Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Attenuation of the discriminative stimulus effects of ethanol by the benzodiazepine partial inverse agonist Ro 15-4513

The aim of the present study was to investigate whether ethanol training affects the ability of Ro 15-4513 to block the discriminative stimulus effects of ethanol dose differentially. Three different groups of rats were trained to discriminate 1.0 g/kg ethanol (n = 8), 1.5 g/kg ethanol (n = 7) or 2.0 g/kg ethanol (n = 8) from water in a two-lever, food-reinforced procedure. Ethanol and water were administered by gavage 20 min before the onset of the session. When the discrimination performance was stable, rats were pretreated with Ro 15-4513 (1-17 mg/kg; i.p.) 5 min before the administration of ethanol. Ro 15-4513 attenuated the discriminative stimulus effects of 1.0 and 1.5 g/kg ethanol but not 2.0 g/kg ethanol in each of the ethanol training groups. Overall, blockade of the discriminative stimulus effects of 1.0 and 1.5 g/kg ethanol by 5.6 mg/kg Ro 15-4513 occurred without significantly altering response rates or blood ethanol concentrations. A decrease in blood ethanol concentration was, however, found with 17 mg/kg Ro 15-4513 in combination with 2.0 g/kg ethanol. These results suggest that the benzodiazepine partial inverse agonist, Ro 15-4513, can attenuate the discriminative stimulus effects associated with low to moderate doses of ethanol (1.0-1.5 g/kg).     

Evidence that RU 24969-induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5-HT1B receptor

1. The behavioural effects of the 5-HT1B receptor agonists, RU 24969 and CGS 12066B, have been investigated in C57/B1/6 mice. 2. RU 24969 (1-30 mg kg-1) produced intense and prolonged hyperlocomotion and other behavioural changes. 3. CGS 12066B caused similar effects, but they were much less pronounced, inconsistent and transient irrespective of whether this drug was given i.p. (1-15 mg kg-1) or i.c.v. (0.2-40 micrograms). However, CGS 12066B (7.5 and 15 mg kg-1) caused a dose-related inhibition of RU 24969 (7.5 mg kg-1)-induced hyperlocomotion indicating that the former is a 5-HT1B partial agonist. 4. RU 24969 (7.5 mg kg-1 i.p.)-induced hyperlocomotion was inhibited by the (-)-, but not (+)-isomers of pindolol (4 mg kg-1) and propranolol (20 mg kg-1) but not by metoprolol (10 mg kg-1) or ICI 118,551 (5 mg kg-1), consistent with an involvement of 5-HT1A or 5-HT1B receptors. 5. The response was not altered by the selective 5-HT1A receptor antagonist, WAY 100135 (5 mg kg-1, s.c.), the 5-HT2A/5-HT2C receptor antagonist, ritanserin (0.1 mg kg-1), the selective 5-HT3 receptor antagonist, ondansetron (1 mg kg-1) or the non-selective 5-HT receptor antagonists methysergide (3 mg kg-1) and metergoline (3 mg kg-1). 6. Although spiroxatrine (0.1 mg kg-1) and ketanserin (1 mg kg-1) inhibited RU 24969-induced hyperlocomotion, these effects were probably due to antagonism of dopamine D2 receptors and alpha 1-adrenoceptors respectively. 7. Taken together, these results indicate that RU 24969-induced hyperlocomotion results specifically from activation of central 5-HTIB receptors.8. Lesioning of 5-HT neurones with 5,7-dihydroxytryptamine (75 microg, i.c.v.) or depletion with pchlorophenylalanine(200 mg kg-1, i.p. for 14 days) had no effect on RU 24969-induced hyperlocomotiondemonstrating that the 5-HTIB receptors involved are postsynaptic and that they do not show super sensitivity.9. The involvement of other monoamine neurotransmitter systems in RU 24969-induced hyperlocomotionwas also examined. The response was inhibited by the al-adrenoceptor antagonist, prazosin(1 mg kg-1), the dopamine DI receptor antagonist, SCH 23390 (0.05 mg kg-1) and the dopamine D2 receptor antagonist, BRL 34778 (0.03 mg kg-1), but not by the M2-adrenoceptor antagonist, idazoxan(1 mg kg-1). Lesioning noradrenergic neurones with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine(100 mg kg-1) markedly attenuated this behaviour. These results show that the hyperlocomotion is expressed via noradrenergic and dopaminergic neurones acting on alpha 1-adrenoceptors, DI and D2 receptors.10. RU 24969 decreased brain concentrations of 5-hydroxyindoleacetic acid whilst simultaneously increasing 5-HT, consistent with the reduction of 5-HT neuronal activity by activation of 5-HTlA and 5-HTIB autoreceptors. RU 24969 increased brain 3-methoxy-4-hydroxyphenylglycol, but not noradrenaline, concentrations which supports the involvement of noradrenergic neurones in the expression of hyperlocomotion. RU 24969 did not alter dopamine, dihydroxyphenylacetic acid or homovanillic acid concentrations in the nucleus accumbens suggesting that the dopaminergic neurones terminating there are not directly involved.     

Hazardous materials and work safety in veterinary practice. 1: Hazardous material definition and characterization, practice documentation and general rules for handling

The role of the nicotinic acetylcholine receptor (nAChR) in the discriminative and aversive stimulus effects of ethanol was studied in rats. In the operant drug discrimination procedure the rats were trained to discriminate between 1.0 g/kg ethanol and saline under the FR10 schedule of sweetened milk reinforcement. Neither the nAChR agonist, nicotine (0.1-0.6 mg/kg) nor the nAChR antagonist, mecamylamine (3.0-6.0 mg/kg) substituted for the ethanol stimulus. Moreover, mecamylamine (0.5-6.0 mg/kg) did not antagonise the ethanol stimulus. The cross-familiarisation conditioned taste aversion procedure was used as an alternative method to study stimulus resemblance between ethanol and nicotine. Six daily injections of nicotine (0.6 mg/kg) significantly decreased a subsequent ethanol-induced taste aversion conditioning. The aversive stimulus effects of ethanol were investigated with the conditioned taste aversion (CTA) paradigm. Mecamylamine (1.0-3.0 mg/kg) did not attenuate an ethanol-induced CTA. These results suggest that: (1) nAChRs are not primarily involved in the discriminative stimulus effects of ethanol when studied with the operant drug discrimination test; (2) nAChRs are not critically involved in the ethanol-induced CTA.     

Comparison of the stimulus properties of ethanol and the Ca2+ channel antagonist nimodipine in rats

A variety of L-type Ca2+ channel antagonists, including the dihydropyridine derivative nimodipine, have been shown to be effective in reducing ethanol intake and preference in animal models of alcoholism. The behavioral mechanism involved in the anti-alcohol effects of nimodipine are, however, not clear yet. The aim of the present study was to investigate the possibility that the effects of nimodipine on ethanol intake are based on stimulus substitution. Therefore, rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (dose range of ethanol tested: 125-1000 mg/kg i.p., ED50 value: 488 mg/kg). In cross-generalization tests with nimodipine (0.15-15 mg/kg i.p.), stimulus substitution was not noted. In addition, a cross-familiarization conditioned taste aversion paradigm was utilized. In rats, 1000 mg/kg i.p. ethanol was used as the reference drug producing a conditioned taste aversion. Effects of preexposure to ethanol (500-1500 mg/kg i.p.) and nimodipine (7.5-30 mg/kg i.p.) on the magnitude of the ethanol-induced conditioned taste aversion were investigated as an index for stimulus similarity between preexposure and reference drug. Preexposure to both ethanol and nimodipine prevented the development of a conditioned taste aversion. Contrary to the drug discrimination results, these latter findings suggest that there may be similarities between the stimulus properties of nimodipine and ethanol. Moreover, the apparent discrepancy between the results obtained in drug discrimination and cross-familiarization conditioned taste aversion suggests that different stimulus properties of ethanol control behavior in both procedures. The finding that, under particular conditions, ethanol and nimodipine appear to share common stimulus properties needs to be further evaluated, as this may be related to the reported anti-alcohol effects of nimodipine and other Ca2+ channel antagonists.     

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.     

Studies on the neuronal circuits involved in the discriminative stimulus effects of 5-hydroxytryptamine1A receptor agonists in the rat

Rats were trained to discriminate 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, 1.25 mg/kg i.p.), a selective and nonselective 5-hydroxytryptamine1A (5-HT, serotonin) receptor agonist, respectively, from saline in a two-lever procedure. The selective 5-HT1A receptor agonist ipsapirone substituted completely for 8-OH-DPAT (ED50, 1.52 mg/kg) and 5-OMe-DMT substituted partially for 8-OH-DPAT, whereas 8-OH-DPAT (ED50, 0.07 mg/kg) and ipsapirone (ED50, 4.15 mg/kg) substituted completely for 5-OMe-DMT. These results suggest that the discriminative stimulus properties of both 8-OH-DPAT and 5-OMe-DMT are 5-HT1A receptor mediated, although 5-OMe-DMT may involve an additional interaction with other 5-HT receptor subtypes. 5-OMe-DMT substituted for 8-OH-DPAT after application in the lateral ventricle (ED50, 3.0 micrograms/rat) and the dorsal raphe nucleus (DRN, 1.1 micrograms/rat). After application in the DRN (ED50 range, 1.4-5.0 micrograms/rat) and the median raphe nucleus (2.3 micrograms/rat), and after bilateral application into the CA-4 region of the dorsal hippocampus (4.1 micrograms/rat), 8-OH-DPAT also produced responding on the 8-OH-DPAT lever. Ipsapirone also substituted for 8-OH-DPAT after application into the DRN and the hippocampus (ED50S, 38 and 62 micrograms/rat, respectively). The 5-HT1A mixed agonist-antagonist (1-(2-methoxyphenyl) 4-[4-(2-pthalimido)butyl]piperazine, i.p. NAN-190) attenuated the discriminative stimulus effects of 8-OH-DPAT injected i.p. (0.1 mg/kg), into the DRN (10 micrograms) or into the hippocampus (2 x 10 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.     

Case of oculocraniosomatic neuromuscular disease associated with parkinsonism with special reference to catecholamine metabolism

Three groups of rats (A, B, C) were trained in a T-maze discriminate between drug-and control solution-induced internal discriminative stimuli. The drugs used to induce discriminative stimuli were: delta 9-THC, 5.0 mg/kg (Group A); ethanol, 1.2 g/kg (Group B), and amphetamine, 1.0 mg/kg(Group C). After discrimination acquisition several drugs were tested for generalization in each group. Group A was tested with delta 8-THC, CBD, CBN, ethanol, pentobarbital,chlorpromazine, amphetamine, and apomorphine; only delta8-THC and CBN induced delta9-THC-like responses. Group B was tested with delta 9-THC, delta 8-THC, CBD, CBN, pentobarbital, and amphetamine; pentobarbital induced ethanol-like response. Group C was tested with delta 9-THC, apomorphine, and ethanol; delta 9-THC and apomorphine elicited amphetamine-like responses.     

Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reconstitution of membrane fusion between pancreatic islet secretory granules and plasma membranes: catalysis by a protein constituent recognized by monoclonal antibodies directed against glyceraldehyde-3-phosphate dehydrogenase

This study was conducted to assess the involvement of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptor systems, located in specific limbic brain regions. in the discriminative stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (i.p.) injections of ethanol (1 g/kg) and saline on a two-lever drug discrimination task. The rats were then implanted with bilateral injector guides aimed at the nucleus accumbens core (AcbC), prelimbic cortex (PrLC), hippocampus area CA1 (CA1), or extended amygdala (i.e., at the border of the central and basolateral nuclei). Infusions of the non-competitive NMDA antagonist MK 801 in the AcbC or CA1 resulted in dose-dependent full substitution for i.p. ethanol. MK 801 infusion in the PrLC or amygdala failed to substitute for ethanol. Injection of the competitive NMDA antagonist CPP in the AcbC also failed to substitute for ethanol. Co-infusion of MK 801 in the hippocampus potentiated the effects of MK 801 in the AcbC, whereas NMDA infusion in the hippocampus attenuated the ability of MK 801 in the AcbC to substitute for ethanol. The direct GABA(A) agonist muscimol resulted in dose-dependent full substitution for i.p. ethanol when it was injected into the AcbC or amygdala, but failed to substitute when administered in the PrLC. Co-infusion of MK 801, but not CPP, potentiated the effects of muscimol in the AcbC. These results demonstrate that ethanol's discriminative stimulus function is mediated centrally by NMDA and GABA(A) receptors located in specific limbic brain regions. The data also suggest that the discriminative stimulus effects of ethanol are mediated by interactions between ionotropic GABA(A) and NMDA receptors in the nucleus accumbens, and by interactions among brain regions.     

Motor effects of lamotrigine in naive and dopamine-depleted mice

Lamotrigine (3,5-diamino-6-[2,3-dichlorphenyl]-1,2,4-triazine) has been hypothesised to possess antiparkinsonian activity, by inhibiting the release of glutamate from basal ganglia neurones. This study therefore examined the motor effects of lamotrigine in naive and reserpine-treated mice and its interactions with dopaminergic agonists. In normal mice, lamotrigine (5-80 mg/kg i.p.) decreased spontaneous locomotor activity with high doses (> or = 40 mg/kg) causing moderately severe impairment to posture and gait. In mice treated 24 h beforehand with reserpine (5 mg/kg i.p.), lamotrigine (5-40 mg/kg i.p.) had no effect on akinesia by itself and did not alter the locomotion induced with the selective dopamine D1 receptor agonist 2,3,4, 5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.). By contrast, motor responses to the dopamine D2 receptor-selective agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and to the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in the presence of benserazide, 100 mg/kg i.p.), were significantly potentiated by 10 and 40 mg/kg i.p. lamotrigine respectively. It is suggested that lamotrigine may enhance the antiakinetic action of L-DOPA in parkinson-like mice by increasing motor responding mediated by dopamine D2 but not dopamine D1 receptors. This interaction profile of lamotrigine with dopamine D1 and D2 receptor mechanisms is opposite to what one sees with antagonists of glutamate receptors.     

Antiemetic effects of morphine on motion- and drug-induced emesis in Suncus murinus

Emetic and antiemetic effects of morphine were investigated in Suncus murinus. Subcutaneous (up to 30 mg/kg) or intracerebroventricular administration (50 micrograms) of morphine failed to cause emesis. However, pretreatment with morphine (s.c.) prevented the emesis induced by nicotine (10 mg/kg, i.p.), copper sulfate (40 mg/kg, p.o.), cisplatin (20 mg/kg, i.p.) and motion stimulus. These results suggest that morphine has only antiemetic potency and may block a common mechanism for the emetic reflex of suncus, because the antiemetic effects of the drug were exerted irrespective of the stimulus.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

The protective effect of moderate alcohol consumption on ischemic stroke

Experiments were designed to investigate the influence of estrous cycle and gender of the rat on the effects of a gamma-aminobutyric acid type A (GABA(A)) receptor active neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), the benzodiazepine, triazolam, and a GABA(A) receptor antagonistic neurosteroid, delta5-androsten-3beta-ol-17-one sulfate (dehydroepiandrosterone sulfate), on food intake and elevated plus-maze learning behaviors. Allopregnanolone (0.25 mg/kg, s.c.) and triazolam (0.25 mg/kg, i.p.) produced a hyperphagic effect, while dehydroepiandrosterone sulfate (5 mg/kg, s.c.) elicited an anorectic effect. However, allopregnanolone was more potent in diestrous females, whereas triazolam exhibited significantly higher hyperphagic potency in estrus females. The extent of anorexia following dehydroepiandrosterone sulfate was alike in male and female rats. The triazolam- and allopregnanolone-induced hyperphagic effect was blocked by bicuculline (1 mg/kg, i.p.), a selective GABA(A) receptor antagonist. In contrast to triazolam, the hyperphagic effect of allopregnanolone was insensitive to flumazenil (5 mg/kg, i.p.), a benzodiazepine antagonist. Vehicle-treated diestrous rats displayed moderately higher latencies in the elevated plus-maze learning task than estrus or proestrus females. Although allopregnanolone and triazolam elicited equipotent learning deficits in plus-maze learning in male and female rats, the magnitude of impairment-induced by triazolam was significantly higher in diestrous females than proestrus females. Dehydroepiandrosterone sulfate enhanced memory performance only in male rats. Although the use of the elevated plus-maze as a learning paradigm with benzodiazepines and neurosteroids may be sensitive to changes in anxiety, the differential data suggest that neurosteroid-induced effects are at least partly specific to learning behavior. These results confirm the role of estrous cycle and sex of rats in modifying the potency of neurosteroids and benzodiazepines on food consumption and learning and memory processes.     

In vivo functional interaction between phencyclidine binding sites and sigma receptors to produce head-weaving behavior in rats

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.     

The influence of caffeine on nicotine's discriminative stimulus, subjective, and reinforcing effects.

Caffeine may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining the association of coffee intake with smoking status. In this study, smokers were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0). Then, generalization of nicotine discrimination was tested, using both 2- and 3-choice ("novel" option) procedures, across a range of doses (0-20 μg/kg) following pretreatment with 0, 2.5, and 5.0 mg/kg caffeine p.o. Nicotine reinforcement was assessed after the end of generalization testing using a choice procedure. Caffeine pretreatment did not alter nicotine discrimination and self-administration. Caffeine and nicotine influenced some subjective and cardiovascular responses, but there were no interaction effects except for diastolic blood pressure. These results do not support the notion that caffeine acutely alters nicotine's discriminative stimulus, subjective, or reinforcing effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine: however nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effect though a different mechanism that nicotine. Give bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selenium and iodine deficiencies and selenoprotein function

The present study was designed to evaluate the roles of 5-HT2 and 5-HT3 receptors in the mouse forced swimming test, by using selective agonists and antagonists of 5-HT(2A/C) and 5-HT3 receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Pretreatment with (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (4 mg/kg, i.p.) or 2-methyl-5-HT (4 mg/kg, i.p.) had no effect on the anti-immobility effects of any antidepressant tested. Prior administration of ritanserin (4 mg/kg, i.p.) or ketanserin (8 mg/kg, i.p.), on the other hand, potentiated the effects of sub-active doses of imipramine (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.) but not of maprotiline (8 mg/kg, i.p.), fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). Pretreatment with ondansetron (1 X 10(-5) mg/kg, i.p.) enhanced the antidepressant-like effects of sub-active doses of the selective serotonin reuptake inhibitors. The results of the present study suggested that, in the forced swimming test, the selective serotonin reuptake inhibitors act partially through 5-HT3 receptor sites, whereas the tricyclic antidepressants exert effects at 5-HT(2A/C) receptor sites. Anti-immobility effects of the selective noradrenaline reuptake inhibitor, maprotiline, do not seem to be mediated by 5-HT(2A/C) or 5-HT3 receptor function.     

Continuous extrapleural intercostal nerve block for post thoracotomy analgesia in children

The influence of the nicotine antagonist dihydro-beta-erythroidine (DH beta E) was examined on various behavioural effects of nicotine in rats. Motor activity was recorded in photocell cages whereas discriminative stimulus effects were examined using two-lever drug discrimination procedures with a tandem schedule of food reinforcement (n = 8 throughout). DH beta E (0.1-3.2 mg/kg) failed to antagonise the decreases in motor activity that nicotine (0.4-0.6 mg/kg) produced in experimentally naive rats, whereas mecamylamine (1.5 mg/kg) completely blocked this effect of nicotine. DH beta E (0.1-3.2 mg/kg) antagonised the increases in motor activity that nicotine (0.4 mg/kg) produced in rats with extensive previous exposure to both nicotine and the photocell apparatus. In rats trained to discriminate either 0.1 or 0.4 mg/kg nicotine from saline, DH beta E (0.1-3.2 mg/kg) blocked the discriminative stimulus effect of nicotine. The block of the discriminative effect could be reversed by increasing the dose of nicotine; DH beta E (1.6 mg/kg) shifted the dose-response curve for nicotine discrimination to the right by a factor of 9.4. In addition, nicotine in doses of 0.32-0.64 mg/kg decreased the overall rate of lever pressing but DH beta E (1.6 mg/kg) did not influence the dose-response curve for this effect. Thus, DH beta E potently blocked the locomotor activating and discriminative stimulus effects of nicotine at doses that did not antagonise its locomotor depressant and operant response rate-reducing effects. This selective blockade supports the involvement of different subtypes of nicotinic receptor in the mediation of diverse behavioural effects. Furthermore, the rightward shift of the dose-response curve for nicotine discrimination suggested a competitive mode of action for DH beta E.