The effects of dopamine D1 and D2 receptor antagonists on the rewarding effects of δ1 and δ2 opioid receptor agonists in mice

The effects of the dopamin D₁ antagonist SCH23390 and the D₂ antagonist sulpiride on the rewarding effects of opioid receptor agonists were examined in mice. Both [d-Pen², Pen⁵]enkephalin (DPDPE, 1–15 nmol, ICV), a selective ₁ opioid receptor agonist, and [d-Ala²]deltorphin II (DELT, 0.5–5 nmol, ICV), a selective ₂ opioid receptor agonist, produced a dose-dependent place preference in mice. The DPDPE (15 nmol, ICV)-induced place preference was abolished by BNTX (0.5 mg/kg, SC), a ₁ opioid receptor antagonist, but not by NTB (0.5 mg/kg, SC), a ₂ opioid receptor antagonist. In contrast, the DELT (5 nmol, ICV)-induced place preference was antagonized by NTB, but not BNTX. Pretreatment with SCH23390 (3 µg/kg, SC) abolished the DPDPE-induced place preference, but not affect the DELT-induced place preference. Moreover, pretreatment with sulpiride (40 mg/kg, SC) did not modify the place preference induced by DPDPE or DELT. In the present study, we found that the activation of both central ₁ and ₂ opioid receptors produced rewarding effects. Furthermore, these results suggest that the rewarding effects of ₁ opioid receptor agonist may be produced through activation of the central dopaminergic system, especially dopamine D₁ receptors, whereas the rewarding effects of ₂ opioid receptor agonists may be produced by some other mechanism(s).     

Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D3 agonist 7-OH-DPAT

Rationale: The purpose of the present investigation was to evaluate the effects of the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D₃ agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D₃/D₂ agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D₂/D₃ antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D₁ agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D₁ antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D₃, and possibly the D₂, receptor can modulate μ agonist-induced antinociception. Received: 30 June 1998/Final version: 12 January 1999     

Activation of dopamine D1 receptors or α1 adrenoceptors is not involved in the EEG effect of nicotine in rats

Based on previous own EEG-studies and behavioural studies of other authors, it has been claimed recently that D₁ receptors are involved in addictive properties of drugs. It seemed, therefore, of interest to study whether nicotine produces D₁-characteristic EEG alterations in rats. EEG was recorded in non-anesthetized, freely moving rats, transmitted telemetrically and underwent power spectral analysis.Nicotine (0.1, 0.2, 0.4 mg/kg s.c.) produced a desynchronization in the EEG and a decrease of power in all of the frequency bands (, , ₁, ₂, ₁) except in ₂. With regard to behaviour, an increase of locomotor activity and some discontinuous sniffing was manifest. The effect of nicotine (0.2 mg/kg) was not antagonized by blockade of dopamine D₁ receptors by SCH 23390 (0.1 mg/kg s.c., 30 min before nicotine), although this drug by itself increased the power in most of the frequency bands. Prazosine (0.2 mg/kg i.p.), a selective antagonist at ₁ adrenoceptors, by itself increased the power in all of the frequency bands, but also failed to antagonize the effects of nicotine (0.2 mg/kg). In contrast, the blocker of nicotinic cholinoceptors mecamylamine (1 mg/kg i.p.) was effective in antagonizing the action of nicotine on the EEG.The results suggest that in nicotine-mediated desynchronization and decrease of power in the EEG, the activation of dopamine D₁ or ₁ adrenoceptors is not involved. Correspondence to: K. Kuschinsky at the above address     

Involvement of the dopamine D1 receptor system in the anxiolytic effect of cedrol in the elevated plus maze and light–dark box tests

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light–dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT_1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D₁ receptor antagonist) or sulpiride (dopamine D₂/D₃ receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D₁ receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.     

Imaging the high-affinity state of the dopamine D2 receptor in vivo: Fact or fiction?

Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.     

The effects of the dopamine D₃ receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D? receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D? receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m2) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D? receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.     

Evidence for a role of D1 dopamine receptors in d-amphetamine’s effect on timing behaviour in the free-operant psychophysical procedure

RATIONALE: Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Studies using the fixed-interval peak procedure implicated D2 dopamine receptors in these effects. Less is known about the effects of dopaminergic manipulations on temporal differentiation in other timing schedules. OBJECTIVE: To examine the effects of a D1 antagonist,8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), and a D2 antagonist, haloperidol, on performance on the free-operant psychophysical procedure, and the ability of these antagonists to reverse the effects of the catecholamine-releasing agent, d-amphetamine on performance. The antagonists' ability to reverse d-amphetamine-induced hyperlocomotion was also examined. MATERIALS AND METHODS: Rats responded on two levers (A and B) under a free-operant psychophysical schedule, in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rate data (percent responding on B [%B] vs time [t]) in each treatment condition, and quantitative timing indices [T50 (value of t corresponding to %B=50) and Weber fraction] were compared among treatments. Effects of the treatments on locomotion were measured in a separate experiment. RESULTS: SKF-83566 (0.015, 0.03, 0.06 mg kg(-1)) did not affect timing performance. Haloperidol (0.025, 0.05 mg kg(-1)) had no effect; a higher dose (0.1 mg kg(-1)) reduced T (50). d-Amphetamine (0.4 mg kg(-1)) reduced T50; this effect was antagonised by SKF-83566 but not by haloperidol. Both antagonists reduced d-amphetamine-induced hyperlocomotion. CONCLUSIONS: The results suggest that d-amphetamine's effect on performance in the free-operant psychophysical procedure is mediated by D1 rather than D2 receptors.     

Comparison of the effects of haloperidol,remoxipride and raclopride on “pre”- and postsynaptic dopamine receptors in the rat brain

Summary The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed GBL-reversal) was used to define the effects of these compounds on presynaptic dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly similar to the doses required to increase dopamine turnover in striatal and limbic areas. The potencies of haloperidol, raclopride and remoxipride in the GBL model were compared with their potencies in behavioural models for postsynaptic dopamine receptors. Haloperidol produced antagonism of GBL-reversal over a similar dose range to that required for antagonism of apomorphine-induced hyperactivity and stereotypy syndromes. Raclopride was effective in the order of potency: antagonism of apomorphine-induced hyperactivity > antagonism of GBL-reversal > antagonism of apomorphine-induced stereotypy. For remoxipride, the dose-response curve for antagonism of GBL-reversal was superimposable over that for antagonism of apomorphine-induced stereotypies, with an ED₅₀ value about 12 times higher than that for antagonism of apomorphine-induced hyperactivity. Thus, the relative potencies of dopamine receptor antagonists at pre- and postsynaptic dopamine receptors vary considerably from compound to compound. Send offprint requests to O. Magnusson     

Blockade of dopamine receptors reverses the behavioral effects of endogenous enkephalins in the Nucleus caudatus but not in the Nucleus accumbens: differential involvement of δ and μ opioid receptors

We have previously (Daugé et al. 1988) demonstrated that injection of the agonist [d-Ala², MePhe⁴, Gly-ol⁵]-enkephalin (DAGO) or the agonist [d-Thr², Leu⁵]-enkephalyl-Thr⁶ (DTLET) into the rat Nucleus accumbens (N.Acc.), or Nuceeus caudatus (N.Caud.) induced a hypoactivity followed by hyperactivity 150 min later in the case of the agonist and a hyperactivity in the case of the agonist. Moreover, naloxone reversible delta-type responses were obtained by local infusion of kelatorphan, ([(R)-3(N-hydroxylcarboxamido-2-benzylpropanoyl)-l-alanine]), a complete inhibitor of enkephalin catabolism, suggesting a tonic control of the behavioral activity of rat by the endogenous opioid peptides. In this work, the putative involvement of the dopaminergic system in these behavioral responses was investigated by using the DA antagonist thioproperazine. In the N.Acc., the behavioral effects of kelatorphan, or of or agonists were not altered by thioproperazine-induced blockade of dopamine receptors. In contrast, the hyperactivity produced by DTLET or by kelatorphan in the N.Caud. was reversed by thioproperazine while the time-dependent biphasic effect resulting from DAGO injection remained unaffected by the DA antagonist. This blocking effect of thioproperazine is in agreement with the previously described -selective enhancement of the release of newly synthesized DA in the striatum but not in the N.Acc.     

Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.     

Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.     

Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia.     

Novel roles for β-arrestins in the regulation of pharmacological sequestration to predict agonist-induced desensitization of dopamine D3 receptors

Background and Purpose

In addition to typical GPCR kinase (GRK)-/β-arrestin-dependent internalization, dopamine D₃ receptor employed an additional GRK-independent sequestration pathway. In this study, we investigated the molecular mechanism of this novel sequestration pathway.

Experimental Approach

Radioligand binding, flow cytometry and cell surface biotinylation assay were used to characterize trafficking properties of D₂ and D₃ receptors. Serine/threonine and N-linked glycosylation mutants of the D₃ receptor were utilized to locate receptor regions involved in pharmacological sequestration and desensitization. Various point mutants of the D₂ and D₃ receptors, whose sequestration and desensitization properties were altered, were combined with knockdown cells of GRKs or β-arrestins to functionally correlate pharmacological sequestration and desensitization.

Key Results

The D₃ receptor, but not the D₂ receptor, showed characteristic trafficking behaviour in which receptors were shifted towards the more hydrophobic domains within the plasma membrane without translocation into other intracellular compartments. Among various amino acid residues tested, S145/S146, C147 and N12/19 were involved in pharmacological sequestration and receptor desensitization. Both pharmacological sequestration and desensitization of D₃ receptor required β-arrestins, and functional relationship was observed between two processes when it was tested for D₃ receptor variants and agonists.

Conclusions and Implications

Pharmacological sequestration of D₃ receptor accompanies movement of cell surface receptors into a more hydrophobic fraction within the plasma membrane and renders D₃ receptor inaccessible to hydrophilic ligands. Pharmacological sequestration is correlated with desensitization of the D₃ receptor in a Gβγ- and β-arrestin-dependent manner. This study provides new insights into molecular mechanism governing GPCR trafficking and desensitization.     

Participation of cardiac presynaptic α1-Adrenoceptors in the bradycardiac effects of clonidine and analogues

Summary The possible involvement of cardiac presynaptic ₂-adrenoceptors in the acute negative chronotropic effect of intravenous clonidine and four selected analogues was tested in pentobarbitone-anaesthetized normotensive rats by establishing the following parameters: 1) the peripheral presynaptic activity (inhibition of tachycardia to stimulation of the spinal cord in pithed rats); 2) central hypotensive potency in intact rats (decrease in mean arterial pressure); 3) overall bradycardiac activity in intact rats (decrease in cardiac frequency); 4) sympathetic bradycardia in bilaterally vagotomized rat; and 5) vagal bradycardia in -blocked rats. The lipophilicity of the imidazolidines (log P) was measure in the octanol/buffer (pH=7.4) reference system at 37°C. Central hypotensive activity as well as vagal bradycardiac potency correlated with the ability to penetrate the central nervous system, as indicated by the overall lipophilic behavior (log P) of the compounds. In contrast, brain penetration was not a prerequisite for the provocation of bradycardia in bilaterally vagotomized rats. This sympathetic bradycardia resembled peripheral presynaptic inhibition. The hydrophilic — poor brain-penetrating — substances already induced maximal sympathetic bradycardia at doses which did not induce hypotension or vagal bradycardia. The lipophilic drugs, however, only showed a preferentially sympathetic bradycardiac effect over vagal bradycardia at low doses. In intact pentobarbitone-anaesthetized rats, the log dose-bradycardiac response curves of the hydrophilic imidazolidines displayed a bisigmoidal character in contrast to their lipophlic analogues, i.e. at the lower dose-range of the hydrophilic drugs, bradycardia in intact rats resembled peripheral presynaptic inhibition, whereas a contribution of increased vagal activity only was significant after maximal sympathoinhibition was achieved. These data provide evidence for the view that the bradycardiac action of clonidine in pentobarbitone-anaesthetized normotensive rats is due, at least in part, to the functional role of cardiac presynaptic ₂-adrenoceptors. The stimulation of these receptors will inhibit the sympathetic neurotransmission in the heart.     

Involvement of µ-opioid receptors in the antitussive effects of pentazocine

Summary The effect of pentazocine on the capsaicininduced cough reflex in rats was investigated. Intraperitoneal injection of pentazocine, in doses from 1 to 10 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of pentazocine (10 mg/kg, i.p.) was significantly reduced by prior injection of naloxone (0.3 mg/kg, i.p.), but it was unaffected by Mr-2266 BS (5 mg/kg, i.p.), an antagonist of -opioid receptors. The antinociceptive potency of pentazocine (30 mg/kg, i.p.), as determined by the formalin test, was significantly reduced by pretreatment with Mr-2266 BS (5 mg/kg, i.p.), whereas naloxane (0.3 mg/ kg, i.p.) had no significant effect on the antinociceptive effect of pentazocine. The antitussive effects of pentazocine (3 mg/kg) and morphine (0.1 mg/kg) were significantly enhanced in rats treated chronically with naloxone (5 mg/kg/day, 5 days), whereas the antitussive effect of U-50,488 H (1 mg/kg, i.p.), a selective -opioid agonist, was not enhanced in these rats. By contrast, the antinociceptive effect of morphine (0.01 mg/kg, i.p.) was significantly enhanced in rats that had been pretreated chronically with naloxone. However, the antinociceptive effects induced by pentazocine (3 mg/kg, i.p.) and U-50,488 H (1 mg/kg, i.p.) were unchanged. These results suggest that pentazocine-induced antitussive effects in rats are mediated via stimulation of µ-opioid receptors. Send offprint requests to J. Kamei at the above address     

Interactions of theβ carboline abecarnil with the high pressure neurological syndrome in a primate model

The neurophysiological interactions between the high pressure neurological syndrome (HPNS) and a new carboline, abecarnil, were studied in the nonhuman primatePapio anubis. Abecarnil is a partial agonist at the benzodiazepine site on the GABA/benzodiazepine receptor. Six animals were exposed on two occasions to pressures of 91 ATA in an environment of helium and oxygen. One exposure was pretreated with a total dose of abecarnil 1.0 mg/kg, the other with an equivalent volume of vehicle. Treatment with abecarnil prevented the severe signs of HPNS occurring between 51 and 91 ATA. Onset pressures of the various signs were unaffected. Some signs, e.g. myoclonus, became more frequent when abecarnil was used. A residual protective effect of abecarnil was present 4 weeks after the dose was given, active at pressures less than 71 ATA. Changes with pressure in the EEG were recorded primarily from the frontal cortex, but were also present in the parietal and occipital areas of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the four conventional wavebands, plus two others, analysed. The most striking change was the prevention by abecarnil of the pressure-induced 100% increase in alpha wave amplitude in the frontal region. It is concluded that modulation of GABA transmission is important in controlling the expression of HPNS.     

Rapid regulation of the dopamine transporter: role in stimulant addiction?

Dopamine (DA) and the DA transporter (DAT) play important roles in psychomotor stimulant behavioral activation and reward. By understanding how DAT activity is regulated, we will better appreciate its contribution to normal neurotransmission and to brain diseases like drug addiction. DAT is regulated long-term by chronic drug administration. It is also regulated in a rapid, dynamic fashion by many factors--including brief exposure to DAT substrates, e.g. DA and amphetamine, and inhibitors, e.g. cocaine. We found that individual differences in the initial and sensitized locomotor responsiveness of rats to cocaine reflect differences in in vivo DAT function. Our ex vivo studies have further suggested that differences in basal and/or rapid cocaine-induced expression of functional DATs in striatum contribute to the differences in initial responsiveness. Studies in model systems have demonstrated that short-term DAT regulation occurs by altered transporter trafficking, and thereby cell surface expression. For example, a rapid, complex regulation of DAT by DA is suggested. Amphetamine causes DAT internalization into early endosomal compartments whereas cocaine appears to up-regulate surface expression of DAT. Future studies are needed to confirm these observations in neurons, as well as to elucidate the mechanisms of rapid DAT endocytic trafficking at neuronal synapses.     

Pharmacological interaction with the sigma1 (σ1)-receptor in the acute behavioral effects of antidepressants

Selective agonists of the sigma-1 (σ(1)) ligand-operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. σ(1)-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the σ(1)-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS). The involvement of the σ(1)-receptor was examined using a co-treatment with the σ(1)-antagonist BD1047 or using σ(1)-knockout (KO) mice. Igmesine but not PRE-084 decreased FST immobility. The SSRI fluoxetine and sertraline, but not fluvoxamine, and the tricyclic antidepressants imipramine, desipramine, and amitriptyline were also effective. Only the effect of igmesine was blocked by BD1047 or in σ(1)-KO mice. Igmesine, PRE-084, fluvoxamine, and sertraline decreased the CFS immobility in a BD1047- and σ(1)-KO-sensitive manner. Among tricyclics, only amitriptyline was effective and its effect was unaffected by BD1047 or in σ(1)-KO mice. The behavioral effects induced by mixed σ(1)-receptor/SSRI antidepressants, like fluvoxamine or sertraline, may therefore involve a non-selective action at both targets. Moreover, the CFS appears to more reliably uncover a σ(1) pharmacological component in antidepressant screening.