The neural mechanisms mediating one-trial and multi-trial behavioral sensitization during early ontogeny are poorly understood. The purpose of this thesis was to assess the importance of D2-like receptors for the induction of cocaine- and methamphetamine-induced one-trial and multi-trial behavioral sensitization during the middle and late preweanling period. In a series of four experiments, rats were injected with saline or the selective dopamine D2-like receptor antagonist raclopride 15 min prior to treatment with the indirect dopamine agonists cocaine or methamphetamine. Acute control groups received two injections of saline. The pretreatment regimens occurred on either PND 16 or PND 20 (one-trial behavioral sensitization) or PND 13-16 or PND 17-20 (multi-trial behavioral sensitization). On PND 17 or PND 21, rats were challenged with either cocaine or methamphetamine and sensitized responding was assessed. With only a single exception, both one -trial and multi-trial cocaine- and methamphetamine-induced sensitization was evident on PND 17 and PND 21. Importantly, the D2-like receptor antagonist raclopride did not prevent the induction of cocaine- or methamphetamine-induced one-trial behavioral sensitization. In regards to multi-trial behavioral sensitization, raclopride failed to inhibit cocaine -induced sensitized responding on PND 17 and PND 21. Interestingly, higher doses of raclopride (0.5 and 1 mg/kg) were able to prevent the induction of multi-trial methamphetamine-induced sensitization on PND 17. Therefore, D2-like receptor antagonism differentially affected methamphetamine -induced behavioral sensitization depending on whether a one-trial or multi-trial paradigm was employed. When considered together, these results suggest that the neural mechanisms underlying the methamphetamine -induced behavioral sensitization of preweanling rats differs depending on the type of experimental paradigm (one- vs multi-trial) being used. Other potential explanations (i.e., nonspecific antagonist effects, impact of contextual conditioning, etc.) for this interesting effect are presented in the Discussion.

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.