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Preclinical studies on the reinforcing effects of cannabinoids. A tribute to the scientific research of Dr. Steve Goldberg - PubMed

Review

Preclinical studies on the reinforcing effects of cannabinoids. A tribute to the scientific research of Dr. Steve Goldberg

Gianluigi Tanda. Psychopharmacology (Berl). 2016 May.

Abstract

Rationale: The reinforcing effects of most abused drugs have been consistently demonstrated and studied in animal models, although those of marijuana were not, until the demonstration 15 years ago that delta-9-tetrahydrocannabinol (THC) could serve as a reinforcer in self-administration (SA) procedures in squirrel monkeys. Until then, those effects were inferred using indirect assessments.

Objectives: The aim of this manuscript is to review the primary preclinical procedures used to indirectly and directly infer reinforcing effects of cannabinoid drugs.

Methods: Results will be reviewed from studies of cannabinoid discrimination, intracranial self-stimulation (ICSS), conditioned place preference (CPP), as well as change in levels of dopamine assessed in brain areas related to reinforcement, and finally from self-administration procedures. For each procedure, an evaluation will be made of the predictive validity in detecting the potential abuse liability of cannabinoids based on seminal papers, with the addition of selected reports from more recent years especially those from Dr. Goldberg's research group.

Results and conclusions: ICSS and CPP do not provide consistent results for the assessment of potential for abuse of cannabinoids. However, drug discrimination and neurochemistry procedures appear to detect potential for abuse of cannabinoids, as well as several novel "designer cannabinoid drugs." Though after 15 years transfer of the self-administration model of marijuana abuse from squirrel monkeys to other species remains somewhat problematic, studies with the former species have substantially advanced the field, and several reports have been published with consistent self-administration of cannabinoid agonists in rodents.

Keywords: Addiction; Cannabis; Delta-9-THC; Dopamine neurochemistry; Drug discrimination; Marijuana substance use disorders; Place conditioning; Self-administration; Spice.

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Conflict of interest statement

The author declares no conflict of interests.

Figures

Figure 1
Figure 1. β-endorphins in the VTA mediate central THC actions

Panel A shows that local intra VTA, but not intra-accumbens shell, injections of β-endorphins potentiate the discriminative effects of small doses of THC, measured by % increase in THC appropriate lever selection, in rats trained to discriminate the subjective effects of THC 3 mg/kg i.p. from THC-Vehicle i.p. Panels B and C show that administration of THC, 3 mg/kg i.p., but not its vehicle, stimulates β-endorphin levels in dialysates from the VTA but not significantly from the accumbens shell. Modified from Solinas et al 2004. See text and the original article for more details about experimental procedures and results.

Figure 2
Figure 2. Effects of changing the time between THC sessions on place conditioning

Panel A shows effects of THC when conditioning sessions with THC were conducted 48 hours apart. Potential dysphoric effects of THC were hypothesized to reduce the likelihood of place preference at low THC doses (1 mg/kg i.p.). In Panel B with 96 hours between THC injections, there was a significant place preference at 1 mg/kg i.p., but also place aversion at higher doses. Modified from Lepore et al 1995. See text and the original article for more details about experimental procedures and results.

Figure 3
Figure 3. Neuroanatomical probe placements and neurochemical effects of WIN55,212-2 self-administration in Sprague-Dawley rats

Top Panel. Schematic drawings showing the location of microdialysis probes in the nucleus accumbens shell or core in rats self-administering WIN55,212-2 (12.5 µg/kg/infusion). Bottom panel shows the time course of changes from basal DA levels in dialysates from the shell and core of the nucleus accumbens in rats during 4 weeks (12 sessions) of WIN55,212-2 self-administration. Modified from Lecca et al 2006. See text and the original article for more details about experimental procedures and results.

Figure 4
Figure 4. Neuroanatomical location of THC injections and number of self-infusion of THC in the shell or VTA as a function of daily sessions

Top panels (A and B) show the location of THC site infusions in the anterior, intermediate or posterior shell, or in the core, and in the anterior, posterior, or dorsal to posterior VTA, or in the substantia nigra. Panels C and D show the number of self-infusions of THC into different accumbens (C) or midbrain (D) sites, earned by rats during consecutive sessions. Session number 4 was characterized by substitution of THC by its vehicle. Modified from Zangen et al, 2006. Please see text or the original article for more details about experimental procedures and results..

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