Neurobiological Effects

Binge/Intoxication Stage

Acute Reinforcing Effects of Cannabinoids

Δ9-THC has been shown to have acute reinforcing effects in animal studies, brain stimulation reward, conditioned place preference, and intravenous self-administration. In drug discrimination studies, rats and monkeys will discriminate Δ9-THC. Cannabinoid receptor agonists can substitute for Δ9-THC, and the effects of these agonists can be blocked by cannabinoid receptor antagonists. No cross substitution has been observed with a wide variety of different neuropharmacological agents, including opioids, anticonvulsants, antipsychotics, serotonergic drugs, psychostimulants, and psychedelics. Only very high doses of anandamide substitute for Δ9-THC.

Intracranial self-stimulation thresholds are lowered by Δ9-THC administration in rats with acute administration. This lowering of thresholds is similar to all other major drugs of abuse. Δ9-THC produces both conditioned place aversion and preference in rodents, depending on the dose and experience of the animals. Place aversion is found with acute administration of moderate to high doses, but place preference is found at low doses and in animals with a history of pre-exposure to Δ9-THC. The potent synthetic cannabinoid receptor agonist CP 55,940 can produce a marked place preference that is reversed by naloxone.

FIGURE 8.17 (Top) Formation and inactivation of N-arachidonoylethanolamine (anandamide). Anandamide can be generated by hydrolysis of N-arachidonyl phosphatidylethanolamine (N-arachidonyl PE), which is catalyzed by phospholipase D (PLD) ➀. The synthesis of N-arachidonyl PE, depleted during anandamide formation, might be mediated by N-acyl transferase activity (NAT) ➁, which detaches an arachidonate moiety (red) from the sn-1 position of phospholipids such as phosphatidylcholine (PC) and transfers it to the primary amino group of PE. The membrane localizations of PLD and NAT are speculative. Newly formed anandamide can be released into the extracellular space, where it can activate G-protein-coupled cannabinoid (CB) receptors located on neighboring cells ➂ or on the same cells that produce anandamide (not shown). Anandamide release in the external milieu has been demonstrated both in vitro and in vivo. Anandamide can be removed from its sites of action by carrier-mediated transport (anandamide transport, AT) ➃, which can be inhibited by AM404. Transport into cells can be followed by hydrolysis catalyzed by a membrane-bound anandamide amidohydrolase (AAH, also called fatty acid amide hydrolase) ➄, which can be inhibited by AM374. Arachidonic acid produced during the AAH reaction can be rapidly reincorporated into phospholipid and is unlikely to undergo further metabolism. In vitro, AAH also can act in reverse, catalyzing the formation of anandamide from arachidonic acid and ethanolamine. The physiological significance of this reaction in anandamide formation is unclear. Abbreviation R indicates a fatty acid group. (Bottom) Formation and inactivation of 2-arachidonylglycerol (2-AG). Hydrolysis of phosphatidylinositol(4,5)-bisphosphate [PtdIns(4,5)P2] by phospholipase C (PLC) produces the second messengers 1,2-diacyl-glycerol (DAG) and inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] ➀. DAG serves as a substrate for DAGlipase (DAGL), which catalyzes the production of 2-AG ➁. This pathway also gives rise to free arachidonic acid. 2-AG can be released into the external milieu, measured in vitro, allowing it to interact with cannabinoid receptors, and its effects can be terminated by uptake into cells (not shown). However, extracellular release of 2-AG has not yet been reported in vivo. Intracellular 2-AG can be hydrolyzed to arachidonic acid and glycerol by an uncharacterized esterase such as monoacylglycerol lipase (MAGL) ➂. [Taken with permission from Piomelli D, Giuffrida A, Calignano A, Rodriguez de Fonseca F. The endocannabinoid system as a target for therapeutic drugs. Trends in Pharmacological Sciences, 2000, (21), 218–224.]

Early Δ9-THC self-administration studies in animals were marked by failure. Researchers were unable to achieve reliable self-administration in laboratory animals largely because of its long duration of action and pronounced aversion, even at modest doses. The advent of synthetic cannabinoid agonists, however, allowed researchers to elicit robust intravenous and intracerebroventricular self-administration of synthetic cannabinoid agonists in mice and squirrel monkeys. Additionally, studies have reported intravenous self-administration of low doses of Δ9-THC in mice and squirrel monkeys (Figures 8.19, 8.20). Squirrel monkeys with unlimited access to food and water were allowed a wide range of doses of Δ9-THC (1.0–8.0 μg/kg/injection) on a fixed-ratio 10 schedule of reinforcement and showed reliable intravenous self-administration. The self-administration of Δ9-THC and a synthetic cannabinoid was blocked by the CB1 receptor antagonist SR141716A.

As with other drugs of abuse, the acute reinforcing effects of Δ9-THC involve activation of the mesocorticolimbic dopamine system. Δ9-THC selectively increases the release of dopamine in the shell of the nucleus accumbens, an effect also observed with all major drugs of abuse (Figure 8.21). Similar increases in extracellular dopamine in the nucleus accumbens have been observed with the synthetic cannabinoid receptor agonist WIN 55,212–2.

Another potential neuropharmacological mechanism for the acute reinforcing effects of Δ9-THC is the release of endogenous opioid peptides. Intravenous Δ9-THC self-administration and intracerebroventricular CP 55,940 self-administration are blocked by the opioid receptor antagonist naltrexone, suggesting a role for opioid peptides in the reinforcing effects of Δ9-THC (see 8.20). These studies indicate that cannabinoids increase the synthesis and release of endogenous opioid peptides, possibly by inhibiting the release of an inhibitory neurotransmitter such as γ-aminobutyric acid (GABA; see below). Both cannabinoid and opioid receptors are also colocalized on medium-spiny γ-aminobutyric acid (GABA) neurons in the nucleus accumbens. As with other drugs of abuse, the sites of action of Δ9-THC may involve actions in the ventral tegmental area, nucleus accumbens, and possibly extended amygdala (8.22).

FIGURE 8.18 Specialized lipid-signaling junctions in the brain. (A) The endocannabinoid lipid 2arachidonoyl-sn-glycerol (2-AG) is thought to mediate retrograde signaling in the hippocampus, cerebellum, and other brain regions. Glutamate (blue circles) released from excitatory axon terminals activates postsynaptic type I metabotropic glutamate receptors (mGluR), stimulating 2AG production through the phospholipase C-β (PLC-β)/diacylglycerol lipase (DGL) pathway. Type 1 mGluR, PLCβ, and DGLα are localized at the perisynapse (light red), a region of the dendritic spine that borders the postsynaptic density (purple). 2AG crosses the synaptic cleft and activates presynaptic CB1 cannabinoid receptors (CB1R), which suppress glutamate release. (B) Hypothetical model of a specialized lipid-signaling junction at hippocampal glutamate-containing synapses. Endocannabinoid-synthesizing enzymes (PLCβ and DGLα) and CB1R are positioned to optimize the transynaptic actions of 2AG. These may be further facilitated by the ability of this lipid messenger to reach CB1 receptors by lateral diffusion through the lipid bilayer. The cleavage of 2AG by monoacylglycerol lipase (MGL), leading to the production of arachidonic acid, might terminate the effects of this messenger. The flipping of 2AG across the bilayer, which may be rather slow, might occur either before or after the interaction of the lipid with CB1 receptors. [Taken with permission from Piomelli D, Astarita G, Rapaka R. A neuroscientist’s guide to lipidomics. Nature Reviews Neuroscience, 2007, (8), 743–754.]

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