Relative Reinforcing Strength of ThreeN-Methyl-d-Aspartate Antagonists with Different Onsets of Action

Abstract

The potential contribution of onset and duration of pharmacological action to the reinforcing strength of three intravenously delivered N-methyl-D-aspartate antagonists was evaluated in this study. The onsets and durations of action of ketamine, phencyclidine, and dizocilpine were evaluated by observation and tabulation of their behavioral effects in rhesus monkeys after i.v. administration. The reinforcing effects of each drug were tested in a paradigm in which the fixed ratio requirements for i.v. drug injection were increased systematically. The peak observable effect of ketamine occurred immediately after its administration. There were some immediately observable effects of phencyclidine, although the peak effect of phencyclidine was delayed for 3 to 10 min. Dizocilpine had few immediate effects and a peak effect 32 min after administration. Ketamine had the shortest duration of action, followed by phencyclidine and dizocilpine. Analysis of demand curves and response output curves that were normalized to account for potency differences among the drugs revealed that ketamine and phencyclidine were equally effective as reinforcers, and they were both much stronger reinforcers than was dizocilpine. The data therefore suggest that a fast onset of action increases the reinforcing strength of drugs, although duration of action may play a role as well.

Unconditioned Behavioral Effects of the Powerful κ-Opioid Hallucinogen Salvinorin A in Nonhuman Primates: Fast Onset and Entry into Cerebrospinal Fluid

“…It is also known that fast onset exacerbates the abuse potential of compounds from different pharmacological classes (Winger et al, 2002;Spencer et al, 2006;Yano and Steiner, 2007); it is unknown whether this is of relevance to the broad experimentation with salvinorin A-containing products in humans. Therefore, we carried out follow-up studies using two specific endpoints, facial relaxation and ptosis, because these endpoints have several advantages: 1) they are more easily quantifiable that rating scale data (above); 2) they are more amenable to the study of ultrafast onset and detailed time course analysis, compared with rating scale data; 3) they are translationally viable (i.e., easily quantifiable in humans); and 4) they are putatively mediated by more defined neuroanatomical/cranial nerve pathways, thus aiding mechanistic interpretation of behavioral and neuroimaging studies.…”

Exposure to Δ-9-Tetrahydrocannabinol (THC) Increases Subsequent Heroin Taking but not Heroin's Reinforcing Efficacy: A Self-Administration Study in Rats

“…heroin injections as the price is varied. Demand curves were calculated using nonlinear regression following the normalization procedure described by Hursh and Winger (1995); see also Giordano et al (2001) and Winger et al (2002). This procedure determines the consumption of heroin at the lowest price for each dose, and then compares the consumption at higher prices to this value.…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…The relationship of these ICSS data to drug self-administration data is less clear. MK801, PCP, ketamine, and memantine all maintain drug selfadministration (Marquis and Moreton, 1987;Koek et al, 1988;Nicholson et al, 1998;Winger et al, 2002). In addition, a behavioral economic analysis of drug self-administration in rhesus monkeys suggested a hierarchy for reinforcing efficacies of ketamine = PCP .…”

“…In addition, a behavioral economic analysis of drug self-administration in rhesus monkeys suggested a hierarchy for reinforcing efficacies of ketamine = PCP . MK801, a hierarchy that aligned with their rates of onset (Winger et al, 2002) but not with their relative efficacies to facilitate ICSS. This apparent discrepancy in abuse-related effects for NMDA channel blockers in ICSS versus drug self-administration procedures would benefit from further study.…”