In addition to anecdotal evidence that cannabis increases appetite, especially for sweet food, in recreational cannabis smokers , several preclinical studies have shown that CB1 receptor agonists facilitate food reward, in particular, the hedonic response to sweet food that Berridge and Robinson call ‘liking’. For example, THC increases the intake of food and increases the consumption of sweet solutions in rats. In addition, low doses of THC increase hedonic reactions to sucrose and decrease aversive reactions to bitter quinine solutions and THC increases the palatability of sucrose in rats. Also, we recently found that the motivation to respond for food, as measured by break points in responding for food under a progressive-ratio schedule , is increased by administration of THC . Interestingly, enhancement of the motivation to respond for food by THC is dependent on actual food consumption , suggesting that both appetitive and consummatory aspects of food reward may involve the endocannabinoid system. Taken together, these findings provide a rationale for the clinical use of CB1 receptor agonists such as Marinol in anorexic cancer and HIV patients . There are contradictory reports on the effects of CBs on brain stimulation reward. Brain stimulation reward or intracranial self-stimulation is an operant procedure where animals have to press a lever to receive a small electrical current in restricted areas of the brain . Brain stimulation reward is arguably the most robust form of reinforcement and is believed to derive from the ability of electrical currents to activate, probably indirectly, the dopaminergic mesolimbic system . In support of this hypothesis, drugs that activate the dopaminergic system and increase dopamine levels in the nucleus accumbens also facilitate brain stimulation reward , whereas drugs that block dopamine receptors reduce thresholds for self-stimulation.
Concerning, CB1 receptor agonists, Gardner and colleagues found that THC facilitates brain stimulation reward ,vertical grow rack system whereas other investigators found no effects of the syntheticagonists CP55,940 or AMG-3 and some investigators have found a reduction of brain stimulation reward with CB1 receptor agonists . These discrepancies, which are likely due to procedural differences, remain to be resolved. A caveat of all experiments with directly acting CB1 receptor agonists is that, for several reasons, these drugs do not provide a realistic picture of the physiological role of the endocannabinoids. First, anandamide is a partial agonist , whereas synthetic CB1 receptor agonists are often full agonists and have higher affinities for CB1 receptors . Second, anandamide and 2-AG have very short half-lives , whereas THC and synthetic CB1 receptor agonists have relatively long half-lives. Finally, systemic injections of these compounds result in the activation of all brain areas containing CB1 receptors, whereas physiological activation of endocannabinoid synthesis and release is likely to be region, neuron or even synapse specific . The availability of mice genetically deprived of CB1 receptors in a tissue-specific manner may help address this possibilityAssessment of the roles the endocannabinoid system plays in brain reward processes was greatly facilitated by the discovery of selective CB1 receptor antagonists/inverse agonists such as rimonabant and AM251 . CB1 receptor antagonists decrease the rewarding effects of a wide variety of abused drugs under certain conditions. For example, the rewarding effects of opioids are generally decreased in both intravenous self-administration and conditioned place preference procedures . There have also been reports that rimonabant and AM251 reduce the rewarding effects of methamphetamine , alcohol and nicotine .
CB1 receptor antagonists do not generally alter self-administration of cocaine under low fixed-ratio schedules or conditioned place preference procedures , but AM251 has been found to significantly reduce self-administration of cocaine under progressive-ratio schedules and rimonabant prevents relapse to cocaine-induced and cue-induced cocaine-seeking behaviour . This suggests that the appetitive and conditioned effects of cocaine, but not its direct reinforcing effects, depend on CB1 receptor activation. The effects of rimonabant on opioid reward may be mediated primarily in the NAcc, as blockade of CB1 receptors in this area reduces heroin self-administration . On the other hand, the modulation of ethanol reward by the CB system appears to take place both in the NAcc and in the prefrontal cortex . The brain sites where CBs act to alter the rewarding effects of nicotine and psychostimulants are not known at present. Drugs of abuse share the ability to elevate extracellular levels of dopamine in the shell of the NAcc, as measured by in vivo microdialysis, and this effect is believed to play an important role in their reinforcing effects . CB1 receptor antagonists have been shown to block the elevations of accumbal dopamine levels induced by administration of nicotine or ethanol , but not by administration of heroin , morphine or cocaine . Transient surges of dopamine in the NAcc, as measured by cyclic voltammetry, are also produced by drugs of abuse and are believed to be involved in drug seeking . Interestingly, the transient increases in dopamine produced by administration of nicotine, ethanol and cocaine in the shell of the NAcc of freely moving rats are all blocked by CB1 receptor antagonists . Consistent with a role for endocannabinoids in the rewarding effects of food and in the regulation of appetite and food intake , blocking endocannabinoid tone with CB1 receptor antagonists reduces intake of food and sweet solutions . Also, injection of rimonabant within 24 h of birth completely prevents milk intake and causes almost 100% mortality in mouse pups . The motivational effects of food measured by a progressive-ratio schedule of food reinforcement and the appetitive aspects of food reward are significantly reduced by rimonabant in rats, indicating that some aspects of food intake regulation involve reward and motivational processes.
In addition, AM251 decreases hedonic reactions to sucrose and increases aversive reactions to quinine . Consistent with these preclinical findings, rimonabant has been found to be effective in the clinical treatment of obesity , although the clinical efficacy of this agent appears to be primarily due to its ability to alter peripheral lipid metabolism, rather than to reduce food intake . As in the case of CB1 receptor agonists, the effects of CB1 receptor antagonists on brain stimulation reward are somewhat controversial. Rimonabant has been shown to increase the threshold for brain stimulation reward in some studies or to produce no change in brain stimulation reward thresholds in other studies .Mice genetically engineered to lack CB1 receptors do not show dramatic changes in body weight, food consumption or fertility , suggesting that CB1 receptors modulate rather than mediate basic reward functions or that other systems can compensate for their absence. By using CB1-null mice, the role of CB1 receptors in the rewarding effects of drugs of abuse has been confirmed. For example, in these mutant mice morphine is not self administered , does not induce conditioned place preferences and does not elevate dopamine levels in the NAcc . Also, the rewarding effects of alcohol are reduced in CB1-null mice, as demonstrated by data showing that CB1-null mice do not develop conditioned place preference with this drug and that they do not prefer it over water in a two-bottle free-choice paradigm . However, another study reported that CB1-null mice show slight and short-lasting decreases in preference for ethanol. Development of conditioned place preferences with cocaine is unaltered in CB1-null mice . On the other hand, development of cocaine self-administration behaviour under fixed-ratio schedules of reinforcement in CB1-null mice was reported to be unaltered when mice were restrained , but was reduced in freely moving mice . In addition, cocaine self-administration was significantly reduced under a progressive-ratio schedule of self-administration in CB1-null mice . These contrasting results highlight the fact that, when working with genetically modified mice such as CB1-null mice, not only methodological differences but also differences in the genetic background may result in very different and sometimes contrasting behavioural outputs . It is interesting to note that CB1-null mice show normal elevations in dopamine levels in the NAcc following administration of cocaine ,grow vertical but no elevations following administration of morphine or ethanol , compared with wild-type controls. Finally, CB1-null mice do not develop conditioned place preferences to nicotine , but they self-administer the drug like wild-type controls . It remains to be seen whether increasing the effort needed to obtain nicotine, as with cocaine , could reveal a role of CB1 receptors in some aspects of nicotine reinforcement as suggested by the results with CB1 receptor antagonists . CB1-null mice have also provided evidence for the involvement of the endocannabinoid system in food reward. For example, CB1-null mice eat less than their wild-type control litter mates after food restriction . Moreover, CB1-null mice respond less for sucrose in a two-lever paradigm, have lower break points under progressive-ratio schedules of sucrose delivery and show less preference for sucrose over water in a two-bottle free-choice procedure .
Genetic ablation of CB1 receptors results in small reduction in body weight, reduction in adiposity and resistance to diet-induced obesity . However, as in the case of CB1 receptor antagonists, these effects appeared to be related more to increased metabolic energy consumption than to differences in rewarding effects of food or hypophagia . Interestingly, in the study by Fride et al. , administration of rimonabant in mice pups lacking CB1 receptors still induced a decrease in milk intake and survival rate, suggesting that some of the effects of CBs on food intake may be mediated by still uncharacterized CB receptors. To date, no study has investigated the effects of CB1 receptor deletion on brain stimulation reward. On the other hand, it should be noted that CB1-null mice show increased anhedonia after chronic mild stress , a measure of reduced activity of the reward system and a model of depression , further supporting a role for the endocannabinoid system in brain reward functions.Although measurements of the effects of systemic or intracranial injections of anandamide provide useful information on the functions of the endocannabinoid system, to provide support for a role of neurally released anandamide in brain reward processes it is also important to measure anandamide released in the brain by different abused drugs, by food and by electrical brain stimulation. Release of neurotransmitters such as dopamine or glutamate can be readily measured by micro-dialysis techniques, but only a few studies have employed microdialysis techniques to measure extracellular brain levels of endocannabinoids . Thus, most information on the modification of endocannabinoid levels comes from measurements of tissue levels in different brain areas. Measuring tissue level of anandamide has the limitation that only one time point can be established at a time, limiting information on the pattern of endocannabinoid release. Using tissue levels, it has been demonstrated that chronic administration of several drugs of abuse leads to region specific increases in anandamide levels. For example, when administered chronically, THC decreases levels of anandamide in the striatum , ethanol decreases levels of anandamide in the midbrain but not in the striatum , nicotine decreases levels of anandamide in the striatum but not in the midbrain , and cocaine and morphine do not alter anandamide levels, either in the striatum or midbrain . However, it is difficult to determine from these studies whether measured levels of endocannabinoids reflected the consequences of chronically administered drug or withdrawal. Vigano et al. compared the effects of chronic versus acute administration of morphine on endocannabinoid levels in the brain. They found that acute administration of morphine increased anandamide levels in the striatum, whereas chronic treatment with the drug failed to do so. In addition, they found that chronic treatment with morphine did not alter the ability of a challenge dose of morphine to increase anandamide levels in the striatum; that is, repeated administration of morphine did not induce sensitization or tolerance to this effect . Thus, chronic administration of drug followed by withdrawal, chronic administration of drug followed by an acute drug challenge and acute administration of drug can lead to very different changes in brain anandamide levels. Such profiles of release may indicate that anandamide is released in response to relevant changes in homoeostasis but not when an adaptive response has already occurred.