Viral-Mediated Gene Transfer to Study the Behavioral Correlates of CREB Function in the Nucleus Accumbens of Rats - Drugs of Abuse: Neurological Reviews and Protocols - page 341

nonpreferred environment. We also counterbalance each treatment group such
that approximately the same number of rats receive drug associated with the white
compartment as in the black compartment. Accordingly, there are four possible
types of drug-environment pairings: the drug paired with the white/preferred
environment; drug with the white/nonpreferred environment; drug with the
black/preferred environment; and drug with the black/nonpreferred environment.
Ideally, each possibility should be represented equally within each group in the
study. Occasionally, rats show strong preferences for one of the environment. We
screen the rats before surgery so that we can eliminate those with large a priori
preferences for a compartment without performing the most labor-intensive
portions of the study (e.g., viral-mediated gene transfer and conditioning).
10. The goal of viral-mediated gene transfer studies is to establish causal relations
between genes and behavior. Accordingly, drug treatments should be given in
some rats when transgene expression is maximal, and in other rats after transgene
expression has waned. Because of the transient nature of viral-mediated transgene
expression—in this case, HSV-mediated transgene expression begins to wane
only a few days after gene transfer—it can be challenging to design behavioral
studies in which repeated drug treatments correspond with maximal transgene
expression. To test the rats while transgene expression is maximal, we developed
a “compressed” place conditioning protocol in which the conditioning portion of
our studies is conducted over 2 d. On each day, the rats receive two conditioning
sessions: nondrug (i.e., vehicle) in the morning, and drug in the afternoon. In this
compressed protocol, it is important that the nondrug pairings always precede
drug pairings; if the rats receive drug in the morning conditioning session, it
is possible that they could associate symptoms of dysphoria (e.g., acute drug
withdrawal) with the nondrug environment during the afternoon session. This
“compressed” conditioning paradigm may generate dose-effect functions for
each drug that are different than those reported in articles in which more extended
conditioning protocols are used. Accordingly, it is advisable to identify the
appropriate dose ranges for each drug in naive animals before initiating labor-
intensive gene transfer studies.
Acknowledgments
Our work with viral vectors is sponsored by NIH (DA12736 and MH63266
to W. C., AG12954 to R. L. N.) and an unrestricted research grant from Johnson
& Johnson (to W. C.).
References
1. Carlezon, W. A., Jr., Thome, J., Olson, V., et al. (1998) Regulation of cocaine
reward by CREB. Science 282, 2272-2275.
2. Carlezon, W. A., Jr., Nestler, E. J., and Neve, R. L. (2000) Herpes simplex
virus-mediated gene transfer as a tool for neuropsychiatric research. Crit. Rev.
Neurobiol. 14, 47-68.