David J. Mokler

The 5HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs ☆

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.

Self-administration of central stimulants by rats: A comparison of the effects of d-amphetamine, methylphenidate and McNeil 4612

Rats were trained to press a lever for the intravenous administration of d-amphetamine. The rate of responding was decreased in a dose-dependent and time-related manner by non-contingent injections of d-amphetamine, methylphenidate or McNeil 4612. Methylphenidate and McNeil 4612 also maintained self-administration behavior when they were substituted for d-amphetamine, whereas substitution of saline for d-amphetamine resulted in extinction of the self-administration behavior. These data suggest that methylphenidate and McNeil 4612, like d-amphetamine, can act as reinforcers in rats.

Behavioral effects of intracerebroventricular administration of LSD, DOM, mescaline or lisuride

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 micrograms) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 micrograms. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 micrograms). DOM (40 to 120 micrograms) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 micrograms ICV vs. 153 micrograms IP). Mescaline was much more potent in disrupting FR-40 behavior by the ICV route than by IP administration. The ICV ED50 for doses of mescaline increasing pause intervals was 74 micrograms, in contrast to an ED50 following systemic administration of 2251 micrograms, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 micrograms ICV and 4 micrograms IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of the initial treatment phenomenon to diazepam in the rat

The initial treatment phenomenon (ITP) to diazepam was investigated using a conditioned suppression of drinking (CSD) paradigm. Female Sprague-Dawley rats were trained to a stable baseline of punished and unpunished responses in the CSD paradigm. In Experiment 1, a control group (1) received vehicle after the CSD session on each of seven drug test days, while group 2 was treated with 3.0 mg/kg diazepam IP after each of these sessions. On drug test days 8–12, diazepam was administered to both groups before the CSD session. Drug test days were separated by 2–3 days when the animals were untreated but performed in the CSD. Prior exposure to diazepam in group 2 after sessions 1–7 conditioned the animals so that a greater release in punished behavior was seen during sessions 8–12 than in the control group (1). In Experiment 2, one group (3) of rats was administered diazepam vehicle after the CSD session for 4 drug test days and another group (4) was injected with 5.6 mg/kg diazepam after the CSD session on these same days. On the next 4 drug test days both groups received diazepam before they performed in the CSD. An ITP was observed in both the control (3) and the drug-conditioned (4) group, although the ITP was less obvious in the conditioned group. After a 28-day period of CSD exposure without vehicle or drug treatments, 5.6 mg/kg diazepam was administered to both groups before the CSD session for an additional 8 drug test days. During this last period both groups exhibited an ITP with no essential differences. These experiments demonstrate that the initial treatment phenomenon is complex, involving several components that include a behavioral tolerance to the disruptive effect of diazepam.

The behavioral effects of hallucinogens in rats following 5,7-dihydroxytryptamine administration into the medial forebrain bundle

The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 micrograms/2 microliter) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratio-40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.

Naloxone alters the effects of LSD, DOM and quipazine on operant behavior of rats

Administration of the indolealkylamine hallucinogen d-lysergic acid diethylamide (LSD), the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine all produced a dose-dependent decrease in fixed ratio (FR-40) response rates and a concomitant increase in the number of 10-second pause intervals. Although naloxone (4.0 mg/kg) had no effect on FR-40 responding per se, the pause-producing effects of LSD and, to a lesser extent, DOM were potentiated by pretreatment with naloxone. The action of quipazine on reinforcers was unaffected by combination with naloxone, while the effect on pause intervals was slightly attenuated by naloxone pretreatment. These data and previous studies suggest that the pause-producing effects of indolealkylamine and phenethylamine hallucinogens reflect their activation of a selective portion of brain 5-HT receptors. The potentiation of these effects by naloxone may relate to a modulation of central 5-HT systems by endogenous opioid mechanisms tending to restore an imbalance in various 5-HT pathways caused by the hallucinogenic 5-HT agonists. The more generalized disruptive effects of quipazine on brain 5-HT systems may be less susceptible to the endogenous opioid modulation or may actually combine with it to induce a greater disruption.

The effects of intracranial administration of hallucinogens on operant behavior in the rat. I: Lysergic acid diethylamide

Lysergic acid diethylamide (LSD) was infused in one microliter volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, LSD (8.6 to 86 micrograms) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 micrograms for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 micrograms. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intracranial administration of hallucinogens on operant behavior in the rat. II. 2,5-Dimethoxy-4-methylamphetamine (DOM)☆

2,5-Dimethoxy-4-methylamphetamine (DOM) was infused into discrete brain regions of rats trained to press a bar for food reinforcement on a fixed ratio-40 (FR-40). Sites were chosen as major areas of the brain 5-hydroxytryptamine (5-HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted with stainless steel cannulae into the brain area to be examined. Bilateral cannulae were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, DOM (20-300 micrograms) was tested on operant behavior by infusing the drug immediately before the operant session. Infusion of vehicle was inactive. DOM produced a dose-dependent decrease in reinforcements and a concomitant increase in 10-sec periods of non-responding (pause intervals). DOM was more potent when infused into the median raphe nucleus than following intracerebroventricular (ICV) administration. DOM was less potent when infused into the dorsal raphe, prefrontal cortex or dorsal hippocampus. Infusion of DOM into the lateral habenular nuclei produced a biphasic dose-response curve. ED50s for increases in pause intervals were 47, 77, 92, 103, and 114 micrograms for infusion into the median raphe, dorsal raphe, prefrontal cortex, lateral habenulae, and dorsal hippocampus, respectively. The ED50 for ICV administration in a previous study was 58 micrograms. The effects of DOM in the lateral habenulae could be divided into two curves; one curve had an ED50 of 69 micrograms, whereas the other had an ED50 of 176 micrograms. Furthermore, the dose-response curve for IP administration of DOM was shifted to the left in animals with cannulae placed into the lateral habenular nuclei. No change was seen in the response to IP administration of DOM in animals cannulated in the remaining sites or in animals with ICV cannulae. Therefore, the effects of DOM in disrupting operant behavior may be more critical with regard to its actions in the lateral habenulae and median raphe. Nonetheless, actions at multiple brain sites probably contribute to the total behavioral effects of the drug.