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Under ordinary conditions, atoms andmolecules of a gas zigzag in all dir-ections and have a wide distributionof speeds related to temperature. At roomtemperature, for instance, gaseous atomsor molecules are most likely to move at thespeed of rifle bullets. Such restlessness puts alimit on the level of detail at which atomicand molecular properties can be studied.

The emergence of methods for slowingand trapping gaseous species has led to arenaissance in atomic physics, which is nowprogressing into molecular/chemical physicsas well. The latest developments come fromBethlem et al.1 and Maddi et al.2 they haveindependently devised kindred techniquesfor slowing molecules that potentially pro-vide new approaches to subsequent trappingand spectroscopy in particular.

Control of atomic behaviour has alreadybecome pretty sophisticated. For instance, aclass of atoms, best represented by the alkalimetals, can now be routinely slowed withlight and loaded into traps (constructedfrom light or magnetic fields)3. This lasercooling relies on the rapid absorption andemission of photons by an atom placed inlight tuned near the atoms resonant fre-quency. With a careful arrangement of thelaser beams, the atoms can preferentiallyabsorb photons from a single direction. Dueto the momentum of the photon, the atomgets small velocity kicks opposite to itsdirection of travel. This can be used to slow abeam of atoms so they can be caught in trapsand cooled to very low temperatures (forexample, evaporative cooling is applied tomagnetically trapped atoms to attainBoseEinstein condensation at tempera-tures below 1 mK). Unfortunately, the ener-gy-level structure of molecules prevents themaintenance of the requisite simple absorp-tionemission cycle and so makes laser slow-ing impractical. In consequence, molecules(and many complex atoms) were relegated tothe sidelines.

Last year, however, two very differentapproaches to cooling and trapping of mol-ecules were successfully implemented. Inone, CaH molecules were cooled with a cryo-genically refrigerated helium buffer gas andloaded into a magnetic trap4. In the other, Cs2molecules were formed from laser-cooledCs atoms and then confined in a light trap5.Now we have the techniques devised byBethlem et al.1 and Maddi et al.2. Like laserslowing of a beam, they produce velocitykicks opposite to the direction of travel.They work with bunches of atoms or molec-ules all travelling in one direction, and make

no recourse to lasers or cryogenics. Insteadthese new methods use time-varying in-homogeneous electric fields to provide thekicks and the resultant slowing.

Inhomogeneous electric fields that canbe turned on or off quickly are produced bypairs of electrodes. The potential energy ofan atom or a molecule varies in a characteris-tic way with the strength of the electric field.Depending on whether the electric dipolesare on average antiparallel or parallel to theelectric field, the particles energy eitherincreases (these are low-field seekers) ordecreases (these are high-field seekers) withincreasing field strength. The energy oflow-field seekers is lowest at minimum fieldstrength and, therefore, in an inhomoge-neous field they seek these low-field regions.In contrast, high-field seekers are forcedtowards the maximum field strength.

Polar molecules possess both high- and

low-field-seeking states in an electric field.Atoms, on the other hand, become polarizedonly in the presence of an electric field and sotheir electric dipoles are always parallel to thefield; they can only be high-field seekers in anelectric field. The technique of Bethlem et al.relies on low-field seekers and, therefore, iswell suited for slowing polar molecules; thatof Maddi et al. relies on high-field-seekingstates and so is potentially suitable for slow-ing both atoms and molecules.

Figure 1 illustrates the two approaches. Inthe scheme of Bethlem et al. (Fig. 1a), molec-ules enter an inhomogeneous electric fieldfrom a field-free region. As they approach theregion of maximum field strength betweenthe electrodes, the potential energy of low-field seekers is increasing. This occurs at theexpense of their translational energy whichis being correspondingly reduced (a conse-quence of energy conservation). To preventthe molecules from regaining the transla-tional energy as they leave the field, the field isquickly switched off. The molecules thus endup in a homogeneous, field-free region wheretheir potential (and thus translational) ener-gy remains constant. To maximize the lossof translational energy, the field has to be

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NATURE | VOL 401 | 21 OCTOBER 1999 | www.nature.com 749

Chemical physics

Molecules are coolJohn M. Doyle and Bretislav Friedrich

Time

Pulse ofpolar molecules

Pulse ofCs

atoms

Time

a

b High voltage High voltage

Figure 1 Principle of molecular and atomic slowing by time-varying inhomogeneous fields. Length oforange arrows indicates speed. a, One of the 63 stages used by Bethlem et al.1 to decelerate a pulsedbeam of CO(a3P) molecules from 225 m s11 to 98 m s11. The two opposing rods are simultaneouslyswitched by two independent high-voltage switches. The decelerating stages are stacked inalternating vertical and horizontal configurations, keeping the molecules focused. They gainpotential energy as they approach the field maximum, and so lose kinetic energy. When the field isswitched off, the molecules are left with reduced velocity. b, A deceleration stage used by Maddi et al.2

to slow a pulse of Cs atoms (released from a magneto-optic trap) from 2 m s11 to 0.2 m s11. The twoopposing condenser plates are simultaneously energized by two independent high-voltage powersupplies. The electric field is turned on when the Cs pulse reaches the uniform field region, therebyinducing an electric dipole in the atoms. As the pulse leaves the plates it passes through an area ofdecreasing field strength. Its potential energy increases at the expense of kinetic energy, resulting inpulse deceleration.

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switched off just at the point where themolecules reach the fields maximum.

Maddi et al. (Fig. 1b) used atoms in theirexperiments, but their scheme could, inprinciple, be applied to molecules. The atomsenter an inhomogeneous electric field from aregion of a large homogeneous electric field.The homogeneous field is formed by twocondenser electrodes that are energized afterthe atoms entry. Atoms in their high-field-seeking states then gain potential energy asthey pass through the inhomogeneous fieldat the exit of the condenser, again at theexpense of their translational energy.

In both versions, the atoms or moleculesarrive in pulses: a pulsed beam of metastablemolecules is created from a supersonic beamexpansion (Bethlem et al.), or a pulsed beamof ground-state atoms is launched from amagneto-optic trap (Maddi et al.). The puls-ing is crucial, because the switching of thefields must be accurately synchronized withthe arrival of the atoms or molecules. Thesetechniques may enable atoms or moleculesto be slowed enough for capture in traps.

Yet another new approach6 to slowingbeams of atoms and molecules is based onsupersonic expansion from a nozzle placedat the end of a spinning armature. The nozzleis oriented so that it moves in the oppositedirection to the discharging gas, and itsspeed roughly equals the speed of theexpanding atoms or molecules. As a result, itcancels the particles speed in the laboratoryframe, leaving the atoms or molecules essen-tially at rest.

Cold molecules should prove useful inspectroscopy and the study of molecularstructure, especially in ultra-high-resolutionspectroscopy, which requires cold (slow) andtrapped (long-interaction-time) samples.An especially promising area for study iscollisions of ultra-cold molecules, when themolecules behave like waves, perhaps givingrise to a new chemistry. The technique mayalso enable the study of collective quantumeffects in molecular systems, including BoseEinstein condensation. Just as atom cooling isopening up new avenues of research, it is like-ly that the same will happen with molecularcooling with repercussions for chemistryand even, perhaps, biology. nJohn M. Doyle is in the Department of Physics, andBretislav Friedrich is in the Department ofChemistry and Chemical Biology, and theDepartment of Physics, Harvard University,Cambridge, Massachusetts 02138, USA. e-mails: jd@jsbach.harvard.edubrich@chemistry.harvard.edu 1. Bethlem, H. L., Berden, G. & Meijer, G. Phys. Rev. Lett. 83,

15581561 (1999).

2. Maddi, J. A., Dinneen, T. P. & Gould, H. Phys. Rev. A (in the

press). http://xxx.lanl.gov/abs/physics/9909027

3. Wieman, C. E., Pritchard, D. E. & Wineland, D. J. Rev. Mod.

Phys. 71, S253S262 (1999).

4. Weinstein, J. D. et al. Nature 395, 148150 (1998).

5. Takekoshi, T., Patterson, B. M. & Knize, R. J. Phys. Rev. Lett. 81,

51055108 (1998).

6. Herschbach, D. Rev. Mod. Phys. 71, S411S418 (1999).

chemical neurotransmitter GABA (g-aminobutyric acid). When GABA binds toits target protein complex the GABAAreceptor a chloride ion-channel opens,allowing chloride ions to move into neuronsand damp down their electrical activity. Ben-zodiazepines bind to a specific site on theGABAA receptor and induce a subtle changein its shape. This change causes GABA towork more efficiently at the receptor, so themovement of chloride ions into the neuronincreases2,3. But because GABAA receptorsare found throughout the brain, benzodi-azepine treatments often affect those circuitsthat control, say, attention or balance, asstrongly as they influence the circuits thatregulate anxiety; hence the side effects.

The situation is further complicatedbecause there are many types of GABAAreceptor2,3. Most are made of a, b and gsubunits arranged in a pentamer, with thechloride ion-channel at the centre. Benzodi-azepines bind at the interface between the aand g subunits4 (Fig. 1). There are six typesof a subunit, a1a6, distributed in variousbrain circuits to make an overlapping mosaicof receptor subtypes. So it is difficult tounderstand what each subtype does. Avail-able drugs are not selective enough, andgenetic studies in mice where the gene fora particular subunit is inactivated oftencause death5 or severe neurological illness6.This is because the brain circuitry has nobrakes on its activity, so it spirals intodysfunction.

In an alternative approach, Rudolph etal.1 have exploited a variable amino acid inthe a subunit known as the R/H site7. The a1,a2, a3 and a5 subunits all have histidine (H)at position 101 of their polypeptide chain,whereas a4 and a6 have arginine (R)7. Thehistidine contributes to the binding pocketfor benzodiazepines, and in vitro studies7

show that only GABAA receptors with thisamino acid at position 101 of their a sub-units are sensitive to these drugs. If histidineis mutated to arginine, drugs such asdiazepam no longer improve the action ofGABA at the GABAA receptor. However,the receptors sensitivity to GABA and itsfunction stay unchanged8.

Rudolph et al. now put this discovery intoa physiological setting. Using the techniqueof homologous recombination, they engi-neered mice in which residue 101 in the a1subunit is mutated from histidine to argi-nine. (The a1 protein is a good first choicefor this experiment because it contributesto over 60% of GABAA receptors in thebrain.) The authors found that drug-free

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Pharmacology

Towards better benzodiazepinesWilliam Wisden and David N. Stephens

Sleeplessness and anxiety afflict us all sometimes to the point of breakdown.The usual treatment is drugs of the ben-zodiazepine family, such as diazepam (Vali-um), which have helped millions of patientssince they were introduced in the late 1950s.Benzodiazepines induce relaxation, but theycan also play tricks on memory (hence theirassociation with date rape), reduce concen-tration, cause physical clumsiness and inten-sify the effects of alcohol. They can also beaddictive. In an exciting study on page 796 ofthis issue, Rudolph et al.1 report the use ofmouse molecular genetics to study the targetfor benzodiazepine action. This work setsthe foundations for developing Valium-likedrugs that ease anxiety or help the onset ofsleep, but without the destructive sideeffects.

To function properly, brain circuits needbalanced positive and negative signals. Thenegative inhibitory signals come from the

Valium-sensitive1 (His)

Valium-insensitive1 (Arg)

Out

In

C

N

H101

R101

N

C

a

b

1

1

Cl

H/R

Figure 1 Structure of the GABAA receptor. Thereceptor is made up of five subunits, and one ofthese, the a1 subunit, is shown from the side (a).In a complete receptor, the subunits form a ringwith the chloride (Cl1) ion-channel at the centre(shown from above, b). The neurotransmitterGABA binds at the interface between the a and bsubunits (green circles), causing the chloridechannel to open. The interface between an a1and a g subunit creates the binding site (redtriangle) for benzodiazepine drugs such asValium. If a key histidine residue (H101) in theextracellular amino-terminal domain of the a1subunit is changed to arginine, thebenzodiazepine-binding site is inactivatedalthough the receptor still responds to GABA4,7.