respectively, C. humicola less than the dose of 40.0 μg mL⁻¹, 0.58 ± 0.03 J mL⁻¹. The biomass and OD₆₀₀ of three micro-organisms growth in the absence of AFS also were obtained. The power–time curve of C. humicola growth coincided with its turbidity curve. It elucidates that microcalorimetric method agreed with the routine microbiology method.     

Lobeline inhibits nicotine-evoked [H]dopamine overflow from rat striatal slices and nicotine-evoked Rb efflux from thalamic synaptosomes

The present study evaluated the interaction of lobeline with neuronal nicotinic acetylcholine receptors using two in vitro assays, [³H] overflow from [³H]dopamine ([³H]DA)-preloaded rat striatal slices and ⁸⁶Rb⁺ efflux from rat thalamic synaptosomes. To assess agonist interactions, the effect of lobeline was determined and compared to S(−)-nicotine. To assess antagonist interactions, the ability of lobeline to inhibit the effect of S(−)-nicotine was determined. Both S(−)-nicotine (0.1–1 μM) and lobeline (>1.0 μM) evoked [³H] overflow from superfused [³H]DA-preloaded striatal slices. However, lobeline-evoked [³H] overflow is mecamylamine-insensitive, indicating that this response is not mediated by nicotinic receptors. Moreover, at concentrations (<1.0 μM) which did not evoke [³H] overflow, lobeline inhibited S(−)-nicotine (0.1–10 μM)-evoked [³H] overflow, shifting the S(−)-nicotine concentration–response curve to the right. S(−)-Nicotine (30 nM–300 μM) increased (EC₅₀ VALUE=0.2 μM) ⁸⁶Rb⁺ efflux from thalamic synaptosomes. In contrast, lobeline (1 nM–10 μM) did not evoke ⁸⁶Rb⁺ efflux, and the lack of intrinsic activity indicates that lobeline is not an agonist at this nicotinic receptor subtype. Lobeline completely inhibited (IC₅₀ VALUE=0.7 μM) ⁸⁶Rb⁺ efflux evoked by 1 μM S(−)-nicotine, a concentration which maximally stimulated ⁸⁶Rb⁺ efflux. Thus, the results of these in vitro experiments demonstrate that lobeline inhibits the effects of S(−)-nicotine, and suggest that lobeline acts as a nicotinic receptor antagonist.     

Involvement of serotonergic and dopaminergic mechanisms in hyperthermia induced by a serotonin-releasing drug, p-chloroamphetamine in mice.

Serotonergic and dopaminergic involvement in hyperthermia induced by a serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine, was investigated in mice. Neither the 5-HT transporter inhibitor fluoxetine nor the 5-HT depleter p-chlorophenylalanine affected p-chloroamphetamine-induced hyperthermia. The dopamine depleter -methyl-p-tyrosine significantly reduced p-chloroamphetamine-induced hyperthermia. The dopamine D₁ receptor antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) antagonized p-chloroamphetamine-induced hyperthermia, although the dopamine D₂ receptor antagonist sulpiride was without effect. These results indicate that p-chloroamphetamine-induced hyperthermia in mice is mediated by dopamine release followed by activation of the dopamine D₁ receptor.     

Reversal of methamphetamine-induced behavioral sensitization by repeated administration of a dopamine D1 receptor agonist

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D₁ receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0 mg/kg, i.p.) to rats once every 3 days for a total of 5 times (days 1–13) induced the enhancement of locomotor activity after MAP challenge (0.5 mg/kg, i.p.) on day 20, verifying the development of behavioral sensitization. The MAP-sensitized rats then received a dopamine D₁ agonist, R-(+)-SKF38393 (3.0 mg/kg, i.p.), once a day for 7 consecutive days (days 21–27). Behavioral analysis on days 30 and 41 revealed that the enhanced locomotor activity was reversed by repeated R-(+)-SKF38393 administration. Moreover, repeated R-(+)-SKF38393 administration reversed the increased dopamine release in the striatum after MAP challenge on day 41. Thus, repeated administration of the dopamine D₁ receptor agonist induces the reversal of established behavioral sensitization to MAP and of increased dopamine release in the striatum, lasting for at least 2 weeks. Dopamine D₁ receptor agonists may be useful therapeutic agents for the treatment of psychostimulant addiction.