Tat3L4F Does Not Produce Significant Behavioral Side Effects

Previous studies have utilized nonselective treatments focused on enhancing 5-HT neurotransmission, such as L-tryptophan (Fletcher et al. 2004; McGregor et al. 1993) and fluoxetine (Carroll et al. 1990; Fletcher et al. 2004; Richardson and Roberts 1991), which were shown to reduce self-administration of cocaine and amphetamine. It was suggested that this occurred due to stimulation of 5-HT2C receptor in the VTA (Fletcher et al. 2004). However, nonselective treatments typically have more side effects. While the selective 5-HT2C agonist R0600175 inhibits the VTA dopamine pathway, R0600175 has also been shown to cause significant side effects in rats such as hypophagia, hypolocomotion, penile erection, motor functional suppression, and anxiety (Alves et al. 2004; Grottick et al. 2000; Higgins and Fletcher 2003; Wood 2003).

Although PTEN inhibitors may reduce the dephosphorylation effects of PTEN on 5-HT2C receptor to suppress the rewarding effects of abused drugs, the role of PTEN as a tumor suppressor may make the use of PTEN inhibitors disadvantageous (Ji et al. 2006). Tat-3L4F interfering peptide is able to suppress the dephosphrylation effects of 5-HT2C receptor while, theoretically, it exerts no significant effects on PTEN itself. However, both Tat-3L4F and R0600175 are able to suppress the firing rate of VTA dopamine neurons and CPP induced by THC, and Tat-3L4F may also share the "side effects" of R0600175. To test this hypothesis, we conducted a battery of behavioral tests showing that R0600175, but not Tat-3L4F, caused anxiety, penile erection, hypophagia, hypolocomotion, and motor functional suppression (Ji et al. 2006).

A possible explanation for the occurrence and absence of those side effects produced by R0600175 and Tat-3L4F, respectively, is that PTEN may regulate an intracellular signaling pathway that is different from that regulated by R0600175. Thus, despite the fact that R0600175 has the strong ability to suppress the rewarding effects of THC, Tat-3L4F may be a safer alternative.

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