Influence of ECBS on acquisition and maintenance of psychostimulant-induced seeking behaviors
Models of conditioning such as the SA paradigm and the conditioned place-preference (CPP) procedure illustrate the reinforcing properties of drugs of abuse and demonstrate their ability to induce and maintain drug-seeking behaviors. Consistent with findings showing the limited involvement of the ECBS in the reinforcing properties of psychostimulants (see Influence of ECBS on Psychostimulants-Induced Behavioral and Reinforcing Effects), modulation of the ECBS appears to have a modest influence on acquisition and maintenance of psychostimulant-taking behavior in animals. In CPP experiments, while CB1 receptor deletion did not affect psychostimulant-induced place conditioning in mice, SR141716A impaired cocaine-, methamphetamine-, and MDMA-induced place conditioning in both rats and mice (262–265, 281, 286, 287). Difference in species, compensatory changes in the knockout animals due to the lack of CB1 receptors, as well as use of more intense conditioning and higher doses of drugs in the genetic deletion studies may have contributed to this discrepancy. This suggests that intensity of conditioning could overcome the effects of blocking ECBS signaling [reviewed in Ref. (274)]. It is important to note that the weaker cannabinoid antagonist CBD did not affect establishment of amphetamine-induced CPP in rats (290) and that the genetic overexpression of cannabinoid receptor CB2 impaired acquisition of both cocaine-induced CPP and SA (271). Thus the CPP model indicates that, although not directly interfering with the rewarding properties of psychostimulant drugs, ECBS could play a role in the perception and memory of psychostimulant reward, depending on environment-related factors.
In general, CB1 receptor invalidation does not seem to affect SA of psychostimulants. Experiments with genetic deletion of CB1 show conflicting results, as both knockout and SR141716A-treated mice still acquired amphetamine- and cocaine-taking behavior in restrained mobility conditions (266, 275), whereas knockout mice showed impaired SA behavior in other protocols (255, 258). Overall, results suggest that learning SA behavior might not require extensive ECBS involvement. Maintenance of such behavior may not depend on CB1 either, as drug-taking responses under a fixed-ratio schedule in animals that had already acquired cocaine SA remained unaffected after CB1 blockade by SR141716A in mice (266, 283), monkeys (280), and rats (250, 256, 269, 283) and by AM251 in rats (250, 277). Only one contradicting report exists in which AM251 decreased methamphetamine SA in conditioned rats (278). Cannabinoid signaling enhancement by the pharmacological FAAH inhibitors – URB597 and PMSF – also failed to affect maintenance of fixed-ratio drug-taking behavior in rats (261) and monkeys (260). On the other hand, cannabinoid stimulation by CB1 agonists had significant effects in several studies. Indeed, WIN 55,212-2 increased acquisition of MDMA SA in mice (286) and exposure to CP55,940 enhances development of cocaine SA in female rats (291). THC failed to alter acquisition of cocaine SA and amphetamine SA in monkeys (272) and rats (290), respectively. In regard to maintenance of drug intake in animals with SA behavior, cannabinoid agonists decreased drug-taking responses in rats – CP55,940 diminished MDMA intake (288) and WIN55,212-2 decreased cocaine administration (292) – and in monkeys – Δ9-THC also decreased cocaine intake (272). Fattore et al. first interpreted the shift in psychostimulant intake produced by CB1 agonists as indicative of a synergistic action of CB1 stimulation on reinforcing properties of the drugs, which, incidentally, could account for the frequent use of cannabis among human psychostimulants users (292). Complementary experiments using progressive-ratio schedules also reveal interaction of CB1 receptors with psychostimulant-induced reinforcing properties. In PR schedules, both genetic deletion and antagonist treatment of CB1 receptors produce a decrease in the maximal effort mice provided to self-administer cocaine, as made apparent by decreases in breaking point measures induced by SR141716A (255, 277, 284) and by AM251 (250) (SR141716A producing no effect in this specific report). This adds to the evidence that the CB1 receptors, while not indispensable for acquisition or maintenance of cocaine-seeking behavior, may exert a specific modulation on motivation and reward salience in psychostimulant addiction.