Discriminative Stimulus In Rats Research Articles

Effects of manipulation of S-O Contingency on the stimulus control of the discriminative stimulus in rats

Effects of manipulation of S-O Contingency on the stimulus control of the discriminative stimulus in rats

Discriminative stimulus effects of the novel imidazoline I₂ receptor ligand CR4056 in rats.

This study examined whether a novel imidazoline I2 receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I2 receptor ligands. Eight male Sprague-Dawley rats were trained to discriminate 10.0 mg/kg CR4056 (i.p.) from vehicle in a two-lever food-reinforced drug discrimination procedure. Once rats acquired the discrimination, substitution and combination studies were conducted to elucidate the underlying receptor mechanisms. All rats acquired CR4056 discrimination after an average of 26 training sessions. Several I2 receptor ligands (phenyzoline, tracizoline, RS45041, and idazoxan, 3.2–75 mg/kg, i.p.) all occasioned > 80% CR4056-associated lever responding. Other drugs that occasioned partial or no CR4056-associated lever responding included methamphetamine, ketamine, the endogenous imidazoline ligand agmatine, the monoamine oxidase (MAO) inhibitor harmane, the α2-adrenoceptor agonist clonidine, the μ-opioid receptor agonists morphine and methadone, and the selective I2 receptor ligands BU224 and 2-BFI. The α1 adrenoceptor antagonist WB4101, α2 adrenoceptor antagonist yohimbine and μ-opioid receptor antagonist naltrexone failed to alter the stimulus effects of CR4056. Together, these results show that CR4056 can serve as a discriminative stimulus in rats, which demonstrates high pharmacological specificity and appears to be mediated by imidazoline I2 receptors.

Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents

The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. Methods Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. Results Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the μ-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. Conclusions Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. Sessions, 63 +/- 8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT)(2C) receptors, and the 5-HT(2C) antagonists, SB242,084, SB243,213 and S32006, revealed dose-dependent and full (> or =80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT(2A) antagonists, MDL100,907 and SR46349-B, the 5-HT(2B) antagonist, SB204,741, and the 5-HT(3) antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT(1A) receptors, the 5-HT(1A) agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks alpha(2)-adrenoceptors, but several alpha(2)-adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H(1) receptors, no substitution was seen with the selective H(1) antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT(2C) receptors display dose-dependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective.

Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats

Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1). The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it. Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed. Gaboxadol (5-20 mg/kg p.o.), a selective extrasynaptic GABA A agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABA B receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABA A receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect. These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.

Olanzapine and JL13 induce cross-tolerance to the clozapine discriminative stimulus in rats

We have previously shown that chronic treatment with clozapine induces tolerance to the clozapine discriminative stimulus in rats. The studies reported here extended this work to assess whether chronic treatment with the clozapine-like antipsychotics olanzapine and 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate (JL13) induced cross-tolerance to clozapine. Two groups of rats were trained to discriminate clozapine (5 mg/kg, intraperitoneal). Training was suspended and the rats were treated with either olanzapine or JL13 at high doses (5 and 20 mg/kg, respectively). These doses were administered twice daily. The clozapine generalization curve was computed three times - before chronic drug treatment, after 10 days of chronic treatment, and after 16 drug-free days. Both olanzapine and JL13 induced cross-tolerance to the clozapine stimulus, shown by significant 3.4 and 3.9 fold parallel shifts to the right in the clozapine generalization curves. Cross-tolerance was lost spontaneously during the drug-free days after treatment as clozapine sensitivity returned to baseline. We interpret these findings as indicative of the development of pharmacodynamic cross-tolerance to clozapine. Possible neuroadaptive mechanisms involved in such cross-tolerance are discussed. The paradigm outlined here allows refinement of antipsychotic drug discrimination assays to identify common chronic effects of such drugs.

α-Ethyltryptamine (α-ET) as a discriminative stimulus in rats

α-Ethyltryptamine (etryptamine, α-ET) is a drug of abuse that first appeared on the clandestine market in the mid-1980s. Its pharmacological actions are poorly understood. In this investigation, it is reported for the first time that α-ET serves as a training drug in drug discrimination studies. Male Sprague–Dawley rats were trained to discriminate (30-min pretreatment time) 2.5 mg/kg of α-ET (ED 50 = 1.3 mg/kg) from saline vehicle using a standard two-lever operant paradigm and a VI-15s schedule of reinforcement for appetitive reward. Once established, the α-ET stimulus was shown to have an onset to action of 30 min and a duration of effect of at least 4 h. In tests of stimulus generalization (substitution), the α-ET stimulus generalized to S(−)α-ET (ED 50 = 1.6 mg/kg) and R(+)α-ET (ED 50 = 1.3 mg/kg). Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). The α-ET stimulus generalized to DOM (ED 50 = 0.4 mg/kg) and PMMA (ED 50 = 0.7 mg/kg), but only partially generalized ( ca. 40% maximal drug-appropriate responding) to (+)amphetamine. The results suggest that α-ET produces a complex stimulus.

Discriminative stimulus properties of the selective and highly potent α 2-adrenoceptor agonist, S18616, in rats: Mediation by the α 2A subtype, and blockade by the atypical antidepressants, mirtazapine and mianserin

The novel spiroimidazoline, S18616, a potent and efficacious agonist at α 2-adrenoceptors (ARs), shows >100-fold selectivity versus α 1-ARs, imidazoline receptors and all other sites examined. Herein, we characterized its discriminative stimulus (DS) properties in rats trained to recognise S18616 (0.01 mg/kg, s.c.) from saline. S18616 dose-dependently (0.0063–0.01) and “fully” (≥80% “S18616” lever selection) substituted for itself. Full substitution was also acquired for the agonist, UK14,304 (0.04–0.16), while the partial agonist, clonidine (0.01–0.08), yielded sub-maximal substitution (67%). Guanfacine (0.16–1.25) and guanabenz (0.00063–0.04), preferential agonists at α 2A-ARs, revealed full substitution for S18616. In contrast, the α 1-AR agonists, cirazoline and ST587 (both 0.04–0.63), did not substitute. The α 2-AR antagonists, RX821,002, atipamezole (both 0.0025–0.04) and idazoxan (0.04–0.63) blocked the S18616 DS, whereas the α 1-AR antagonists, prazosin (0.16–0.63) and WB4101 (0.04–0.63), were inactive. Prazosin is also a preferential antagonist at α 2B/2C- versus α 2A-ARs and a further preferential α 2B/2C-AR antagonist, BRL41,992 (0.63–2.5), was likewise ineffective. In contrast, the α 2A-AR antagonist, BRL44,408 (0.04–0.16), dose-dependently abolished the S18616 DS. Finally, the “atypical” antidepressants, mirtazapine (0.16–10.0) and mianserin (0.63–10.0), which behave as antagonists at α 2A-ARs, dose-dependently blocked the S18616 DS. In conclusion, S18616 elicits a robust DS in rats that principally reflects engagement of α 2A-ARs. This novel procedure should prove useful in the characterisation of psychoactive drugs which interact with α 2-ARs.

Modulation of a (+)amphetamine discriminative stimulus in rats by 8-hydroxy-2-( N, N-di- n-propylamino)tetralin (8-OH DPAT)

It is well established that the discriminative stimulus (DS) effect of amphetamine involves a dopaminergic and/or noradrenergic mechanism. These catecholamines can be modulated by the 5-HT 1A serotonin receptor agonist 8-hydroxy-2-( N, N-di- n-propylamino)tetralin (8-OH DPAT). The present study was conducted to determine whether 8-OH DPAT could influence the DS effects of (+)amphetamine. Administration of 8-OH DPAT doses to Sprague–Dawley rats trained to discriminate 1 mg/kg of (+)amphetamine (ED 50 = 0.33 mg/kg) using a two-lever operant paradigm (VI-15 s schedule of reinforcement for appetitive reward) failed to result in stimulus generalization when administered alone, and failed to antagonize the stimulus effect when administered in combination with the training dose of (+)amphetamine. However, administration of 8-OH DPAT doses that produced saline-like responding (i.e., 0.01–0.1 mg/kg; < 20% amphetamine-appropriate responding) in combination with the ED 50 dose of (+)amphetamine resulted in the animals' making a progressively greater number of responses on the drug-appropriate lever such that a combination of 0.1 mg/kg of 8-OH DPAT plus (+)amphetamine (0.33 mg/kg) elicited 91% (+)amphetamine-appropriate responding. In a separate study, administration of (+)amphetamine doses in combination with fixed doses of 8-OH DPAT (either 0.01 or 0.1 mg/kg) resulted in an apparent leftward shift of the dose–response curve. The results indicate that (+)amphetamine can be more effective as a discriminative stimulus in the presence of 8-OH DPAT than in its absence.

Discriminative stimulus properties of tianeptine

In view of the difficulties in using antidepressant agents as training drugs in drug discrimination research, it was reasoned that tianeptine, because of its short duration of action and its lack of toxicity associated with long-term administration, would be well-suited to establish a discriminative stimulus cue in rats and, hence, a valuable tool in the investigation of the neural basis of depression. A drug discrimination procedure was used to determine whether tianeptine was associated with a specific discriminative stimulus effect, and substitution tests were conducted to determine whether this effect was mediated by serotonergic mechanisms. Rats were trained to discriminate 10 mg/kg tianeptine from saline and were tested with fluoxetine, a selective serotonin (5-HT) reuptake inhibitor; venlafaxine, a 5-HT/noradrenaline reuptake inhibitor; 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist; and caffeine, a nonselective antagonist of adenosine receptors. Tianeptine induced a specific, robust, and sustained discriminative stimulus in rats. Fluoxetine and 8-OH-DPAT partially substituted for tianeptine by producing >50% of tianeptine-appropriate lever responding. In contrast, venlafaxine and caffeine induced responding on a saline-associated lever. The discriminative stimulus effect of tianeptine is mediated by serotonergic mechanisms, but what is surprising is that this mechanism seems to be, at least partially, enhanced by serotonergic transmission.

Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit.

The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors.

The Selective Serotonin2A Receptor Antagonist, MDL100,907, Elicits a Specific Interoceptive Cue in Rats

Employing a two-lever, food-reinforced, Fixed Ratio 10 drug discrimination procedure, rats were trained to recognize the highly-selective serotonin (5-HT)2A receptor antagonist, MDL100,907 (0.16 mg/kg, i.p.). They attained criterion after a mean ± S.E.M. of 70 ± 11 sessions. MDL100,907 fully generalized with an Effective Dose (ED)50 of 0.005 mg/kg, s.c.. A further selective 5-HT2A antagonist, SR46349, similarly generalized with an ED50 of 0.04 mg/kg, s.c. In distinction, the selective 5-HT2B antagonist, SB204,741 (0.63 and 10.0 mg/kg), the 5-HT2B/2C antagonist, SB206,553 (0.16 and 2.5 mg/kg) and the selective 5-HT2C antagonists, SB242,084 (2.5 and 10.0 mg/kg,) and RS102221 (2.5 and 10.0 mg/kg), did not significantly generalize. In conclusion, selective blockade of 5-HT2A receptors by MDL100,907 elicits a discriminative stimulus in rats which appears to be specifically mediated via 5-HT2A as compared with 5-HT2B and 5-HT2C receptors.

Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats.

Although drug discrimination procedures have proven difficult to apply to antidepressant agents, we recently characterized discriminative stimulus properties of the selective serotonin (5-HT) reuptake inhibitor, citalopram, in rats. However, discriminative stimulus properties of selective norepinephrine (NE) reuptake inhibitors remain to be evaluated. We determined the potential discriminative stimulus properties of the highly selective NE reuptake inhibitor and antidepressant, reboxetine. Employing a two-lever discrimination procedure, rats were trained to discriminate reboxetine (2.5 mg/kg, IP) from saline. In parallel, the influence of reboxetine (2.5 mg/kg) upon dialysate levels of monoamines in frontal cortex and dorsal hippocampus of freely moving rats was determined. After 54+/-10 training sessions, reboxetine elicited robust stimulus recognition, fully generalizing to itself with an ED50 of 1.2 mg/kg. Two further NE reuptake inhibitors, desipramine (5.3) and maprotiline (1.8), as well as the 5-HT/NE reuptake inhibitor, venlafaxine (1.0), likewise generalized. In contrast, the 5-HT reuptake inhibitors, paroxetine, citalopram and sertraline, and the DA reuptake inhibitors, GBR12935 and bupropion, did not show significant generalization. Reboxetine markedly increased dialysate levels of NE, but not 5-HT, in frontal cortex and hippocampus. Dopamine (DA) levels were also (though less markedly) enhanced in frontal cortex. In parallel with an elevation in extracellular levels of NE, the selective NE reuptake inhibitor, reboxetine, elicits a specific discriminative stimulus in rats.

Self-administered ethanol as a discriminative stimulus in rats

The neurochemical and behavioral effects produced by drugs can differ based on whether self-administered or experimenter-administered. In addition, self-administered drugs, particularly those taken orally or by inhalation, have peripheral stimulus effects that are not present following experimenter administration. One drug with highly prominent peripheral stimulus effects when taken orally is ethanol. The purpose of the present experiment was to examine whether orally self-administered (SA) ethanol would serve as a discriminative stimulus and to determine if the peripheral effects of ethanol play a major role in the discriminative stimulus of orally SA ethanol. Twelve Long-Evans rats were trained to orally self-administer 750 mg/kg of 10% (w/v) ethanol and then discriminate that dose of ethanol from SA water. Six of twelve rats were successfully trained to discriminate oral SA ethanol from water. Intraperitoneal experimenter-administered and orally SA ethanol doses of 100–1320 mg/kg were tested for substitution. SA and i.p. ethanol doses of 750, 1000, and 1320 mg/kg fully substituted for the SA training dose. SA doses of 100, 320 and 560 mg/kg partially substituted for the SA ethanol training dose, whereas the 100 and 320 mg/kg i.p. ethanol doses did not substitute for SA ethanol. The ED 50 values for SA and i.p. ethanol were not significantly different from one another. The results indicate that SA ethanol can serve as a discriminative stimulus in rats and that i.p. ethanol can substitute for SA ethanol. In addition, the results also show that the discriminative stimulus effects of SA ethanol are primarily mediated by CNS drug effects.

(R)-methanandamide and Delta 9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide.

(R)-methanandamide (AM-356), a metabolically more stable chiral analog of the endocannabinoid ligand anandamide, was used as a representative of fatty acid ethanolamide CB1 receptor ligands to characterize the discriminative stimulus functions of anandamides. Rats discriminated between 10 mg/kg (R)-methanandamide and vehicle administered IP 15 min prior to session onset. Another group of rats was initially trained to discriminate between 3 mg/kg Delta9-THC and vehicle given IP 30 min prior to session onset; for anandamide testing, the animals were retrained with 1.8 and 5.6 mg/kg Delta9-THC. A two lever operant methodology (FR10) was used. Delta9-THC was more potent than (R)-methanandamide at both 15 and 30 min post-injection, irrespective of the training drug used. Additional tests with 10 and 18 mg/kg (R)-methanandamide suggested that the effects were declining by 1 h. The cannabinoid antagonist SR 141716 (0.3 and 1 mg/kg) produced rightward shifts in the Delta9-THC dose-response curve for Delta9-THC-appropriate responding and for (R)-methanandamide-appropriate responding (surmountable antagonism). SR-141716 (0.3 and 1 mg/kg) antagonized the ability of (R)-methanandamide to occasion either Delta9-THC-appropriate responding or (R)-methanandamide-appropriate responding. This antagonism was surmountable only at a dose of 0.3 mg/kg SR-1421716 in the (R)-methanandamide-trained rats. SR-141716 did not antagonize the rate-decreasing effects of (R)-methanandamide in either the Delta9-THC or the (R)-methanandamide trained rats. Response suppression precluded testing doses higher than 30 mg/kg (R)-methanandamide. Tests with SR-141716 (1 and 10 mg/kg) alone resulted in <3% Delta9-THC-appropriate responding. With 10 mg/kg SR-141716, response rate was significantly lower as compared to the rate observed during a vehicle test. Tests with anandamide (10 and 18 mg/kg) resulted in 41% and 85% (R)-methanandamide-appropriate responding at a 3-min pre-treatment time, but in a maximum of 15% (R)-methanandamide-appropriate responding at a longer (15 min) pre-treatment time. In the Delta9-THC (1.8 and 5.6 mg/kg) trained rats, anandamide never produced more than about 20% Delta9-THC-appropriate responding. The results add to a growing body of evidence indicating that there are both similarities and dissimilarities between classical cannabinoids such as THC and endogenous fatty acid ethanolamides.

The 5-HT 3 agent N -(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay

There is some, albeit conflicting, evidence that 5-HT3 receptors might be involved in the actions of abused stimulants. Most studies have focussed on examinations of 5-HT3 antagonists; this might be due to a lack of high-affinity 5-HT3 agonists that readily penetrate the blood-brain barrier. N-(3-Chlorophenyl) guanidine (MD-354) is a member of a novel class of 5-HT3 ligands developed in our laboratories. We have previously demonstrated that MD-354 can exert agonist effects and now further explore this action. Rats (n=9) were trained to discriminate 2 mg/kg MD-354 from saline vehicle in a two-lever drug discrimination task (VI-15 s schedule of reinforcement). The actions of agents with 5-HT3 character were evaluated. The emetic and antiemetic actions of MD-354 were also examined using the shrew as test subject. Various agents with demonstrated 5-HT3 agonist properties substituted for the MD-354 stimulus (MD-354 ED50=0.5 mg/kg): quipazine (ED50=0.2 mg/kg), meta-chlorophenylbiguanide (mCPBG, ED50=1.4 mg/kg), 2-methyl 5-HT (ED50=4.5 mg/kg), 1-(2-naphthyl)biguanide (2-NBG, ED50=1.9 mg/kg), and N-(2-naphthyl)guanidine (2-NG, ED50=0.7 mg/kg). Administration of the training dose of MD-354 in combination with the 5-HT3 antagonists zacopride and tropisetron resulted in stimulus antagonism (AD50=0.02 mg/kg); administered alone, however, zacopride engendered 81% MD-354-appropriate responding (ED50=0.03 mg/kg). MD-354 was shown to produce an emetic effect in the shrew at very high doses (i.e., 40 mg/kg); however, when administered in combination with cisplatin, MD-354 behaved as an antiemetic agent at 10 mg/kg. Taken together, the results indicate that MD-354 is a 5-HT3 agonist and that it might be an agent with partial agonist activity.

Lack of effects of glycine B receptor ligands on the psychostimulant-induced discriminative stimuli in rats

To examine the role of glycine B receptors in the stimulus effects induced by psychostimulants, separate groups of rats were trained to discriminate amphetamine (AMPH; 1 mg/kg) from saline (SAL), or cocaine (COC; 10 mg/kg) from SAL, using a two-lever operant procedure. Substitution studies showed that neither 1-aminocyclopropanecarboxylic acid (ACPC; 200 mg/kg) nor 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-(H)quinolone (L-701,324; 3 mg/kg), being a partial agonist or an antagonist at glycine B receptors, respectively, generalized for the training drugs. Combination tests of glycine B ligands demonstrated that injection of a fixed dose of ACPC (200 mg/kg) or L-701,324 (3 mg/kg) together with different doses of AMPH or COC practically did not modify dose-response curves of the psychostimulants, nor did it affect their ED 50 values. Our results indicate that glycine B receptors do not play a role in the discriminative effects of AMPH and COC.

Active cocaine immunization attenuates the discriminative properties of cocaine.

Anticocaine antibody, resulting from immunization with the cocaine-keyhole-limpet-hemocyanin (KLH) conjugate, weakened the ability of cocaine to act as a discriminative stimulus in rats. Subjects were given extensive training to discriminate 5.0 mg/kg of cocaine from saline prior to immunization. Several weeks following immunization with cocaine-KLH, subjects failed to reliably discriminate cocaine from saline. Nonimmunized control rats retained the ability to discriminate cocaine from saline throughout the experiment. These results further demonstrate that active immunization is effective in blunting cocaine effects. Immunized subjects were able to discriminate 20 mg/kg of cocaine, however, suggesting that anticocaine antibody may be overwhelmed by large cocaine doses.

A three-choice discrimination procedure dissociates the discriminative stimulus effects of d-amphetamine and (+/-)-MDMA in rats.

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA) produces subjective effects in humans that are similar to, but distinguishable from, those of psychostimulants. Drug discrimination studies in nonhumans have yielded inconsistent results regarding the similarities between MDMA and the psychomotor stimulant d-amphetamine. This study successfully used a 3-choice operant procedure to establish MDMA and d-amphetamine as discriminative stimuli in rats. Cocaine produced complete substitution for d-amphetamine, and LSD produced dose-dependent increases in MDMA-appropriate responding with nearly complete substitution (78%) for MDMA. The hallucinogen 2,5-dimethoxy-4-bromoamphetamine only partially substituted for MDMA and severely disrupted response rate. Fenfluramine and both isomers of 3,4-methylenedioxyamphetamine (MDA) all produced complete substitution for MDMA. The serotonin-receptor antagonist pirenpirone only partially blocked MDMA discrimination.

Hormones of the Hypothalamo–Pituitary–Gonadal Axis in Drug Discrimination Learning

DE BEUN, R. Hormones of the hypothalamo–pituitary–gonadal axis in drug discrimination learning. PHARMACOL BIOCHEM BEHAV 64(2) 311–317, 1999.—More than 30 years ago, T-maze studies with progesterone indicated that sex hormones have the potential to act as a discriminative stimulus in rats. Despite these early positive findings, the interest in discriminative stimulus properties of sex hormones remained low; few studies were dedicated to the investigation of discriminative stimulus properties of hypothalamo–pituitary–gonadal axis hormones (i.e., LHRH, LH/FSH, sex steroids). Nevertheless, the few studies that were published showed some interesting, and often sex-dependent results. Applying various methodologies (T-, or Y-maze, two-lever drug discrimination, taste aversion procedures), it was found that not only progesterone but also the two other principal sex steroids estradiol and testosterone can serve as discriminative stimuli in rodents. In addition to these gonadal hormones, the hypothalamic peptide LHRH (having a key role in the neuroendocrine regulation of steroid release from the gonads) appears to generate discriminative stimulus properties. Interestingly, recent (but preliminary) studies in postmenopausal women suggest that estradiol (and possibly progesterone) may also function as a discriminative stimulus in human subjects.