Effects of endocannabinoid neurotransmission modulators on brain stimulation reward, Styliani Vlachou et al., 2006

Effects of endocannabinoid neurotransmission modulators on brain stimulation reward

Styliani Vlachou, George G. Nomikos & George Panagis

Psychopharmacology, 2006, 188, 293–305

Doi : 10.1007/s00213-006-0506-0



Rationale : The endogenous cannabinoid system is responsive to the neurobiological actions of Δ9-tetrahydrocannabinol (THC) and other cannabinoid ligands. While numerous studies have focused on the behavioral and pharmacological effects of THC and cannabinoid agonists in experimental animals, most recent work focuses on compounds that modulate endocannabinoid neurotransmission. However, the relevant studies concerning the ability of endocannabinoid modulators to modify reward processes in
experimental animals remain rather scarce.

Objectives : The present study examined the effects of drugs modulating endocannabinoid neurotransmission on brain reward function using the rate–frequency curve shift paradigm of intracranial self-stimulation (ICSS).

Methods : Animals were implanted with electrodes into the medial forebrain bundle (MFB). After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of the fatty acid amide hydrolase (FAAH) inhibitors phenylmethylsulfonyl fluoride (PMSF) (0, 15, 30, and 60 mg/kg) and URB-597 (0, 0.3, 1, and 3 mg/kg) and the selective anandamide reuptake inhibitor OMDM-2 (0, 3, 10, and 30 mg/kg).

Results : The highest dose of URB-597 and OMDM-2 significantly increased the threshold frequency required for MFB ICSS, while PMSF increased the threshold frequency in all doses tested. The cannabinoid 1 (CB1) receptor antagonist SR141716A reversed the actions of URB-597 and OMDM-2, but not PMSF, without affecting reward thresholds by itself.

Conclusions : These results indicate that under the present experimental conditions endocannabinoid modulators do not exhibit reinforcing properties, but rather have inhibitory influence on reward processes. The anhedonic effects of URB-597 and OMDM-2, but not PMSF, observed at the highest doses in this study are probably mediated through direct CB1 receptor stimulation.

Keywords : Intracranial self-stimulation . Endogenous cannabinoids . Anandamide transport .
Reward . Fatty acid amide hydrolase (FAAH) . Phenylmethylsulfonyl fluoride (PMSF) .OMDM-2 . URB-597 . SR141716A



Within the last 15 years, the discovery of the endogenous cannabinoid system has boosted cannabinoid pharmacology and led to an increasing number of investigations on its role in physiology and pathophysiology and on the therapeutic potential of compounds that modify endocannabinoid neurotransmission. In the brain, this endocannabinoid system is mainly comprised by the cannabinoid 1 (CB1) receptor and its endogenous ligands with cellular mechanisms for their production, release, and degradation (Ameri 1999; Chaperon and Thiébot 1998; Tanda and Goldberg 2003; Bisogno et al. 2005; Fowler et al. 2005; Pazos et al. 2005). It is generally accepted that the endocannabinoid system plays a modulatory role in the control of motor behavior, learning and memory, nociception, emesis, appetite, and mood (Inui 2001; Romero et al. 2002; Fowler et al. 2005; Kirkham 2005; Lundqvist 2005; Vickers and Kennett 2005; Viveros et al. 2005). Among the endogenous cannabimimetic substances, anandamide is as yet the best studied and known. Anandamide is released on demand by stimulated neurons; it binds to and activates cannabinoid receptors with relatively high affinity, potency, and efficacy and is rapidly eliminated through a two-step process consisting of a carrier-mediated transport followed by intracellular hydrolysis (Di Marzo et al. 1994; Beltramo et al. 1997; Giuffrida et al. 1999). Recently, an anandamide transport process was identified (Moore et al. 2005), while anandamide hydrolysis is catalyzed by the enzyme fatty acid amide hydrolase (FAAH), a membrane-bound serine hydrolase (Cravatt et al. 1996; Patricelli et al. 1999).

Recent studies have provided strong experimental evidence that endogenous cannabinoids are released from depolarized postsynaptic neurons and act retrogradely onto presynaptic neurons to suppress subsequent neurotransmitter release (Maejima et al. 2001; Wilson and Nicoll 2001; Freund et al. 2003). This neuromodulatory action of endocannabinoids at the synapse is mediated via CB1 receptors (Schlicker and Kathmann 2001). It is interesting to note that endocannabinoid levels and/or cannabinoid receptor density are purportedly affected in several neuropsychiatric disorders such as Parkinson’s disease, Huntington’s disease, multiple sclerosis, epilepsy, certain types of pain, and excitotoxicity (Gubellini et al. 2002; Lastres-Becker et al. 2002; Kathuria et al. 2003; Marsicano et al. 2003; Wallace et al. 2003; Fujiwara and Egashira 2004; Lichtman et al. 2004; Ortiz et al. 2004).
Therefore, it should be possible to treat these pathological conditions using drugs that modulate endocannabinoid levels (Lambert and Fowler 2005; Mackie 2005). In fact, the knowledge of the mechanisms through which the endogenous levels of endocannabinoids and the activation of cannabinoid receptors are regulated might have an enormous impact on the development of selective compounds with beneficial effects (Martin 2002; Ortega-Gutiérrez 2005; Pertwee 2005).