Characterization of the ethanol-like discriminative stimulus effects of 5-HT receptor agonists as a function of ethanol training dose

 A drug discrimination procedure was used to characterize the ethanol-like effects of a variety of 5-HT₁ agonists. Previous studies found that the degree of substitution of the 5-HT_1B/2C agonist TFMPP (m-trifluoromethylphenylpiperazine) depended on the training dose of ethanol. The present studies extend this initial finding to four additional 5-HT agonists with different selectivity for 5-HT_1A, 5-HT_1B, or 5-HT_2C receptors: CGS 12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate), mCPP [1-(3-chlorophenyl)piperazine diHCl], RU 24969 [5-methoxy-3(1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole succinate and 8-OH DPAT [(±)-8-hydroxy-2-(di-n-propylamino)tetralin HBr]. Separate groups of rats were trained to discriminate 1.0 g/kg (n=7), 1.5 g/kg (n=6) or 2.0 g/kg (n=8) ethanol from water. Following training, three to five doses of each 5-HT agonist were tested twice in each rat. The most selective 5-HT_1B agonist tested, CGS 12066B (3–17 mg/kg; IP), completely substituted for the 1.0 g/kg ethanol, but not for 1.5 or 2.0 g/kg ethanol. Likewise, the 5-HT_1B/2C agonist mCPP (0.56–1.7 mg/kg; IP) completely substituted only in the 1.0 g/kg ethanol training group. The 5-HT_1A/1B agonist RU 24969 (0.1–3.0 mg/kg; IP) substituted for all training doses of ethanol, although in a lower proportion of the rats tested in the 2.0 g/kg ethanol training group. Finally, the 5-HT_1A agonist 8-OH DPAT (0.1–1.0 mg/kg; IP) did not substitute completely for any ethanol training dose. The results consistently show that agonists with 5-HT_1B activity produce discriminative stimulus effects similar to low and intermediate, but not high, ethanol training doses. Received: 10 September 1996 / Final version: 25 March 1997     

Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists

The ability of selective 5-HT₃ receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT₃ receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT₃ receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT₃ receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT₂ receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT₃ mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT₃ receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT₃ activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.     

Characterization of the discriminative stimulus effects of N-methyl- D-aspartate ligands under different ethanol training conditions in the cynomolgus monkey ( Macaca fascicularis)

RATIONALE: The current study was designed to extend our knowledge of the N-methyl- D-aspartate (NMDA) glutamate receptor system in mediating the discriminative stimulus effects of ethanol in non-human primates. OBJECTIVES: To characterize the discriminative stimulus effects of the NMDA uncompetitive antagonists dizocilpine, phencyclidine (PCP) and ketamine in male and female monkeys under different ethanol training conditions. METHODS: Adult male ( n=8) and female ( n=9) cynomolgus monkeys ( Macaca fascicularis) were divided into four groups and trained to discriminate 1.0 g/kg ethanol ( n=8) versus water or 2.0 g/kg ethanol ( n=9) versus water in a 2 x 2 design with training dose and sex as main group factors. Ethanol (20% w/v) solutions were administered intragastrically (IG) and responding was maintained under a fixed ratio schedule of food reinforcement. Dose-response determinations for dizocilpine [IG and intramuscular (IM)], PCP (IM) and ketamine (IM) were made under two training intervals (30 and 60 min). RESULTS: Dizocilpine, PCP and ketamine dose-dependently substituted for ethanol in three of four training conditions, the notable exception being in males trained with 2.0 g/kg ethanol. Ethanol-like discriminative stimulus effects were greater with IM dizocilpine than with IG dizocilpine. At the lower ethanol training dose (1.0 g/kg), there were no sex differences in the ethanol-like discriminative stimulus effects of dizocilpine, PCP or ketamine, nor were there sex differences in the potencies to produce ethanol-like discriminative stimulus effects. Sex differences were readily apparent with the higher ethanol training dose (2.0 g/kg), with the NMDA ligands failing to substitute for ethanol in male monkeys, probably due to the rate-suppressive effects of these compounds. CONCLUSIONS: These data suggest that NMDA receptor-mediated activity is a component to the discriminative stimulus effects of ethanol in male and female nonhuman primates. However, NMDA uncompetitive antagonists were less likely to produce discriminative stimulus effects similar to a high ethanol training dose in male monkeys. In comparison to consistent substitution by GABA(A) positive modulators for ethanol, substitution patterns produced by NMDA uncompetitive antagonists suggest a less robust mediation of the ethanol discriminative stimulus through NMDA receptor systems in nonhuman primates.     

Characterization of the discriminative stimulus effects of GABAA receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions

Rationale: Some evidence suggests an involvement of nucleus accumbens in spatial learning. However, it is controversial whether the mesoaccumbens dopaminergic pathways play a specific role in the acquisition of spatial information. Objective: The goal of these experiments was to investigate the effect of dopaminergic manipulations in the nucleus accumbens on a non-associative task designed to estimate the ability to encode/transmit spatial and non-spatial information. Methods: The effects of focal administrations of the D1 and D2 dopamine receptor antagonists, SCH 23390 (6.25, 12.5, 50 ng/side) and sulpiride (12.5, 50, 100 ng/side), respectively, and dopamine (DA; 1.25 and 2.5 μg/side) into the nucleus accumbens were studied on reactivity to spatial and non-spatial changes in an open field with objects. Results: Both SCH 23390 and sulpiride impaired reactivity to spatial change. However, several differences were found in the effects induced by the two DA antagonists. SCH 23390 did not affect locomotor activity and only slightly impaired exploration of the novel object. On the contrary, the D2 antagonist, induced a general, dose-dependent, impairment on all variables measured. Local administration of DA increased locomotor activity, but did not affect reactivity to spatial and non-spatial changes. Conclusions: These results demonstrate a facilitatory role of mesoaccumbens dopamine in the acquisition of spatial information. Moreover, they suggest that nucleus accumbens D1 DA receptors, play a more selective role in the modulation of spatial learning than accumbens D2 DA receptors. Electronic Publication     

Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats

Rationale The serotonin (5-hydroxytryptamine; 5-HT) 5-HT₂ receptor (5-HT₂R) family is an important regulator of the behavioral responsiveness to cocaine. Objective The present study is an analysis of the role of the 5-HT₂R subtypes (5-HT_2AR, 5-HT_2BR, and 5-HT_2CR) in the discriminative stimulus effects of cocaine. Methods Male Wistar rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task, and we investigated the ability of the 5-HT_2AR antagonist 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene (SR 46349B), the 5-HT_2BR antagonist N-(1-methyl-5-indolyl)-N′-(3-methyl-5-isothiazolyl) urea (SB 204741), and the 5-HT_2CR antagonist [(+)-cis -4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-bC)(2,6)naphthyridine (SDZ SER-082) to substitute for or to modulate the stimulus effects of cocaine. Results Pretreatment with SR 46349B (0.5–1 mg/kg) resulted in a rightward shift of the cocaine dose–response curve, while SDZ SER-082 (1 mg/kg) shifted the dose–response for cocaine to the left; SB 204741 (1–3 mg/kg) was inactive. Conclusions Our pharmacological analyses of selective antagonists of 5-HT_2AR, 5-HT_2BR, and 5-HT_2CR indicate oppositional influence of 5-HT_2AR and 5-HT_2CR on the stimulus effects of cocaine and exclude a role for the 5-HT_2BR. These data suggest that 5-HT_2AR and 5-HT_2CR may be important in modulating the subjective effects of cocaine in humans.     

Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP)

Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h washout period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD.     

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; IG) from ethanol (2.0 g/kg; IG) from water (4.7 ml; IG) using food reinforcement. Substitution tests were conducted following administration of the GABA_A positive modulators allopregnanolone (5.6–30.0 mg/kg; IP), diazepam (0.3–10.0 mg/kg; IP) and pentobarbital (1.0–21.0 mg/kg; IP), the non-competitive NMDA antagonist phencyclidine (0.3–10.0 mg/kg; IP), the 5-HT₁ agonists TFMPP (0.3–5.6 mg/kg; IP) and RU 24969 (0.3–3.0 mg/kg; IP), and isopropanol (0.10–1.25 g/kg; IP). 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. Received: 18 November 1997 / Final version: 10 February 1998     

5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats

 Rats were trained on a fixed ratio 10, food-reinforced schedule to recognize a discriminative stimulus (DS) elicited by the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram (2.5 mg/kg, IP). The preferential, high efficacy agonist at 5-HT_2C receptors, Ro60-0175, dose-dependently generalized to citalopram with an ED₅₀ of 0.3 mg/kg, IP. Further, the selective 5-HT_2C receptor antagonist, SB242,084, dose-dependently (ED₅₀=0.1 mg/kg, IP) blocked the citalopram DS. These data suggest that 5-HT_2C receptors are involved in the DS properties of the SSRI, citalopram, in rats. They do not, however, exclude a potential role of other 5-HT receptor types. Received: 15 October 1998 / Final version: 10 December 1998     

The effects of opiate antagonists on the discriminative stimulus properties of ethanol

The effects of naloxone HCl (1.0 mg/kg, 10.0 mg/kg) and naltrexone HCl (1.0 mg/kg, 10.0 mg/kg) on the discriminative stimulus properties of ethanol were measured in order to assess the role of opiate pathways in that behavioral property of ethanol. Forty-eight Sprague-Dawley rats were trained to perform ethanol: saline discriminations on a DRL 10″ schedule of reinforcement in a double lever operant paradigm. Discrimination training for 170 days established 0.6 mg/kg IP ethanol doses as a discriminative stimulus producing at least 80% of all responses as drug appropriate lever choices during 10 min test sessions. After that performance criterion was achieved the effects of the opiate antagonists on the discrimination were assessed by administering naloxone (1.0 mg/kg, IM, 10.0 mg/kg IM) or naltrexone (1.0 mg/kg, IM, 10.0 mg/kg, IM) 15–30 min before the ethanol test dose. Neither antagonist produced significant changes in the performance of the ethanol-saline discrimination. These data demonstrate that the discriminative stimulus properties of ethanol do not require intact opiate pathways. That result implies that the neuropharmacological mechanisms mediating ethanol's stimulus properties in rodents are different from the mechanisms mediating many other behavioral actions of ethanol, including its reinforcing properties.     

Discriminative stimulus effects of ethanol, pregnanolone, and dehydroepiandrosterone (DHEA) in rats administered ethanol or saline as adolescents

Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol abuse and dependence as an adult. To test this possibility, ethanol (0.18-1.8 g/kg) and two neurosteroids, pregnanolone (1-10 mg/kg) and dehydroepiandrosterone (DHEA, 1-100 mg/kg), were administered alone and in combination to adult, male Long-Evans rats discriminating 1 g/kg ethanol (15% v/v) under a fixed ratio (FR) 20 schedule of food presentation after adolescent treatment with 15 injections of ethanol (n = 9, 2 g/kg, 20% v/v) or saline (n = 7). When compared as adults, ethanol-treated adolescents (as opposed to saline-treated adolescents) had higher percentages of ethanol-lever responding at doses smaller than the training dose, and higher response rates after both control and ethanol injections. Neither pregnanolone nor DHEA substituted for ethanol in either adolescent-treated group up to doses that substantially decreased response rates. When administered with ethanol, 1 and 3.2 mg/kg of pregnanolone enhanced the discriminative stimulus effects of small ethanol doses more in saline-treated adolescents than in ethanol-treated adolescents. Unlike pregnanolone, 32 and 100 mg/kg of DHEA attenuated the discriminative stimulus effects of ethanol modestly in both adolescent-treated groups. These results in adult rats suggest that adolescent ethanol administration can enhance the discriminative stimulus effects of small ethanol doses and affect the capacity of pregnanolone, but not DHEA, to interact with ethanol's discriminative stimulus effects.     

Interaction of the discriminative stimulus properties of diazepam and ethanol in pigeons

One group of pigeons (n = 5) was trained to discriminate between the effects induced by 5.6 mg/kg of diazepam (DZP) and the vehicle whereas other pigeons (n = 5) had to discriminate between 3.0 g/kg of ethanol (ETOH) and the vehicle, administered intragastrically (IG) 10 and 40 min prior to the training sessions respectively. Once trained, the pigeons were tested with either diazepam or ethanol alone and in combination. The birds trained to discriminate between DZP and the vehicle mostly performed non-drug associated responses when tested with ETOH (0.56 to 3.0 g/kg). Tests with other doses of DZP (0.3 to 3.0 mg/kg) in the diazepam-trained birds resulted in an ED50 value of 1.4 mg/kg. The birds trained to discriminate between ETOH and the vehicle generalized DZP to ETOH, the ED50 value for diazepam being 3.0 mg/kg. Tests with other doses of ETOH (0.56 to 2.0 g/kg) in this latter group resulted in an ED50 value of 1.3 g/kg. Tests with combinations of DZP and ETOH produced a shift of the dose-response curves to the left indicating drug additivity. The discrimination of 5.6 mg/kg of IG administered DZP but not that of ETOH (3.0 g/kg) was attenuated by injections of the analeptic bemegride (ED50 = 5.5 mg/kg), thus suggesting a difference in the cueing processes of the two drugs. When tested singly, bemegride induced non-drug responding or complete suppression of responding in the birds at the doses of 3.0 and 10.0 mg/kg respectively. In conclusion, the discriminable effects of DZP and ETOH are additive or even supra-additive, but the stimulus properties of the two drugs are not identical.     

The discriminative stimulus properties of cocaine: effects of microinfusion of cocaine, a 5-HT1A agonist or antagonist, into the ventral tegmental area

 Serotonin (5-HT) afferents may modulate the dopamine mesoaccumbens circuit, which has been shown to be critically involved in the locomotor stimulatory, discriminative stimulus, and rewarding properties of cocaine. In the present study, we investigated the role of 5-HT_1A receptors in the ventral tegmental area (VTA) in mediating the discriminative stimulus effects of cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task. After acquiring the cocaine-saline discrimination, rats were stereotaxically implanted with bilateral guide cannulae into the VTA or adjacent substantia nigra reticulata (SNR). Intraperitoneal administration of cocaine (0.625–10 mg/kg) produced a dose-related increase in drug-lever responding. Both intra-VTA and intra-SNR infusion of cocaine (12.5–50 μg/0.5 μl/side) engendered primarily saline-like responding. Microinjection of the 5-HT_1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (DPAT; 0.1–10 μg/0.5 μl/side) or the 5-HT_1A antagonist WAY 100635 (0.01–1.0 μg/0.5 μl/side) into the VTA or SNR did not substitute for the systemic cocaine cue. Further, intra-VTA or intra-SNR DPAT or WAY 100635 in combination with systemic doses of cocaine did not alter (i.e., attenuate or potentiate) the systemic cocaine cue. Overall, these data indicate that 5-HT_1A receptors in the VTA do not mediate or modulate the discriminative stimulus effects of cocaine in the rat. Received: 15 April 1997 / Final version: 21 October 1997     

Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal

Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)_1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats. Received: 3 August 1999 / Final version: 23 November 1999     

Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB)

Gammahydroxybutyrate (GHB) satisfies many of the criteria for consideration as a neurotransmitter including having specific receptor sites, endogenous synthesis, and heterogeneous CNS distribution. GHB has been reported to be illicitly used, to induce physical dependence, and to relieve effects from alcohol and heroin withdrawal. GHB has also been shown to have antidopaminergic activity to displace³H[MK-801] binding in brain membranes, and to have some in vivo effects similar to the typical antipsychotics. To characterize the behavioral pharmacology of GHB further, we evaluated it for its reinforcing effects upon IV administration in rhesus monkeys with PCP self-administration histories, its ability to produce heroin- and PCP-like discriminative stimulus effects, and for its ability to antagonize cocaine discrimination in rats. The results indicated that GHB (300–7500 μg/kg per infusion) was not self-administered above vehicle control rates, although self-infusions occurred at levels sufficient to produce signs indicative of sedation. Also, neither heroin nor PCP discriminative stimulus effects generalized to injections of GHB up to 300 mg/kg IP, and GHB did not effectively antagonize the cocaine discriminative stimulus when tested up to 300 mg/kg IP. These data indicate that GHB is unlike PCP as a reinforcer and that neither PCP nor heroin generalize to injections of GHB, nor can injections of GHB attenuate the discriminative stimulus effects of cocaine.     

Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB)

Gammahydroxybutyrate (GHB) satisfies many of the criteria for consideration as a neurotransmitter including having specific receptor sites, endogenous synthesis, and heterogeneous CNS distribution. GHB has been reported to be illicitly used, to induce physical dependence, and to relieve effects from alcohol and heroin withdrawal. GHB has also been shown to have antidopaminergic activity to displace ³H[MK-801] binding in brain membranes, and to have some in vivo effects similar to the typical antipsychotics. To characterize the behavioral pharmacology of GHB further, we evaluated it for its reinforcing effects upon IV administration in rhesus monkeys with PCP self-administration histories, its ability to produce heroin- and PCP-like discriminative stimulus effects, and for its ability to antagonize cocaine discrimination in rats. The results indicated that GHB (300–7500 μg/kg per infusion) was not self-administered above vehicle control rates, although self-infusions occurred at levels sufficient to produce signs indicative of sedation. Also, neither heroin nor PCP discriminative stimulus effects generalized to injections of GHB up to 300 mg/kg IP, and GHB did not effectively antagonize the cocaine discriminative stimulus when tested up to 300 mg/kg IP. These data indicate that GHB is unlike PCP as a reinforcer and that neither PCP nor heroin generalize to injections of GHB, nor can injections of GHB attenuate the discriminative stimulus effects of cocaine. Received: 13 February 1996/Final version: 10 May 1996     

Effect of modification of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA) on ethanol tolerance

Rats were permanently depleted of brain dopamine (DA), serotonin (5-HT), 5-HT+norepinephrine (NE), or NE +DA by intraventricular injection of either 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) with or without pretreatment with desmethylimipramine (DMI). Following 1 week of recovery from surgery, daily treatment with ethanol (5 g/kg, PO) or isocaloric sucrose was carried out for a period of 20–25 days. Testing at 5-day intervals showed that chronic ethanol treatment produced tolerance to the hypothermic and motor impairing effects of ethanol. Depletion of 5-HT alone retarded tolerance, while depletion of NE or DA alone produced no effect. Combined depletion of both NE and 5-HT, however, completely inhibited tolerance development. The inhibition of tolerance development by combined depletion of both NE and 5-HT is dicussed in terms of a reciprocal relationship between these two systems.     

Substitution of the selective serotonin reuptake inhibitors fluoxetine and paroxetine for the discriminative stimulus effects of ethanol in rats

 Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT_2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT_1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT_2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs. Received: 22 November 1996 / Final version: 30 January 1997     

Antagonism of the discriminative stimulus effects of the kappa-opioid agonist spiradoline

This study compared the potency of mixed-action opioids (i.e., agonist-antagonists) and pure antagonists to block the discriminative stimulus effects of spiradoline, a kappa-opioid agonist. Rats were trained to discriminate between 3.0 mg/kg spiradoline and saline (SC) in a two-choice discrete-trial procedure. Graded doses of test drugs were administered in combination with 3.0 mg/kg spiradoline and the dose that reduced selection of the spiradoline-appropriate choice lever by 50% (AD₅₀) was calculated. Ten drugs blocked the discriminative effects of spiradoline in an orderly dose-dependent manner. They spanned a 150-fold potency range, from diprenorphine (5 times as potent as naloxone) to nalbuphine (0.03 times as potent as naloxone). Antagonism was stereoselective: 0.1–1.0 mg/kg (–)-N-allylnormetazocine (NANM) reduced spiradoline-appropriate responding by 50% whereas 3.0 mg/kg (+)-NANM did not. (–)-Pentazocine (0.1–10 mg/kg) and butorphanol (0.1–3.0 mg/kg) also did not block the discriminative effects of spiradoline. Antagonism was surmountable when graded doses of spiradoline were tested with a fixed dose of diprenorphine, naloxone, or levallorphan. Apparent pK_B values derived from the interactions between those three drugs and spiradoline were in accord with relative antagonist potencies based upon the AD₅₀s. Because the potency of a competitive antagonist is determined by its receptor affinity, the relative potencies of mixed-action opioids and pure antagonists in blocking the discriminative stimulus effects of spiradoline can provide an estimate of the relative in vivo affinities of these drugs for the kappa-opioid receptor. Present address: Weinberg Consulting Group, 1220 19th Street, Suite 300, Washington, DC 20036-2400, USA     

Dopaminergic activity and the discriminative stimulus effects of mu opioids in pigeons: importance of training dose and attenuation by the D3 agonist (±)-7-OH-DPAT

 The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors, releasers, a D₁ agonist, a D₂ agonist and a D₃ agonist engendered partial substitution (50–79% butorphanol responding) for the butorphanol stimulus in the low-dose group. In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group, the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D₁ antagonist (+)-SCH 23390 and the D₂ antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol. Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin [(±)-7-OH-DPAT] attenuated butorphanol’s stimulus effects in a dose-dependent manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol, and in the high-training dose group, activation of the D₃ receptor by (±)-7-OH-DPAT results in the attenuation of the discriminative stimulus effects of mu opioids. Received: 19 May 1997 / Final version: 30 September 1997     

A comparison of the discriminative stimulus effects of ethanol,barbital, and phenobarbital in rats

Five different groups of rats were trained in a food-motivated, bar-pressing task to discriminate from the nondrug condition (physiologic saline, i.p.) the effects produced by i.p. injections of ethanol (330, 660, or 990 mg/kg), sodium barbital (80 mg/kg), or sodium phenobarbital (25 mg/kg). The establishment of highly effective discriminations required 20–40 training sessions for all drugs, with the exception that rats trained with 330 mg/kg of ethanol required 80–100 training sessions. After the drug-nondrug discriminations were well established, cross tests revealed that ethanol did not elicit drug-appropriate responding in the groups trained with sodium barbital or sodium in the groups trained with sodium barbital or sodium phenobarbital. However, both barbiturates elicited drug-approppriate responding to some extent in rats trained with ethanol as the discriminative stimulus. With barbital, the greatest generalization was observed in rats trained with the low dose of ethanol (330 mg/kg). The findings emphasize the need for the use of several training doses and for transfer tests in both directions when the stimulus effects of drugs are compared.A preliminary report of part of these findings was presented at the Annual Meeting of the American Society for Pharmacology and Therapeutics, Davis, California, 1975.