James B. Appel

Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine

Evidence suggests that stimulants such asd-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D1 and D2) exist, we investigated the role of both of these receptor subtypes in mediating the internal “state” produced by these stimulants. Two groups of rats (N=8/group) were trained to discriminate intraperitoneal (IP) injections of eitherd-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D1 and D2 agonists and antagonists. The D2 agonist quinpirole (0.0313–0.125 mg/kg) mimicked both stimulant cues while the D1 agoinst SKF 38393 (5–20 mg/kg) substituted partially for cocaine but notd-amphetamine. Combination tests with DA antagonists indicated that both the D1 antagonist SCH 23390 (0.0063–0.25 mg/kg) and the D2 antagonist haloperidol (0.125–0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) ford-amphetamine was blocked by both DA antagonists. The ability of both D1 and D2 antagonists to attenuate the stimulus effects ofd-amphetamine and cocaine raises the possibility that a synergistic (“enabling”) interaction between D1 and D2 receptors may modulate stimulant cues.

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D2 against LY-171555 (0.05–0.25 mg/kg); but not to the D1 agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D1 antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D2 antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D1or D2 receptor activation; for example, the stimulus properties of this substance might involve both D1and D2 receptor activation.

An analysis of some discriminative properties of d-amphetamine

Male albino rats were trained and tested on a two-lever discrimination task based upon the presence or absence of d-amphetamine (1.0 mg/kg). This compound was found to produce strong discriminative cues (i.e., 90% correct choice behavior). A dose-effect function was then ascertained and the discriminative ED50 (following training with 1.0 mg/kg) was found to be 0.23 mg/kg d-amphetamine.In order to determine the effective duration of d-amphetamine action, the interval between injection and testing was varied; it was found that the discriminative effects of the drug began to dissipate between 60 and 90 min post-injection.In an attempt to compare the discriminative cues of other drugs with those of d-amphetamine, injections of LSD (0.04 and 0.08 mg/kg), psilocybin (0.50 and 1.0 mg/kg), THC (0.50 and 1.0 mg/kg), mescaline (5.0 and 10.0 mg/kg), and caffeine (6.0 and 20.0 mg/kg) were given during extinction. In all cases, the rats responded predominantly on the saline-related lever. Only methamphetamine (1.0 mg/kg) produced d-amphetamine-like responding.Finally, alpha-methyl-para-tyrosine (AMPT), a compound which depletes brain catecholamines (CA), was found to disrupt the d-amphetamine-saline discrimination.

Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD).

The neuropharmacological mechanisms underlying the behavioral effects ofd-lysergic acid diethylamide (LSD) were assessed by comparing the discriminative stimulus properties of LSD with those of agonists and antagonists that act selectively at putative serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes (5-HT1 and 5-HT2). Male Sprague-Dawley rats (N=23) were trained to discriminate LSD (0.08 mg/kg) from saline and given substitution tests with the following agents: 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT; 0.02–0.64 mg/kg), Ru 24969 (0.2–3.2 mg/kg),m-chlorophenylpiperazine (MCPP; 0.1–1.6 mg/kg), 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.1–1.6 mg/kg), and quipazine (0.2–3.2 mg/kg). Only quipazine mimicked LSD. In combination tests, BC 105 (0.2–3.2 mg/kg), 2-bromolysergic acid diethylamide (BOL; 0.1–1.6 mg/kg), Ly 53857 (0.4–3.2 mg/kg), metergoline (0.05–0.8 mg/kg), ketanserin (0.2–3.2 mg/kg), and pipenperone (0.0025–0.08 mg/kg), all of which act as 5-HT2 antagonists, blocked the LSD cue; only spiperone (0.02–0.32 mg/kg) was without effect. Although commonalities may exist among “5-HT agonists”, the present results demonstrate that such “agonists” are not identical. Since putative 5-HT1 agonists do not mimic LSD and the LSD cue is potently blocked by 5-HT2 antagonists, it appears that 5-HT2 neuronal systems are of greater importance than 5-HT1 systems in mediating the discriminative stimulus and, perhaps, other effects of LSD.

The discriminative stimulus properties of LSD: Mechanisms of action☆

Abstract The CNS correlates of d -lysergic acid diethylamide (LSD) actions were investigated by means of a sensitive and specific behavioural assay procedure. Rats were trained to discriminate D-LSD from saline in two lever operant chambers. After intraperitoneal injections of 0.08 mg/kg of LSD, reinforcement could be obtained only by responding on one particular lever (left or right); responding on the opposite lever was reinforced only after saline injections. Once the LSD and saline exerted reliable stimulus control over lever choice (85% correct), rats were tested with various agents which alter the functional activity of the transmitter-containing neuronal systems. l -Tryptophan, chlorimipramine and fluoxetine, all of which increase the synaptic availability of serotonin, neither blocked nor, by themselves, mimicked (transferred to) LSD. However, quipazine, a putative serotonin agonist, produced an almost complete (78%) transfer to LSD. The presumed serotonin antagonists: methiothepin, 2-bromo-D-lysergic acid diethylamide, methysergide, cyproheptadine and cinanserin, blocked the LSD cue in a dose-related manner. The potent dopamine antagonists: haloperidol, fluphenazine, trifluoperazine, α-flupenthixol, and (+)-butaclamol, were without effect on the discriminability of LSD as were α- and β-adrenergic, cholinergic and histaminergic antagonists. Apomorphine, a dopamine agonist, produced a partial transfer to LSD. These data indicate that the discriminative stimulus properties of LSD may be mediated by post-synaptic serotonin or LSD receptors. Dopamine receptors did not seem to be involved in the LSD stimulus cue.

Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) has effects both characteristic of a serotonin (5-hydroxytryptamine; 5-HT) agonist and antagonist. To investigate the mechanism(s) of action of 8-OHDPAT in vivo, rats were trained to discriminate 8-OHDPAT (0.4 mg/kg) from saline and given various neuroactive compounds during substitution test sessions. Of the 5-HT agonists tested, d-lysergic acid diethylamide, 5-methoxy-n,n-dimethyltryptamine, quipazine, Ru 24969 and 1-(m-trifluoromethylphenyl) piperazine did not mimic the training drug; the dopamine agonists apomorphine and SKF 38393 as well as the alpha 2-adrenoceptor agonist clonidine engendered predominantly saline-lever responding. However, the novel anxiolytics buspirone and ipsapirone as well as the ergot derivative lisuride substituted completely for 8-OHDPAT. In combination tests, 5-HT (ketanserin, metergoline, methysergide, pirenperone), dopamine (haloperidol) and norepinephrine antagonists (prazosin, propranolol) failed to attenuate the 8-OHDPAT cue. The similar stimulus properties of 8-OHDPAT and the novel anxiolytics (buspirone, ipsapirone) are mirrored by the common abilities of these agents to selectively inhibit 5-HT1A binding and release punished responding. Thus, the subpopulation of 5-HT1A receptors may mediate the behavioral effects of these compounds in animals and, in turn, the anxiolytic effects of buspirone and ipsapirone in humans. Although not primarily selective for 5-HT, lisuride may also mimic 8-OHDPAT by direct or indirect stimulation of 5-HT1A receptors.

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED50 of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substututions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.

Signal detection theory and the psychophysics of pain: an introduction and review.

&NA; A brief explanation of signal detection theory is presented, followed by a review of the literature in which differences in pain report were analyzed to determine if changes were in sensitivity (physiological processes) or in response bias (a subjects willingness to report that a signal occurred). Three kinds of studies are reviewed: modification, procedural, and comparative and normative. The advantages of using a signal detection approach in pain research are emphasized. It is concluded that experimenters applying signal detection analysis to pain research should give greater consideration to methodological procedures and be cognizant of all possibilities for shifts in sensitivity (d′).

Discriminative stimulus properties of the serotonin agonist MK 212

In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969, and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) failed to substitute completely. The 5-HT1/5-HT2 antagonists BC 105, metergoline, and methysergide completely blocked the MK 212 cue, while the selective 5-HT2 antagonists ketanserin and pirenperone, the dopamine antagonists haloperidol and spiperone, and the beta-noradrenergic antagonist propranolol were without effect. The substitutions of fenfluramine and MCPP for MK 212 support a role for 5-HT in the MK 212 cue; however, the lack of substitution of many other 5-HT agonists is difficult to explain. The complete antagonism by 5-HT1/5-HT2 but not by selective 5-HT2, antagonists suggests the possibility that 5-HT1 receptors mediate the stimulus properties of MK 212. Further research is needed to support this hypothesis and to investigate the relative role of 5-HT and other neurotransmitters in the stimulus effects of MK 212.

Discriminative stimulus properties of quipazine: Direct serotonergic mediation

Rats were trained to discriminate intraperitoneal injections of quipazine (1.0 mg/kg) from saline in a two-lever drug discrimination task. After reliable levels of accuracy (> 85%) were attained, various agents which alter the functional activity of serotonergic (5-HT) neuronal systems were tested either alone or in combination with quipazine. Neither the 5-HT precursor, l-tryptophan, nor the 5-HT re-uptake inhibitors, fluoxetine and citalopram (Lu 10-171), either alone or in combination, elicited responding on the quipazine-appropriate lever. However, fenfluramine, a drug which releases endogenous 5-HT from nerve terminals, produced 84% quipazine-like responding. The dopamine (DA) agonists, apomorphine and amphetamine, did not transfer to quipazine. Of the several neurotransmitter antagonists tested, those which block 5-HT were also found to block the quipazine cue. Para-chlorophenylalanine (PCPA), which depletes central 5-HT by inhibiting its synthesis, significantly potentiated a sub-threshold dose (0.25 mg/kg) of quipazine and reduced the transfer of fenfluramine to quipazine, suggesting that quipazine exerts its discriminatory effect by directly stimulating central 5-HT receptors. Since the potent hallucinogen, d′lysergic acid diethylamide (LSD). has been shown to transfer to a relatively high dose of quipazine (2.5 mg/kg), this compound and other known hallucinogens were tested for transfer to the dose of quipazine (1.0 mg/kg) used in the present experiment. Mescaline, LSD, and psilocybin all produced strong transfers to the quipazine cue. These data suggest the possibility that quipazine may possess hallucinogenic properties.