Mouse models of drug-seeking and drug-induced plasticity

A central problem facing the treatment of drug addiction is the enduring vulnerability to relapse displayed by users despite months or even years of abstinence. In order to gain a greater understanding of the neural mechanisms underpinning this process, animal models of relapse to drug-seeking have been developed. Transgenic approaches with mice have become increasingly popular in recent years and have aided in the identification of multiple candidate genes and molecules with therapeutic potential for the treatment of addiction. One such candidate is the adenosine A2A receptor, which is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to play a crucial, integrative role in processes such as reward, motivation and drug-seeking. Therefore one of the main aims of this thesis was to examine the impact of adenosine A2A receptor deletion on the mediation of primary reward, drug-induced plasticity and drug-seeking behaviour. In order to benefit from technologies which allow targeted deletion of particular molecules in mice, validation of mouse models of relapse to drug-seeking are required. Therefore the second main aim of this thesis was to investigate the neuroanatomical substrates involved in two models of drug-seeking: cue-induced opiate-seeking after protracted abstinence and primed reinstatement of a previously extinguished cocaine-induced conditioned place preference. Analysis of expression of the neural activity marker Fos revealed that the neuroanatomical substrates of drug-seeking in these mouse models broadly supports the existing cortico-striatolimbic circuitry found in the literature. In addition, however, a number of brain regions previously not investigated in drug-seeking behaviour were identified. These were the lateral habenula and various hypothalamic nuclei for primed reinstatement of CPP and withdrawal-associated regions for opiate-seeking following protracted abstinence. An additional observation was that circuitry typically associated with foraging, arousal, feeding and hunting were found to be common to reward-seeking for both natural and drug rewards. Decreased morphine self-administration and breakpoint were observed in AM knockout mice. These data support a decrease in the motivation to consume the drug, consistent with decreased opiate reward in A2A knockout mice. In support of this finding, a place preference to morphine was not observed in A2A knockout mice but was present in wildtype mice. In comparison, A2A knockout mice exhibited a robust place preference to cocaine. This indicates that the mediation of the acute rewarding effect of opiates but not cocaine is altered in A2A knockout mice. In contrast, A2a knockout mice exhibited robust relapse to opiate-seeking following abstinence and similarly robust primed reinstatement of a previously extinguished cocaine-induced place preference. These data suggest that A2a receptor deletion has no impact on drug-seeking behaviour in the paradigms examined. Collectively, the data regarding the involvement of the adenosine A2a I receptor in mediating the responses to opiates and psychostimulants supports a facilitatory role for this receptor in mediating the rewarding effects of opiates but not cocaine or drug-induced plasticity. In conclusion, this thesis characterises and validates multiple mouse models of relapse to drug-seeking behaviour. The neuroanatomical substrates underlying opiate-seeking, cocaine-seeking and sucrose-seeking were found to have similar yet divergent properties. In addition, comparisons were made between the operant and conditioned place preference models of reinstatement, as well as the reinstatement model of drug-seeking versus relapse to drug-seeking after abstinence. Though genetic deletion of the receptor did not impact on drug-seeking in either paradigm, profound influences on opiate reward were demonstrated and provide support for the investigation of this receptor as a potential therapeutic target in the treatment of addiction