Stimuli effects

Many electrophysiological studies have shown that single-unit activity of noradrenergic neurons in the locus coeruleus is increased by sensory stimuli. Effective stimuli range from those causing physical discomfort (e.g. footshock) and interoceptive... 

Beltramino C. and Taleisnik S. (1983). Release of LH in the female rat by olfactory stimuli. Effect of the removal of the vomeronasal organs or lesioning of the accessory olfactory bulbs. Neuroendocrinology 36, 53-58. 

Besides such antigen-antibody reactions, which play a critical role in the pathogenesis of many allergic, anaphylactic, and hypersensitivity reactions, histamine also can be released from tissue stores in response to physical stimuli, effects of the so-called histamine liberators, a number of chemical substances, various drugs, and toxins. 

Beltramino, C., and S. Taleisnik Release of LH in the Female Rat by Olfactory Stimuli. Effect of the Removal of the Vomeronasal Organs or Lesioning of the Accessory Olfactory Bulbs. Neuroendocrinology 36, 53-58 (1983). 

As reviewed earlier in the section on the pharmacology of ethanol, several neurotransmitter systems appear to influence the reinforcing or discriminative stimulus effects of ethanol. Although these systems appear to function interactively in their influences on drinking behavior, the medications that have been employed to treat alcohol dependence affect neurotransmitter systems relatively selectively. Consequently, these systems will be discussed individually here. 

Hundt W, Holter SM, Spanagel R Discriminative stimulus effects of glutamate release inhibitors in rats trained to discriminate ethanol. Pharmacol Biochem Behav 59 691-695, 1998... 

Quertemont E, Grant KA Role of acetaldehyde in the discriminative stimulus effects of ethanol. Alcohol Clin Exp Res 26 812—817, 2002... 

Glennon RA et al. (1988) NAN-190 an cU ylpiperazine analog that antagonizes the stimulus effects of the 5-HTlA agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur J Pharmacol 154(3) 339-341... 

To summarize the data in table 1, neither MDMA nor MBDB has hallu-cinogen-like discriminative stimulus properties. Symmetrical transfer of the MDMA and MBDB stimulus indicates that their primary discriminative stimulus effects are very similar. For both MDMA and MBDB, there is enantioselectivity for the S isomer, with about a twofold eudismic ratio. Finally, the substitution of (- )-amphetamine and cocaine in MDMA-trained rats may indicate that MDMA has some psychostimulant-like properties, while hffiDB seems to lack this activity. 

However, the specific serotonin uptake inhibitor fluoxetine failed to produce an MBDB-like cue and failed to block the stimulus effects of MBDB when it was given prior to a training dose of MBDB. Table 3 summarizes results of fluoxetine testing in MBDB-trained rats. In other exploratory studies, pretreatment of MDMA-trained rats with either methysergide or ketanserin failed to block completely the MDMA-discriminative stimulus. 

Glennon. R.A., and Young, R. MDA A psychoactive agent with dual stimulus effects. Life Sci 34 379-383, 1984b. 

Examination of the stimulus properties of a large number of phenalkylamines and related derivatives shows many can be characterized as producing either AMPH-like stimulus effects or DOM-like stimulus effects. The structures of some of these agents are shown in figure 1. Certain other agents could not be reliably classified as either AMPH-like or DOM-like because, at the highest dose tested, they either produced vehicle-appropriate (i.e., saline-appropriate) responding or resulted in disruption of behavior. 

Various phenallcylamines were shown to produce either DOM-like or AMPH-like stimulus effects the structure-activity requirements for these activities are different from the standpoints of aromatic substitution patterns, terminal amine substituents, and optical activity. Thus, it has been possible to formulate two distinct SARs. It should be realized, however, that phenalkylamines need not produce only one of these two types of effects certain phenallcylamines can produce pharmacological effects like neither DOM nor AMPH. Moreover, they can produce effects that are primarily peripheral, not central, in nature (Glennon 1987a). The fact that an agent produced DOM- or AMPH-like effects does not imply that it carmot produce an additional effect conversely, if an agent does not produce either DOM- or AMPH-like stimulus effects, it is not necessarily inactive. 

Methoxy-Substituted Derivatives. Phenalkylamines lacking aromatic substituents do not produce DOM-like stimulus effects. None of the three possible monomethoxy derivatives, 2-methoxy-(OMA), 3-methoxy-(MMA), or 4-methoxyphenylisopropylamine (PMA), produce DOM-like effects. Of the six dimethoxy analogs (DMAs) (i.e., 2,3-DMA, 2,4-DMA, 2,5-DMA, 2,6-DMA, 3,4-DMA, and 3,5-DMA), only the 2,4- and 2,5-dimethoxy derivatives 2,4-DMA and 2,5-DMA, respectively, are active. These two agents are essentially equipotent and are approximately one-tenth as potent as DOM. For purposes of comparison, the potencies of 2,5-DMA and DOM are 23.8 and 1.8 pmol/kg. Five trimethoxy analogs (TMAs) have been examined 2,3,5-TMA is approximately one-third as potent as... 

DMA. None of the three possible tetramethoxy analogs has been investigated, and the pentamethoxy analog does not produce DOM-like stimulus effects. From these studies, it is apparent that the 2,4- and 2,5-dimethoxy substitution pattern plays an important role certain 2.6-dimethoxy derivatives are also active, depending upon what substituents are present at the 4-position. 

TMA, to produce mescaline, results in a similar (i.e., 2.5-fold) decrease in activity. Although these a-desmethyl analogs produce stimulus effects similar to those of DOM, there is some evidence that the spectrum of effects produced by these agents, in rats and in humans, is not... 

Ephedrine, for example, produces weak AMPH-like activity (Huang and Ho 1974b). (+)Norpseudoephedrine (cathine) also produces AMPH-like stimulus effects. The oxidized analogs of norephedrine and ephedrine, cathinone and methcathinone, respectively, however, are potent AMPH-like agents (table 2). 

MDA) does not produce AMPH-like effects. The 3-OH, 4-OMe, and the 3-OMe 4-OH analogs of amphetamine are also inactive. Thus, it is surprising that 3,4-MDA possesses AMPH-like character. Likewise, neither MMA, PMA, nor 3,4-DMA produce DOM-like effects yet 3,4-MDA does. 2-Methoxy 4,5-MDA (MMDA-2) and 2,4,5-TMA share a common substitution pattern interestingly, these agents are essentially equipotent in producing DOM-like stimulus effects. Table 3 displays selected results. 

Recent work shows that, in rodents, MDMA is metabolized, at least in part, to MDA, and that racemic MDMA is preferentially metabolized to 5 (+)MDA (Fitzgerald et al. 1987). The extent to which MDMA metabolites might contribute to the stimulus properties of MDMA is unknown at this time. Because 5 (-b)MDA is capable of producing AMPH-like stimulus effects, involvement of this metabolite might explain some of the different results reported for MDMA (particularly if different animal species and various presession injection intervals were employed). In contrast, certain other potential metabolites of MDMA, such as 3-hydroxy-PMA, 4-hydroxy-MMA, 3,4-dihydroxy-AMPH (a-tnethyldopamine), N-methyl-3-hydroxy-PMA, N-methyl-4-hydroxy-MMA, N-methyl-3,4-dihydroxy-AMPH (N-methyl-a-methyldopamine) do not produce AMPH-like stimulus effects, but may be capable of producing other, distinct types of central activity or may somehow interfere with potential AMPH-like effects. 

Phenalkylamine analogs appear to produce central stimulus effects along AMPH-like to DOM-like continuum, depending upon the substituent groups present... 

NOTE (A.) MDA produces both types of stimulus effects. (B.) Trifurcated model is presented to account for a possible third, as yet undefined, type of central effect. Certain phenalkylamines may exert effects better described by the MDA component of this model than by either pure AMPH-like or DOM-like action. 

Teal, J.J., and Holtzman, S.G. Discriminative stimulus effects of cyclazocine in the rat. J. Pharmacol Fxp Ther 212 368-376, 1980. Tempel, A. Gardner, E-L. and Zukin, R.S. Visualization of opiate receptor upregulation by light microscopy autoradiography. Proc Natl Acad Sci USA 81 3893-3897, 1984. 

Shannon, H.E. Discriminative stimulus effects of phencyclidine Structure-activity relationships. In Kamenka, J.M. Domino,... 

Herling, S. Solomon, R.E. and Woods, J.H. Discriminative stimulus effects of dextrorphan in pigeons. J. Pharmacol Exp Ther 227 723-731, 1983. 

Herling, S. Coale, E.H., Jr. Hein, D.S. Winger, G. and Woods, J.H. Similarity of the discriminative stimulus effects of keta-mine, cyclazocine, and dexoxadrol in the pigeon. Psvchopharma-coloav (Berlin) 73 286-291. 1981. 

Teal, J.J., and Holtzman, S.G. Discriminative stimulus effects of prototype opiate receptor agonists in monkeys. Fur J Pharmacol 68 1-10, 1980. 

The discriminative stimulus effects of PCP differ considerably from those of other drugs of abuse (Poling et al. 1979 Shannon 1981). Animals do not generalize from PCP to other drugs of... 

Among the more important series of discoveries in behavioral research with PCP are the reports that drugs chemically distinct from PCP also have PCP-like discriminative stimulus effects. 

Shannon, H.E. Discriminative stimulus effects of phencyclidine Stucture-activity relationships. In Kamenka, J.M. Domino, E.F. and Geneste, P., eds. Phencyclidine and Related Arvl -cvcl ohexami nes Present and Future Appli cati ons. Ann Arbor ... 

JH. Discriminative stimulus effects of BW373U86 a nonpeptide ligand with selectivity for delta opioid receptors. J Pharmacol Exp Ther 1993 267 888-895. 

Ranaldi, R., Anderson, K.G., Carroll, F.I., Woolverton, W.L. Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys interaction with methamphetamine. 

Munzar, P., Laufert, M.D., Kutkat, S.W., Novakova, J., Goldberg, S.R. Effects of various serotonin agonists, antagonists, and uptake inhibitors on the discriminative stimulus effects of methamphetamine in rats. J. Pharmacol. Exp. Ther. 291 239, 1999. 

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