Development of Cell-Type-Specific Viral Vectors to Tease Apart the Neural Circuitry that Contributes to Drug Addiction - Viral Vector Approaches in Neurobiology and Brain Diseases - page 150

neural underpinnings of these normal processes will also be impor-
tant for isolating the maladaptations in brain circuits that occur
during the development and maintenance of drug addiction.
Historically, researchers have relied on lesion techniques and
pharmacological manipulations in animal models, as well as obser-
vational studies such as gene expression changes following acute
and repeated drug exposure, to help delineate the relevant brain
circuits involved in addiction. Although this work has led to a wealth
of information regarding the identity of key molecular neuroadapta-
tions in brain regions [ 1 - 5 ], nonetheless, there remains a shortage
of effi cacious treatments for addicts, suggesting that the systems
underlying addiction are highly complex and have not yet been fully
delineated. Although more work is needed to tease apart the intrica-
cies within these circuits, constraints within previous techniques
have limited their ability to do so. For example, the damage pro-
duced by a lesion is often permanent; however, lesions can also lead
to compensatory changes in cellular function, as well as neuronal
sprouting [ 6 ]. It can also be diffi cult to target subsets of cells within
a given brain region using lesion techniques. In addition, pharma-
cological agents often lack receptor selectivity and the same recep-
tors may reside on different cell populations within a given brain
region, making the contribution of specifi c cell types in the pathol-
ogy of addiction diffi cult to ascertain. Thus, methods that allow us
to probe neurocircuitry with anatomical and phenotypic precision
at specifi c stages in the evolution of addictive behavior, without
causing compensatory adaptations themselves, are needed.
Recent technological advances are now making it much easier
to achieve this precision and target the role of specifi c cell types in
order to address these circuit-related questions. For example,
transgenic mouse models now allow for very precise manipulation
of cell-specifi c targets; however, they are time-consuming and
costly to generate. Another method, which is described here, is to
use viral vectors with cell-type-specifi c promoters in order to
restrict gene expression to select cell populations within a given
brain region. This method is faster than transgenic mouse produc-
tion and can be used readily across animal models, including rats
and primates, which is not yet practical for transgenic technology.
Viral vectors for targeted gene expression can be used for a variety
of cell-specifi c manipulations, including increasing or knocking-
down expression of receptor subtypes as well as more generally
increasing or decreasing cell function.
The emergence of novel tools for selectively and transiently
modulating neuronal activity is allowing researchers to overcome
the constraints of earlier methods. One such technique is using cell-
type-specifi c viral vectors that express DREADDs ( D esigner
R eceptors E xclusively A ctivated by D esigner D rugs). This strategy
utilizes transgenic, engineered receptors that are activated by an
otherwise inert ligand and therefore produce no off-target pharma-
cological effects [ 7 ]. There are currently three available DREADD