Addiction is a complex process in which behavioral sensitization may be an important component. While the behavioral effects of sensitization are well established, the intricate neurobiology of the phenomenon is still largely unknown. Dopamine systems mediate the induction of behavioral sensitization in adult rats, but there is a large amount of evidence showing that other neurotransmitter systems also modulate the induction process. For example, the α1b-adrenergic and 5-HT2A receptor systems are known to modulate the sensitized responding of adult rats, but the roles that these receptor systems play in the induction and expression of behavioral sensitization during the preweanling period has yet to be investigated. Therefore, the purpose of this thesis was to determine whether the serotonergic and adrenergic receptor systems mediate the induction and/or expression of cocaine-induced one-trial behavioral sensitization in preweanling rats. I used a novel approach to address this question, as the receptors of interest were “protected” from the alkylating effects of EEDQ (an irreversible nonselective receptor antagonist) by prior treatment with selective antagonist drugs. More specifically, rats were given ritanserin (a serotonergic receptor antagonist), prazosin (an adrenergic receptor antagonist), or a combination of the two drugs prior to an injection of EEDQ. To study the induction of behavioral sensitization, this series of injections was administered on PD 18 (24 h before the pretreatment injection of cocaine). To study the expression of behavioral sensitization, the injections were administered on PD 20, which was the day between the drug pretreatment day and the test day. In all experiments, the test day (i.e., the day on which the challenge dose of cocaine was given) was on PD 21. Control experiments were performed for both the induction and expression paradigms in order to determine whether prazosin and ritanserin independently affected sensitization. Results showed that the receptor inactivation caused by EEDQ blocked both the induction and expression of cocaine-induced one-trial behavioral sensitization. Importantly, administering prazosin and ritanserin did not protect the induction of the sensitized locomotor response, which suggests that serotonergic and adrenergic receptors do not mediate cocaine-induced one-trial behavioral sensitization in preweanling rats. This conclusion should be tempered, however, because co-administration of prazosin and ritanserin affected the locomotor activity and sensitized responding of cocaine-treated rats independent of the actions of EEDQ. Considering both past and present results, the most harmonious conclusion is that multiple receptor systems (i.e., dopaminergic, serotonergic, adrenergic, etc.) work in unison to produce the complex phenomenon of behavioral sensitization.

The neurochemical changes occurring between the preweanling period and adolescence could be crucial for understanding the role development plays in the manifestation of psychotic behaviors. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) fully attenuates the DA agonist-induced behaviors of adult rats, while potentiating the DA agonist-induced locomotor activity of preweanling rats. My specific hypotheses were as follows: (1) Systemically administered EEDQ would block the cocaine-induced locomotor activity of adult rats. (2) Systemically administered EEDQ would potentiate the cocaine-induced locomotion of preweanling rats. (3) EEDQ would increase the Emax values (a measure of D2 receptor sensitivity) of preweanling rats, but not adolescent or adult rats. And, (4) EEDQ would reduce dorsal striatal β-arrestin-2 (ARRB2) and GRK6 levels (measures of D2 receptor sensitivity) of preweanling rats. Behavioral results were as expected, because EEDQ attenuated the locomotion of adult and adolescent rats, while EEDQ potentiated locomotor activity of preweanling rats. EEDQ enhanced the GTPγS binding of preweanling rats, while depressing ARRB2 levels. These results are consistent with the overarching hypothesis that EEDQ causes DA supersensitivity in preweanling rats. Thus, it is here proposed that EEDQ inactivates a significant number of D2 receptors in preweanling rats, but that the remaining D2 receptors are supersensitive and capable of mediating a potentiated locomotor response.