Understanding the neurobiological consequences of early exposure to psychotropic drugs: linking behavior with molecules

Abstract

Children receive significant exposure to psychotropic drugs. Some psychiatric disorders are diagnosed and treated in children as young as 2 years old, resulting in exposure to prescription stimulants, antidepressants, and mood stabilizers during brain development. Difficulties in diagnoses at such young ages increase the likelihood that children who are not affected by these disorders receive drug exposure inadvertently. Additionally, the increased availability of caffeine-containing beverages in schools has facilitated exposure to this stimulant in children. However, the consequences of exposure to psychotropic drugs during brain development are not understood. When we exposed rats to the prescription stimulant methylphenidate during early adolescence, we discovered long-lasting behavioral and molecular alterations that were consistent with dramatic changes in the function of brain reward systems. In future work, it will be important to determine if other classes of psychotropic drugs cause these same effects, and whether these effects will also occur if drug exposure begins during other periods of development. Moreover, it will be critical to use more powerful behavioral methods that are sensitive to high-level aspects of motivation and cognitive function, and to establish causal links between developmental exposure-related alterations in these complex behaviors and specific alterations in the molecular biology of key brain regions. This approach may identify classes of psychotropic drugs that have high or low propensities to cause behavioral and molecular adaptations that endure into adulthood. It may also identify periods of development during which administration of these agents is particularly safe or risky.

Fig. 1

Schematic depiction of how CREB activity in the nucleus accumbens (NAc) shell may act as a ‘hedonic thermostat’. Elevated expression of CREB increases transcription of dynorphin, which in turn causes aversive and/or depressive-like states (including dysphoria and anhedonia). Conversely, disruption of CREB activity decreases dynorphin transcription, enabling hedonic processes. (Based on Carlezon et al., 1998; Pliakas et al., 2001.)

Fig. 2

Effect of early exposure to MPH on behavior and the molecular biology of the NAc shell. (A) Exposure to MPH during early adolescence made intermediate doses of cocaine aversive (possibly reflecting dysphoria) and high doses less rewarding (possibly reflecting anhedonia) when the rats were tested during adulthood. (B) Exposure to MPH during pre-adolescence caused substantial increases in CREB levels within the NAc shell during adulthood, but it did not regulate any of the other drug-sensitive proteins studied. (Modified from Andersen et al., 2002.)

Fig. 3

To put gene array or proteomics data into biological contexts, genes or proteins can be grouped according to their cellular location (i.e., membrane, postsynaptic membrane, mitochondrion, etc.) or their function (i.e., transcription factor, signal transduction element, mitochondrial respiration, vesicular fusion, etc.). Furthermore, functions can overlap with cellular locations, such as ‘mitochondrion’ and ‘mitochondrial respiration’, ‘nucleus’ and ‘transcription factors’. Computer programs are available that calculate hypergeometric distributions to determine if particular functions or locations are more affected than would be expected by chance.

Fig. 4

Schematic description of one strategy to establish causal relationships between psychotropic drug exposure-induced alterations in molecular biology and alterations in behavior. Ideally, molecular and behavioral analyses initially proceed in parallel, and involve drug exposure at different periods of brain development (e.g., early, mid, and late adolescence). When exposure-related molecular adaptations are identified, genetic engineering techniques can be used to mimic such changes to explore whether any particular adaptation is sufficient to cause alterations in motivation (e.g., using ICSS), learning (e.g., using FPS), or attention (e.g., using 5CSRTT).