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382

novel target for antidepressant drugs
and offers a new strategy for treatment
of depression.
Taken together, GPCR heteroreceptor complexes and their receptor–
receptor interactions represent a new
fundamental principle in molecular
medicine for integration of transmitter signals in the plasma membrane.
A novel understanding of the molecular basis of CNS diseases is given
together with new strategies for theirtreatment by targeting heteroreceptor
complexes based on a new pharmacology with combined treatment,
multi-targeted drugs and heterobivalent drugs. Our perspective on thefuture of research on heteroreceptor
complexes is the further development
and employment of multiple techniques for use in cellular models, brain
tissue and in vivo studies to understand their role in discrete brain
circuits. The advancement of theproximity ligation assay will be of
special importance as will be the development of selective heterobivalent compounds for the heterocomplexes.

FUNDING AND DISCLOSURE
The authors declare no conflict ofinterest.

ACKNOWLEDGMENTS
This work was supported by theSwedish Research Council and theAFA insurance.
Kjell Fuxe1 andDasiel O Borroto-Escuela1
1

Department of Neuroscience, Karolinska Institutet,
Stockholm, Sweden
E-mail: Kjell.Fuxe@ki.se..............................................................................................

Borroto-Escuela DO, Perez-Alea M, Narvaez M,
Tarakanov AO, Mudo G, Jimenez-Beristain A et al(2015). Enhancement of the FGFR1 signaling in the
FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance forneuroplasticity and depression. Biochem Biophys
Res Commun 463: 180–186.
Fuxe K, Borroto-Escuela DO, Romero-Fernandez W,
Palkovits M, Tarakanov AO, Ciruela F et al (2014).
Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G proteincoupled receptor field. Neuropsychopharmacology
39: 131–155.
George SR, Kern A, Smith RG, Franco R (2014).
Dopamine receptor heteromeric complexes andtheir emerging functions. Prog Brain Res 211:
183–200.
Guo W, Urizar E, Kralikova M, Mobarec JC,Shi L, Filizola M et al (2008). Dopamine D2
receptors form higher order oligomers at physiological expression levels. EMBO J 27: 2293–2304.
Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA(2009). Allosteric communication between protomers of dopamine class A GPCR dimers modulates
activation. Nat Chem Biol 5: 688–695.
Portoghese PS (1992). Edward E. Smissman-BristolMyers Squibb Award Address. The role of concepts in structure-activity relationship studies ofopioid ligands. J Med Chem 35: 1927–1937.
Neuropsychopharmacology Reviews (2016) 41, 380–382;
doi:10.1038/npp.2015.244

Hippocampal
Neurogenesis andMemory Clearance
We are constantly forgetting. For amoment, consider what you have donetoday. It might be relatively straightforward, for example, to recall yourjourney to work. Similarly, you mightrecall easily the people you encountered and conversations you had,even with a fair degree of clarity. Wekeep a good record of these ordinary,everyday events. But what about
memories of similar, everyday activities that occurred a week ago? Or amonth or a year ago? Unless something extraordinary occurred, it isunlikely that you can recall much ofwhat happened, and certainly not inany great detail. This reflects the factthat while we are continuously encoding our experiences, the vast majorityof these encoded experiences (ormemories) are ‘cleared away’ and onlya small portion ultimately retained.
The hippocampus is thought to be
the automatic encoder, with the cortex
serving as the final repository for thefraction of memories that are successfully consolidated (Wang and Morris,2010). But how are memories cleared
from the hippocampus?
Recent work has identified one likely
clearance mechanism. In the hippocampus, new cells are continuously
generated in the subgranular zone ofthe dentate gyrus. Most of these newcells differentiate into granule cells andmigrate into the granule cell layer,...................................................................................................................................................

Neuropsychopharmacology

where, after a few weeks, they synaptically integrate into the hippocampal
circuitry. There has been plenty ofinterest in how these newly generated
neurons might facilitate the formationof new memories (eg, by increasing
the mnemonic capacity or facilitating
certain types of computations carriedout by the dentate gyrus, such as
pattern separation) (Christian et al,2014). However, as new cells integrate
into the hippocampus they necessarily
remodel existing circuitry. This remodeling may degrade memories alreadystored in those circuits (or at least
render them difficult to access)(Deisseroth et al, 2004; Weisz
and Argibay, 2012). We recently provided experimental support for thisprediction (Akers et al, 2014). Voluntary exercise increases hippocampal
neurogenesis in adult mice. We foundthat running-induced increases inneurogenesis led to forgetting of established contextual fear and spatialmemories. While running induces a
number of physiological changes, theforgetting effects appeared to dependon elevated neurogenesis, since
genetically attenuating this consequence of running prevented forgetting. Furthermore, pharmacological(eg, memantine, fluoxetine) and genetic (conditional deletion of p53 fromneural progenitors) interventions
that artificially elevate hippocampal
neurogenesis, when introduced after
training, similarly weakened existinghippocampus-dependent
memories,suggestingthatrunning-induced
forgetting is mediated by a neurogenic
mechanism.
There are two important implications of these findings. First, not only
do they tell us about how forgetting
normally occurs, but perhaps additionally they hint at an important functional consequence of ongoingneurogenesis in the adult hippocampus. Established memories interferewith encoding of new memories,
especially when the new and established memories are in conflict with
one another. By continuously clearing
hippocampal
memories,
ongoing
neurogenesis may serve to minimize
this form of proactive interferenceHOT TOPICS.....................................................................................................................................................................

383(Frankland et al, 2013). Second, thesefindings identify a mechanism that
could be targeted in memory-relateddisorders. For example, inefficientneurogenesis-mediated clearance may
contribute to human disorders characterized by problems with memory
interference (eg, in old age and Alzheimer’s disease) or rumination (eg, inPTSD and depression). Interestingly,
stress may compound these conditions
by further lowering the rates of ongoing neurogenesis.

FUNDING AND DISCLOSURE
The authors declare no conflict ofinterest.

ACKNOWLEDGMENTS
This project was supported by Canadian
Institutes of Health Research (CIHR)
grants to PWF (MOP-86762) and SAJ(MOP-74650), and a Brain and Behavior Foundation (NARSAD) to SAJ.
Paul W Frankland1,2,3,4 andSheena A Josselyn1,2,3,41
Program in Neurosciences & Mental Health, The
Hospital for Sick Children (SickKids), Toronto, Ontario,Canada; 2Department of Psychology, University ofToronto, Toronto, Ontario, Canada; 3Department ofPhysiology, University of Toronto, Toronto, Ontario,
Canada; 4Institute of Medical Science, University ofToronto, Toronto, Ontario, Canada
E-mail: paul.frankland@sickkids.ca or
sheena.josselyn@sickkids.ca..............................................................................................

Akers KG, Martinez-Canabal A, Restivo L, Yiu AP,
De Cristofaro A, Hsiang HL et al (2014).
Hippocampal neurogenesis regulates forgetting
during adulthood and infancy. Science 344:
598–602.
Christian KM, Song H, Ming GL (2014). Functions anddysfunctions of adult hippocampal neurogenesis.
Annu Rev Neurosci 37: 243–262.
Deisseroth K, Singla S, Toda H, Monje M, Palmer TD,Malenka RC (2004). Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron
42: 535–552.
Frankland PW, Kohler S, Josselyn SA (2013). Hippocampal neurogenesis and forgetting. Trends Neurosci 36: 497–503.
Wang SH, Morris RG (2010). Hippocampalneocortical interactions in memory formation, consolidation, and reconsolidation. Annu Rev Psychol
61: 49–79 (C41–C44).
Weisz VI, Argibay PF (2012). Neurogenesis interfereswith the retrieval of remote memories: forgetting inneurocomputational terms. Cognition 125: 13–25.
Neuropsychopharmacology Reviews (2016) 41, 382–383;
doi:10.1038/npp.2015.243

Translational Studies ofSex Differences in
Sensitivity to Opioid
Addiction
The rapid escalation of opioid addiction, fueled by the increased potency
and availability of prescription opioid
painkillers, has been declared an
epidemic in the US. Although opioid
addiction has historically exhibited a
substantially higher prevalence inmen, adolescent girls are now abusing
opioids at a higher rate than boys, theprevalence of fatal opioid overdoses
has increased at a higher rate among
women relative to men, and womenare more likely to use opioids tomanage stress. This commentary highlights three examples of recent
advancements and ongoing challenges
in translational studies of sex differences in sensitivity to the addictive
properties of mu opioid receptor(MOR) agonists such as morphine,oxycodone and heroin.
One recent advancement in mechanistic understanding of these sex
differences is the finding in ex vivo
hippocampal slice preparations that aform of MOR-dependent cellular learning is dramatically enhanced in proestrous female rats, when 17-β estradiol
levels are at their peak (Harte-Hargroveet al, 2015). This female-specific,
estradiol-dependent lowering of thresholds for synaptic plasticity may explain,in part, why female rats with highestradiol levels acquire opioid selfadministration behavior more rapidly
than males (Roth et al, 2002). Althoughthese findings mirror the observed‘telescoping’ course of illness in womenrelative to men—characterized by amore rapid progression from initiationof opioid use to an opioid use
disorder—there is not direct clinicalevidence that estradiol contributes tothe telescoping effect.
In a second example, a mouse modelof the human MOR A118G SNP
replicates many of the phenomena
observed in human variants, including
reduced morphine analgesia in G allele
carriers. But detailed studies of themouse model also demonstrate thatG/G females are significantly less sensitive than A/A females to morphine
reward and withdrawal-induced negative affective states, whereas males
exhibit similar responses to morphine
regardless of allele status (Mague et al,2009). These types of sex by geneinteractions, which can have profoundeffects on addiction risk, are an important future direction in humanassociation studies.
As a final example, recent preclinicalfindings report that female rats are
more sensitive than males to the stresspeptide corticotropin releasing factor(CRF) in neural circuits that mediate
opioid withdrawal-induced negative
affective states (Valentino et al, 2013).
Specifically, CRF-mediated internalization of CRF type 1 receptors is lessefficient in females compared withmales such that females have more
CRF receptors available for activationin response to stress. Although thistype of mechanism could explain why
women are more likely than men touse opioids to self-medicate stress andanxiety (McHugh et al, 2013), there areno published clinical trials testing theefficacy of CRF antagonists in female
opioid addicts.
Substantial sex differences exist
across all substances of abuse and inalmost every facet of substance use
disorders (Greenfield et al, 2010).
Recent mandates from funding andregulatory organizations (eg, NIH andFDA) requiring researchers to consider
both sexes in their studies will certainly
advance our understanding of these sex
differences. However, translation frompreclinical to clinical research often
results in an apparent attenuation ofeffects, as highly controlled studies in
simple systems can fail to match
clinical findings from complex humansamples. As such, it is essential toexamine not only main effects of sex
on behavioral endpoints, but also
potential mechanistic differences that
may vary between and within thesexes.
Translational
approaches
designed with the power to identify
these complex interactions are themost likely to lead to optimal...................................................................................................................................................

Neuropsychopharmacology