Noboru Hiroi

Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor

There is increasing evidence that genetic factors can influence individual differences in vulnerability to drugs of abuse,. Serotonin (5-hydroxytryptamine, 5-HT), acting through many receptors can modulate the activity of neural reward pathways and thus the effects of various drugs of abuse. Here we examine the effects of cocaine in mice lacking one of the serotonin-receptor subtypes, the 5-HT1B receptor. We show that mice lacking 5-HT1B display increased locomotor responses to cocaine and that they are more motivated to self-administer cocaine. We propose that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug. This altered state might be responsible for their increased vulnerability to cocaine.

Region-specific induction of δFosB by repeated administration of typical versus atypical antipsychotic drugs

Whereas acute administration of many types of stimuli induces c‐Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region‐specific accumulation of novel Fos‐like proteins of 35–37 kD. These proteins, termed chronic FRAs (Fos‐related antigens), have recently been shown to be isoforms of ΔFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos‐like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these ΔFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces ΔFosB in caudate–putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of ΔFosB in any of the three brain regions, and even tended to reduce ΔFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of ΔFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of ΔFosB in CP and NAc is most dependent on antagonism of D2–D3 dopamine receptors, with antagonism of D1‐like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of ΔFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long‐lasting Fos‐like transcription factors that could mediate some of the persistent and region‐specific changes in brain function associated with chronic drug exposure. Synapse 33:118–128, 1999. 

Neuronal and behavioural abnormalities in striatal function in DARPP-32- mutant mice

We investigated the role of the protein phosphatase inhibitor, dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa (DARPP‐32), in the expression of striatal neuropeptides and in biochemical and behavioural responses to repeated cocaine administration, using DARPP‐32 knock‐out mice. The striatum of DARPP‐32‐mutant mice showed heightened substance‐P‐like immunoreactivity, but normal levels of other neuropeptides. Repeated cocaine administration increased levels of ΔFosB, a Fos family transcription factor, in the striatum of wild‐type mice, and this increase was abolished in DARPP‐32‐mutant mice. Cocaine (20 mg/kg) acutely induced the same level of locomotor activity in the mutant and wild‐type mice, but the mutants showed a higher rate of locomotor sensitization to repeated cocaine exposures. These data show that DARPP‐32 is involved in regulating substance P expression in the striatonigral pathway, and in biochemical and behavioural plasticity with chronic administration of cocaine.

Nuclear Memory: Gene Transcription and Behavior

Publisher Summary The most widely studied immediate early genes belong to the Fos family. This family includes c-fos, fosB, fra1, and fra2 . When activated, these genes transcribe their protein products, designated C-FOSF, FosB, FRA1, and FRA2, respectively. The initial impetus to examine the induction of these genes and proteins has the assumption that they could be used to “map” neurons and neuronal networks activated by biologically significant stimuli. These proteins play crucial roles in regulating particular cell functions. These proteins bind to a DNA sequence by forming heterodimers with protein products of another immediate early gene family, Jun. The Fos-Jun dimers bind to the consensus sequence TGACTCA, called activator protein-1 (AP1) sequence. When they bind to this DNA sequence, they activate or repress the transcription of other genes. One Fos family member protein that has a predicted molecular weight around 35 kDa is an alternatively spliced form of FosB, termed ΔFosB that lacks a portion of exon 4. Despite its truncated nature, however, ΔFosB seems to have functional activity as a transcription factor. It has been demonstrated that ΔFosB variants constitute the long-lasting AP1 activity induced in the striatum after repeated cocaine treatment. The present set of findings described in this chapter shows that the long-lasting AP1 complex contains ΔFosB variants and that fosB gene products could play a crucial role in cocaine sensitization. In more general terms, this set of findings suggests that transcriptional regulation in the cell nucleus could play a critical role in the formation of certain types of memory.

Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research

Neuropsychiatric disorders constitute the single greatest source of the global burden of disease, but it seems that philanthropy and advocacy aimed at supporting research to alleviate the burden of these disorders often are overshadowed by corresponding efforts in many other areas of medicine. For example, the United States public donates five times more money to cancer than to mental health research (1), and for the United Kingdom public, the equivalent figure is a staggering 900 times more (2). In this context, it is particularly sobering that we recently lost two towering mental health advocates and philanthropists, Constance E. Lieber and Theodore R. Stanley ( Figures 1 and 2). These two individuals made an enormous and enduring impact through the initiatives that they created and sustained, through their personal contributions, and through their ability to mobilize others. For the editors, editorial board members, and editorial committee members of Biological Psychiatry who constitute the authors of this commentary, the losses are personal. Each of us has received research support made possible through the actions of these unique individuals. In acknowledging our gratitude, we hope that our collective efforts to advance the understanding of mental illness and its treatment are a lasting testament to their impact.