the role of central da systems in the acute effects of drugs of abuse was recognized long ago ( wise , 1980 , 1987 ; di chiara and imperato , 1988 ) . even before ( ahlenius et al . , 1973 ) , attempts were made to prevent human alcohol - induced euphoria through administration of the da synthesis inhibitor alpha methyl - para - tyrosine . although theoretically ineccepibile , this approach ( reduction of drug - induced da increments to prevent abuse ) is unlikely to have a practical validity as any compound with da antagonistic ( i.e. , neuroleptics ) properties is known to be aversive in humans . on the other hand , widely documented experimental evidence suggests that the mesolimbic dopamine system is  hypofunctional  in the addicted brain ( melis et al . , 2005 ) . in brief , the hypothesis contends that decreased da function in addicted subjects results in a decreased interest to non - drug - related stimuli and increased sensitivity to the drug of choice ( melis et al . , 2005 ) , leading to propose that restoring da function might be therapeutically advantageous . alcohol - dependent ( in the present context the term  dependent ,  when referred to a non - human experimental subject , indicates a condition in which the subject has shown unequivocally a proof of dependency , i.e. , somatic signs of withdrawal ) rats show a profound reduction of spontaneous firing rate and burst firing of antidromically identified nucleus accumbens ( nacc)-projecting ventral tegmental area ( vta ) da - containing neurons in rats ( diana et al . , 1993 ) and mice ( bailey et al . , 2001 ) resulting in a concomitant reduction of microdialysate da in the nacc ( rossetti et al . further , the reduced dopaminergic activity outlasts somatic signs of alcohol - withdrawal ( diana et al . , 1996 , 2003 ) thereby suggesting a role for da in the lasting consequences of alcohol dependence while excluding the possibility of a da role in somatic aspects of withdrawal . further , original ( pre - dependence ) da levels in the nacc are restored when ethanol is self ( weiss et al . , 1996 ) and/or passively administered ( diana et al . , 1993 , 1996 ) . these observations are paralleled by intracranial self stimulation ( icss ) studies showing that ethanol - withdrawn rats are capable of maintaining the icss behavior provided that the stimulus current intensity is increased ( schulteis et al . , 1995 ) . this important observation strongly indicates that the neural substrate responsible for maintaining the icss behavior is hyperpolarized , or more refractory , in the alcohol - dependent subject as compared with its control . since the neural substrate of icss involves da axons ( yeomans , 1989 ; yeomans et al . , 1993 ) near the stimulating electrode , the results are complementary to those reported above and well support a deficitary function of da neurons . in addition , the perseverance of the reduction in da activity ( beyond resolution of somatic signs of withdrawal ) has also been documented in morphine - dependent rats ( diana et al . , 1999 ) , while a dichotomy between da function and somatic withdrawal has been observed in cannabinoid  withdrawn rats ( diana et al . , 1998 ) . similarly , conditioned heroin withdrawal decreases reward sensitivity ( kenny et al . , 2006 ) which persists well beyond the initial phase of withdrawal . these findings , observed across different addicting compounds and experimental conditions , suggest that da hypofunction persists over time , although reverting to  normality  ( diana et al . , 1999 , 2006 ) , eventually with species - specific time course . in addition to basic literature , reports in humans are also supportive of a compromised role of da transmission in alcoholics . while alcohol increases da release in healthy subjects ( boileau et al . , 2003 ) with some gender differences ( urban et al . , 2010 ) , a reduced number of da receptors has been observed ( volkow et al . , 1996 ; martinez et al . , 2005 ) in alcoholics that appears to be accompanied by a blunted da release ( martinez et al . , 2005 , 2007 ; volkow et al . , 2007 ) . while the reduced number of da receptors could be , at first sight , be viewed as suggesting an increased da release , it should be noted that by administering the da inhibitor alpha methyl - para - tyrosine , martinez et al . indeed , while healthy controls do show an increased raclopride binding after acute alpha methyl - para - tyrosine administration , cocaine - dependent subjects do not ( or to a significantly lesser extent ; martinez et al . , 2009 ) . similar results were obtained with the dopamine releasing agent methylphenidate ( volkow et al . , 2007 ) and amphetamine ( martinez et al . , 2005 ) in alcoholics . notably , artificially increasing the brain levels of dad2 receptors , using a replication - deficient adenoviral vector containing the rat cdna insert for dad2 into the nacc , reduces alcohol intake in spontaneously drinking rats , thereby offering the counterproof that a potentiation of da transmission may have beneficial effects on alcohol - seeking and alcohol - taking , in experimental models ( thanos et al . , 2001 , 2004 ) . in line with this conclusion , a spontaneous high number of da d2 receptors has been shown to have a protective role in non - alcoholic members of alcoholic families ( volkow et al . , 2006 ) . these findings further support the notion that the number of da receptors ( and consequently da transmission ) inversely correlates with alcohol drinking . these observations may suggest that  boosting  da neurons to produce more available da in the synaptic cleft could alleviate some of the symptoms of addiction and alcoholism , thereby acquiring a therapeutic character . in theory , this could be achieved by two different strategies : ( 1 ) da - potentiating drugs and ( 2 ) tms . although medications that increase da activity could be effective in treating alcohol abuse disorders , conflicting results have been produced ( swift , 2010 ) . for example , it was suggested that the da agonist bromocriptine reduced drinking in alcoholics ( lawford et al . , 1995 ) , but a randomized , double - blind , placebo - controlled study using a long - acting injectable bromocriptine preparation in 366 alcoholic - dependent individuals did not find difference in alcohol relapse between medication and placebo ( naranjo et al . , 1997 ) . another example is the stimulant medication modafinil ( da indirect agonist ) , found to improve cognition in 40 alcoholics with organic brain syndrome , but effects on drinking could not be measured ( saletu et al . , however , modafinil reduced cocaine use in a placebo - controlled study with 62 cocaine - dependent individuals ( dackis and obrien , 2005 ) , while another trial did not find differences between modafinil and placebo tested for methamphetamine users ( shearer et al . , 2010 ) . while evidence for the use of da agonists as a treatment for alcohol and/or substance use disorders is inconclusive ( swift , 2010 ) , there has been a revived interest for these drugs , possibly because adequate neurobiological rationale ( melis et al . , 2005 ) is now available . for example , aripiprazole ( semba et al . , 1995 ; burris et al . , 2002 ; shapiro et al . , 2003 ) a partial da agonist which in principle should antagonize da when tone is high , whereas should increase da transmission when basic tone is low , represents a proposed treatment for alcohol abuse disorders ( kenna et al . , 2009 ) . human laboratory alcohol studies have shown that aripiprazole reduces drinking ( kranzler et al . , 2008 ) , especially in the more impulsive alcoholic ( voronin et al . , 2008 ) . an fmri study demonstrated that aripiprazole significantly attenuates neural activity in the ventral striatum in response to alcohol cues ( myrick et al . further , a 12-week , double - blind , placebo - controlled treatment study with 295 alcohol - dependent individuals found that aripiprazole initially decreased heavy drinking days compared to placebo , but this significant effect was not present when the target dose of 30  mg was reached ( anton et al . , 2008 ) . this trial also showed greater side - effects and greater study discontinuation in the aripiprazole arm , as compared to placebo ( anton et al . , 2008 ) . interestingly , an open - label study of aripiprazole ( martinotti et al . , 2009 ) and a recent human laboratory study ( kenna et al . , 2009 ) suggests that lower doses of aripiprazole ( 515  mg per day ) may be better tolerated and still reduce drinking with effects on relapse comparable to those obtained with the opiate antagonist naltrexone ( martinotti et al . , 2009 ) . in summary , dopamine plays a key role in the addiction process , but significant side - effects have limited the use of medications that work directly on the dopaminergic system . the use of da partial agonists with lower side effect profiles , and appropriate dosing represent important directions for future research in this area . increasing da tone with appropriate pharmacological tools , is only one of the possible strategies . endogenous activity of da - containing neurons can be augmented with non - pharmacological tools such as tms ( strafella et al . , 2001 ) thereby providing , in principle , an adjunct to the therapeutic arsenal  against addiction , endowed with lesser systemic side - effects and limited contraindications . however , while the rationale is  neurochemical  for pharmacological agents ( neurotransmitter receptors , brain area etc . , ) , it must be anatomically based for tms . being that da - containing neurons are located deeply in the brainstem ( thereby making the neurons inaccessible to direct tms stimuli ) it becomes unavoidable to reach them indirectly through neurons located elsewhere in the brain . the dorsolateral prefrontal cortex ( dlpfcx ) by projecting monosynaptically to the rat ( carr and sesack , 2000 ) and primate ( frankle et al . , 2006 ) vta may serve this function . these studies show a projection from the pfc to midbrain da neurons , terminating both within the sn proper as well as in the vta . they arise from a broad region of the pfc , including the dlpfcx , cingulate , and orbital cortices . indeed , these pyramidal neurons ( figure 1 ) could be exploited as the primary target of the tms stimulus and their increased activity to produce , ultimately , an enhancement in da availability in the synaptic cleft in the nacc . schematically , the hypothesized circuit ( figure 2 ) would be the following : tms    dlpfcx    vta    da increase in forebrain projection site ( i.e. , nacc ) . in this context , it is imperative to employ stimulation parameters consonant with the physiological activity of the system under study to restore pre - drug da levels . for instance , it has been shown that dlpfcx stimulation produces bursts in rat da neurons ( gariano and groves , 1988 ; murase et al . , 1993 ) , highlighting the importance of stimulation parameters . indeed , burst firing is more efficacious than single spiking ( of identical frequency but evenly spaced action potentials ) in inducing da release in terminal areas ( gonon , 1988 ; manley et al . , 1992 ) . consistently , the role of dlpfcx in regulating basal da activity through the vta has been reported ( taber et al . , 1995 ; karreman and moghaddam , 1996 ) . confocal reconstruction of golgi - stained pyramidal neurons from dlpfcx obtained by a projection of 55 scans for a depth of 27.5  m in the z - axis . the scheme illustrates the proposed circuit to be activated by the tms stimulus ( green ) which , by activating the pyramidal neuron ( yellow ) with its neurotransmitter glutamate , would excite : ( 1 ) da - containing neurons of the vta ( red ) and ( 2 ) msn of the nacc ( blue ) . among the various factors that are likely to influence its efficacy , the importance of the baseline cortical activation state on the impact of tms is fundamental ( silvanto and pascual - leone , 2008 ) . this state - dependency is key as the neural impact of any external stimulus represents an interaction with the ongoing brain activity at the time of stimulation . the effects of any external stimulus are therefore not only determined by the properties of that stimulus but also by the activation state of the brain . accordingly , it has been shown that baseline cortical activity determines whether tms hampers or hastens behavior ( silvanto et al . the state - dependency principle described above would also apply to the state of the da system . amplify  the effect of tms as compared with that expected in a normo - functioning da system . the responsivity of the neuron(s ) to electrical and synaptic stimuli is strictly dependent on its morphological features , which in turn , are deeply modified by drugs of abuse ( robinson and kolb , 2004 ) and withdrawal from chronic treatment with opiates ( sklair - tavron et al . , 1996 ; spiga et al . , 2003 , 2005 ) , psychostimulants ( robinson and kolb , 1997 ) have been shown to produce reductions in da cells size ( sklair - tavron et al . , 1996 ; spiga et al . , 2003 ) , paralleled by persistently ( diana et al . , 2006 ) altered patterns of synaptic connectivity , and spines density in the nacc and pfcx ( robinson and kolb , 1997 ) . these architectural changes would be expected to modify intrinsic spontaneous action potential generating capacity and responsiveness of the system to the tms stimuli . accordingly , realistic computational analysis ( spiga et al . , 2010 ) of cannabis - dependent rats , generated by input of experimentally verified morphometrical and electrophysiological properties , predicts a lower action potential generation of nacc medium spiny neuron ( msn ) . these results suggest that msn , of cannabis - dependent rats are likewise hypofunctional . considering that the main drive of these neurons is cortical glutamate ( glu ; see discussion in spiga et al . , 2010 , and references therein ; kalivas and hu , 2006 ) it raises the possibility of a reduction of glu as a causal factor . this finding , thus offers the additional possibility that stimulation of these units through tms may be advantageous in restoring pre - drug physiological activity . indeed , tms cortical application should increase the activity of glutamate - containing cortico - fugal fibers monosynaptically impinging upon the spine s heads of nacc msn ( groenewegen et al . , 1991 ) . considering the fundamental role glu plays in synaptic plasticity ( russo et al . , 2010 ) , its role could also be exploited in ltp - like stimulation parameters , ultimately aimed at producing lasting and enduring restoration of original physiological activity . these characteristics must be considered and coherently inserted into a framework to obtain optimal stimulation parameters . in vivo recordings of vta - projecting dlpfcx neurons 2001 ) and a tms stimulus frequency of 10  hz could be a reasonable frequency to obtain a significant increase in vta - projecting neurons aimed at stimulating the deficient  dopamine system and its post - synaptic counterpart ( i.e. , msn of the nacc ) . another factor to be considered is that all previous studies ( see above ) applied the tms stimulus monolaterally , yet obtaining a reduction of alcohol craving ( mishra et al . , 2010 ) . while alcohol intake was not measured , and contralateral effects can not be excluded a priori , it is possible that application of tms bilaterally , as in the case of the h - coil ( feil and zangen , 2010 ) , would yield stronger cortical activation ( larger number of fibers activated ) with an increased probability of a significant increment of bilateral da release . it should be noted that unilateral tms application has already been reported to increase da release ( strafella et al . , 2001 ) omolaterally in the human striatum , as well as in rodents ( keck et al . , 2002 ; zangen and hyodo , 2002 ) , and even in morphine - withdrawn rats ( erhardt et al . , 2004 ) , thereby supporting the rationale outlined above . ( 2001 ) proposed activation of ( glu - containing ) cortico - fugal fibers making synaptic contact with da - containing terminals in the ventral striatum , to explain their results , it should be noted that the existence of axo - axonic contacts has always being questioned based on the lack of appropriate anatomical observations ( groenewegen et al . , 1991 ; meredith et al . , while many technical details for optimal stimulation parameters need further investigation and optimization , the tms appears to deserve careful experimental scrutiny as a potential therapeutic tool in alcoholics and other addicts . indeed , with its nearly absent systemic effects , minimal side - effects , and a low degree of invasiveness , tms may offer the first opportunity for an efficacious , non - pharmacological , therapeutic tool in alcoholism and other chemical dependencies . if appropriately combined with a solid neurobiological rationale ( da system ) , it may offer a unique opportunity for developing further the first electrophysiological  approach in studying and eventually treating the devastating and widespread brain disease of addiction . the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
dopamine ( da ) transmission is deeply affected by drugs of abuse , and alterations in da function are involved in the various phases of drug addiction and potentially exploitable therapeutically . in particular , 
 basic studies have documented a reduction in the electrophysiological activity of da neurons in alcohol , opiate , cannabinoid , and other drug - dependent rats . 
 further , da release in the nucleus accumbens ( nacc ) is decreased in virtually all drug - dependent rodents . in parallel , these studies are supported by increments in intracranial self stimulation ( icss ) thresholds during withdrawal from alcohol , nicotine , opiates , and other drugs of abuse , thereby suggesting a hypofunction of the neural substrate of icss . 
 accordingly , morphological evaluations fed into realistic computational analysis of the medium spiny neuron of the nacc , post - synaptic counterpart of da terminals , show profound changes in structure and function of the entire mesolimbic system . in line with these findings 
 , human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous da in the ventral striatum of cocaine , heroin , and alcohol - dependent subjects , thereby offering visual proof of the  dopamine - impoverished  addicted human brain . 
 the lasting reduction in physiological activity of the da system leads to the idea that an increment in its activity , to restore pre - drug levels , may yield significant clinical improvements ( reduction of craving , relapse , and drug - seeking / taking ) . in theory , 
 it may be achieved pharmacologically and/or with novel interventions such as transcranial magnetic stimulation ( tms ) . 
 its anatomo - physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts .