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The reinforcing and 1396 Neuropsychopharmacology: The Fifth Generation of Progress subjective effects of morphine in post-addicts: a dose-response individual vulnerability to amphetamine self-administration purchase prometrium online pills medications zovirax. Discriminative stimulus effects of opioids the rewarding effects of the specific dopamine uptake inhibitor in pigeons trained to discriminate fentanyl order prometrium with a mastercard symptoms depression, bremazocine and GBR12783 cheap prometrium 200 mg on line treatment quadriceps tendonitis. Repeated exposures intensify rather than diminish the tion of cocaine self-administration with and without condi- rewarding effects of amphetamine, morphine, and cocaine. Pharmacogenetics of responses to alcohol and genes that ethanol reward, but not ethanol aversion, in mice lacking 5- influence alcohol drinking. Intra-amygdala muscimol de- effects on oral cocaine-reinforced behavior. J Exp Anal Behav creases operant ethanol self-administration in dependent rats. Excessive ethanol drinking noncontingent cocaine on drug-seeking behavior measured following a history of dependence: animal model of allostasis. Postcocaine anhedonia: an animal model an incentive-sensitization theory of addiction. Cocaine self- havior produced by heroin-predictive environmental stimuli. Rodriguez de Fonseca F, Carrera MRA, Navarro M, et al. Acti- injections of SCH23390 on intravenous cocaine self-adminis- vation of corticotropin-releasing factor in the limbic system dur- tration under both a fixed and progressive ratio schedule of ing cannabinoid withdrawal. Conditioned cued recovery of responding crose-substitution procedure in food- and water-sated rats. Alco- following prolonged withdrawal from self-administered cocaine hol Clin Exp Res 1986;10:436–442. Motivational conse- under concurrent signalled differential-reinforcement-of-low- quences of naloxone-precipitated opiate withdrawal: A dose- rates schedules. Decreased brain reward mance maintained by buprenorphine, heroin and methadone produced by ethanol withdrawal. Relative sensitivity to pies for treatment of cocaine and opioid abuse using drug self- naloxone of multiple indices of opiate withdrawal: A quantita- administration procedures. The conditioned reinforcing effects strain of rat, stimulus intensity, and intrinsic efficacy at the mu of stimuli associated with morphine reinforcement. The importance of a opioid receptor agonists studies with place and taste preference compound stimulus in conditioned drug-seeking behavior fol- conditioning. Sensitization to the condi- ety Neurosci Abstr 1999;25:1574. Positive reinforcement produced by electrical review. Naltrexone and coping administration in rhesus monkeys. J Pharmacol Exp Ther 1994; skills therapy for alcohol dependence: a controlled study. Conditioned stimulus control of the expression of 71. Factors that predict sensitization of the behavioral activating effects of opiate and Chapter 97: Recent Advances in Animal Models of Drug Addiction 1397 stimulant drugs. Control of ing and memory: the behavioral and biological substrates. Hills- cocaine-seeking behavior by drug-associated stimuli in rats: ef- dale, NJ: LEA, 1992:129–151. Tolerance and sensitization to the behav- cellular dopamine levels in amygdala and nucleus accumbens. Measures of cocaine- cer in normal weight rhesus monkeys: dose-response functions. Naltrexone in caine-seeking behaviour under a second-order schedule of rein- the treatment of alcohol dependence. Ethanol-associated environmental stimuli potently conditioning theory for research and treatment. Arch Gen Psy- reinstate ethanol-seeking behavior following extinction and ab- chiatry 1973;28:611–616. In satellite symposium entitled: CNS Mechanisms in 101. An experimental framework for evaluations of de- Alcohol Relapse. Research Society on Alcoholism Annual Meet- pendence liability of various types of drugs in monkeys. SCHUCKIT This is an exciting and challenging time in the search for related individuals using a transmission disequilibrium or a genes that have impact on the risk for alcohol abuse and haplotype relative risk approach (3,7). Family, twin, and adoption stud- The second and usually more labor-intensive technique ies offer solid evidence that genetic factors contribute to the is the genetic linkage study, or genome scan. This approach risk for severe and repetitive alcohol-related life problems, requires determining the presence of the phenotype and and at least 30genetically influenced characteristics are gathering blood for genotyping from either multiple genera- being evaluated for their possible impact on the alcoholism tions of a large number of families or a large number of risk (1–4). Similar to other complex genetic disorders, these sibling pairs. The relationship between the phenotype and risk factors are heterogeneous, and combine to explain an genetic signposts, or markers, across the 23 chromosomes estimated 60% of the variance, often interacting with envi- is then evaluated. Unfortunately, genome scans are likely ronmental forces that contribute to the remaining 40% to identify only relatively powerful genes that explain a sub- (1–3). Complicating the search for specific genetic influ- stantial proportion of the risk, and the data are best analyzed ences even further is the probability that most of the charac- only when the mode of inheritance (e. The potential linkage of a particular charac- ple genes, and the lack of precision of the definition of the teristic to a specific signpost helps identify areas of chromo- broad phenotype, alcohol abuse, or dependence (1,4). This chapter describes some of the more promising re- Most of the genetic studies have used variations in two ap- sults of the application of such approaches to alcohol use proaches described in more detail in Chapter 99, as well as disorders, and briefly synthesizes the wide range of pheno- in additional recent review articles (1,3,6). Candidate gene typic and genotypic markers into a framework focusing on studies (also called case-control, association, or forward ge- the several possible themes of potentially related characteris- netic investigations) begin with the hypothesis that a specific tics described in Table 98. Reflecting space limitations, gene is related to the characteristic under study (7). If a emphasis is placed on genetic factors relating to alcoholism, limited number of multiple forms, or polymorphisms, of rather than to drugs in general; most studies focus on human the gene are known, the proportion of individuals with and rather than animal work; and review articles are often high- without the characteristic who have the specified polymor- lighted rather than a series of primary data sources. Although this approach is an important step in identifying specific genes related to a phe- notype, it is prone to false-positive results that occur if there are additional differences between groups with and without the characteristic (8). POSSIBLE BROAD FAMILIES OF RISK FACTORS fication, can be overcome by two variations of case-control studies where the relationship between the genetic marker Level of response (LR) and the characteristic, or phenotype, is evaluated among P3/disinhibition/ASPD/type 2/B Independent axis I disorders Opioids Alcohol metabolizing enzymes M. Schuckit: Department of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, California.

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Methylation was inversely correlated with markers and symptoms of PTSD generic 200 mg prometrium fast delivery symptoms quotes, and may prove useful in distinguishing between veterans who have PTSD from those who do not generic 100mg prometrium visa medications quotes. Perroud et al (2014) studied the transmission of PTSD from mother to child buy genuine prometrium on line medicine 44175. They studied mothers who had been pregnant (and their subsequent children) who were exposed/not exposed to the Rwandan Tutsi genocide. They found that PTSD (and depression) was transmitted from mother to offspring, and was associated with transmission of higher methylation of the promoter of the promoter of the GR gene and lower GR levels. Antisocial personality disorder Here we continue to consider the trauma of childhood sex abuse, but move away from the GR. Beach et al (2011) studied females who had experienced childhood sex abuse. They found increased methylation of the promoter region of the serotonin transporter gene (5HTT). Thus, the connection between childhood sex abuse and antisocial personality disorder may be mediated by epigenetic marks placed on the promoter region of 5HTT. Chronic social defeat stress in mice (a model of depression) is associated with increased histone methylation at the promoter regions of BDNF gene in the hippocampus. Imipramine treatment reversed this process by histone acetylation at the promoters. Thus, histone remodeling has been implicated in the pathophysiology and treatment of depression (Tsankova et al 2006). In human inpatients with major depressive disorder increased methylation of the insulin dependent glucose transporter 1 (GLUT1) was demonstrated (Kahl et al, 2016). After treatment, remitters (but not non-remitters) demonstrated significant lowering of GLUT1 methylation. Drug and alcohol addiction Findings of many epigenetic changes have been reported in association with addiction to many different agents. So far, many are from animal studies, however, Andersen et al (2015) have reviewed robust changes in DNA methylation in humans with a range of substance abuse disorders. In laboratory animals, Maze et al, (2010) described histone methylation in the nucleus accumbens (an important pleasure center) associated with cocaine use. Sun et al (2012) described similar molecular events in response to chronic morphine administration. Sakharkar et al (2016) demonstrated that intermittent alcohol consumption in adolescent rodents decreased histone acetylation which reduced brain-derived neurotrophic factor (BDNF) and neurogenesis in the hippocampus of adults. Vassoler et al (2013) described amazing transgenerational epigenetic effects in the offspring of male rats which have been self-administering cocaine. The male offspring (but not the females) display little interest in the self-administration of cocaine. These animals feature modification of histone acetylation and Bdnf promoter and increased BDNF in the medial prefrontal cortex (mPFC). Schizophrenia Wockner et al (2014) performed genome-wide DNA methylation analysis on post-mortem human brain tissue from patients with schizophrenia and controls. Two clusters were identified, one contained 88% of people with schizophrenia and 12 % of controls, and the other contained 27% of people with schizophrenia and 73% of controls. These findings indicate that differential DNA methylation is important in the etiology of schizophrenia. Eventually it may be possible to identify aberrant DNA methylation profiles which can be translated into a diagnostic test for use with blood or saliva samples. Montano et al (2016) studied 689 people with schizophrenia and found some overlap with the above study. Major psychosis In this section, schizophrenia and bipolar disorder are considered together. There is some evidence that these disorders may not be distinct (Craddock and Owen, 2005). However, to date, epigenetic studies support a distinction. Dempster et al (2011), conducted a genome-wide study of peripheral blood of monozygotic twins discordant for schizophrenia and bipolar disorder. They found differences in DNA methylation which they believe explained the different phenotypes. Rubin et al (2016) studied DNA methylation of the oxytocin receptor gene, and reported higher methylation in schizophrenia than bipolar disorder. Other psychiatric disorders It is probable that epigenetic modifications will be important in most psychiatric disorders. Eating disorders (Pjetri et al 2012), anxiety (Hunter & McEwen 2013), OCD (Nissen et al, 2016), ADHD (Schuch et al, 2015) and borderline personality disorder (Teschler et al, 2016) have all been studied or studies are in the planning stage. SUICIDE Suicide is not a mental disorder and is not always the result of mental disorder (Pridmore 2015). A postmortem study of the Wernicke area of suicide subjects found hypermethylation of the promoter of BDNF, which could explain the downregulation of BDNF expression in this population (Keller et al 2010). A recent genome-wide investigation of the brains of suicide subjects, demonstrated 366 promoters that were differentially methylated in the hippocampus of suicide completers compared to controls. The effects of these changes remain to be confirmed (Labonte et al 2013). Reviews (Lockwood et al, 2015) support a role for epigenetics in depression and suicide, but it is not clear whether identified changes are associated with depression, or suicide or both. GRAY MATTER VOLUME Methylation of the serotonin transporter gene is associated with hippocampal increased gray matter volume (hippocampal caudate, insula and caudate nucleus grey matter volumes). Thus, epigenetic processes can alter brain structure (Dannlowski et al, 2014). TREATMENT Changing epigenetic markers - a form of treatment There is great interest in finding ways to alter epigenetic status in the hope of therapeutic outcomes. Weaver et al (2004&5) (working with rodents) used central infusion of a histone deacetylase inhibitor to remove epigenetic marks and the effects of maternal care. Changing epigenetic markers – a consequence of treatment There is interest in understanding the impact of established treatments on the epigenome. These effects need to be taken into consideration when seeking to describe epigenetic patterns of particular disorders. Perroud et al (2013) have demonstrated that in borderline personality disorder, response to psychotherapy was associated with a decrease in methylation of the promoter of the BDNF gene. De Jong et al (2014) suggest that electroconvulsive seizure in animals (a model of ECT) has a robust impact on epigenetic mechanisms, which may be useful in the development of electrical treatments. Changes in DNA methylation changes have been demonstrated with valproic acid and quetiapine (Houtepen et al, 2016). Mentioned above, imipramine treatment reversed histone methylation associated with depression (Tsankova et al 2006).

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Even tubule to interstitium is increased prometrium 200mg on line treatment quad strain, favoring increased volum e reab- though the proxim al tubule hydrostatic pressure (Pt) m ay be sorption purchase prometrium discount medications hyponatremia. M echanisms of Sodium and Chloride Transport along the Nephron FIGURE 2-15 Lumen Cellular m echanism s and regulation of sodium chloride (N aCl) and volum e reabsorption along the proxim al tubule order 100 mg prometrium otc symptoms 2. The sodium -potas- + α Renal sium adenosine triphosphate (N a-K ATPase) pum p (shown as Na + nerves white circle with light blue outline) at the basolateral cell m em - Seefigure 2-13 brane keeps the intracellular N a concentration low; the K concen- H+ + tration high; and the cell m em brane voltage oriented with the cell AT1 All interior negative, relative to the exterior. M any pathways partici- – + Seefigure 2-7 pate in N a entry across the lum inal m em brane. O nly the sodium - hydrogen (N a-H ) exchanger is shown because its regulation in DA1 Dopamine states of volum e excess and depletion has been characterized exten- sively. Activity of the N a-H exchanger is increased by stim ulation – ↑FF H O of renal nerves, acting by way of receptors and by increased lev- 2 ~ Seefigure 2-14 els of circulating angiotensin II (AII), as shown in Figures 2-7 and 3Na+ 2K+ 2-13 [25–28]. Increased levels of dopam ine (DA1) act to inhibit activity of the N a-H exchanger [29,30]. Dopam ine also acts to + ↓Pi inhibit activity of the N a-K ATPase pum p at the basolateral cell Na+ ↑ m em brane. As described in Figure 2-14, increases in the filtra- - + onc Cl tion fraction (FF) lead to increases in oncotic pressure ( onc) in per- Interstitum itubular capillaries and decreases in peritubular and interstitial hydrostatic pressure (Pi). These changes increase solute and volum e absorption and decrease solute backflux. W ater flows through water channels (Aquaporin-1) N a and Cl also traverse the paracel- lular pathway. K recycles back V2 AVP through apical membrane K channels (ROM K) to permit continued 2Cl – operation of the transporter. In this nephron segment, the asymmet- K – ric operations of the luminal K channel and the basolateral chloride – PR PGE2 channel generate a transepithelial voltage, oriented with the lumen K positive. Although 20-HETE Cl arginine vasopressin (AVP) is known to stimulate Na reabsorption by 20-COOH-AA TAL cells in some species, data from studies in human subjects sug- c-P450 gest AVP has minimal or no effect [31,32]. The effect of AVP is Arachidonic ~ mediated by way of production of cyclic adenosine monophosphate acid 3Na+ 2K+ (cAM P). Prostaglandin E (PGE ) and cytochrome P450 (c-P450) 2 2 metabolites of arachidonic acid (20-HETE [hydroxy-eicosatetraenoic + – acid] and 20-COOH-AA) inhibit transepithelial NaCl transport, at Na least in part by inhibiting the Na-K-2Cl cotransporter [33–35]. PGE2 also inhibits vasopressin-stimulated Na transport, in part by activat- ing Gi and inhibiting adenylyl cyclase. Increases in medullary Interstitum NaCl concentration may activate transepithelial Na transport by increasing production of PGE2. Inset A, Regulation of NKCC2 by chronic Na delivery. As in other nephron segm ents, Aldo receptor + Aldo intracellular N a concentration is m aintained low by the action of + Na Seefigure Y the N a-K ATPase (sodium -potassium adenosine triphosphatase) pum p at the basolateral cell m em brane. N a enters distal convolut- + ed tubule (DCT) cells across the lum inal m em brane coupled direct- Cl α ly to chloride by way of the thiazide-sensitive N a-Cl cotransporter. Transepithelial + ~ N a transport in this segm ent is also stim ulated by sym pathetic 3Na+ 2K+ nerves acting by way of receptors [41,42]. AT1 All Seefigure 2-7 DCT – + Interstitum Disorders of Sodium Balance 2. In these cells, sodi- FIGURE 2-19 um (N a) enters across the lum inal m em brane through N a channels Cellular m echanism of the m edullary collecting tubule (M CT). The m ovem ent of cationic N a from lum en to cell depolar- Sodium (N a) and water are reabsorbed along the M CT. Atrial natri- izes the lum inal m em brane, generating a transepithelial electrical uretic peptide (AN P) is the best-characterized horm one that affects gradient oriented with the lum en negative with respect to intersti- N a absorption along this segm ent. This electrical gradient perm its cationic potassium (K) to dif- nine vasopressin (AVP) and aldosterone are not as consistent fuse preferentially from cell to lum en through K channels [46,49]. Prostaglandin E2 (PGE2) inhibits N a transport by inner (RO M K). N a transport is stim ulated when aldosterone interacts m edullary collecting duct cells and m ay be an im portant intracellu- with its intracellular receptor. This effect involves both lar m ediator for the actions of endothelin and interleukin-1 [50,51]. This second m essenger inhibits a lum inal N a channel Arginine vasopressin (AVP) stim ulates both N a absorption (by that is distinct from the N a channel expressed by the principal cells interacting with V2 receptors and, perhaps, V1 receptors) and of the cortical collecting tubule, as shown in Figure 2-18 [52,53]. V2 Under norm al circum stances, AN P also increases the glom erular fil- receptor stim ulation leads to insertion of water channels (aquapor- tration rate (GFR) and inhibits N a transport by way of the effects in 2) into the lum inal m em brane. V2 receptor stim ulation is on the renin-angiotensin-aldosterone axis, as shown in Figures 2-7 m odified by PGE2 and 2 agonists that interact with a receptor to 2-10. AC— adenylyl cyclase; ATP— adenosine nation of increased distal N a delivery and inhibited distal reabsorp- triphosphate; cAM P— cyclic adenosine m onophosphate; CCT— cor- tion leads to natriuresis. In patients with congestive heart failure, tical collecting tubule; Gi— inhibitory G protein; Gs— stim ulatory distal N a delivery rem ains depressed despite high levels of circulat- G protein; R— Ri receptor. Thus, inhibition of apical N a entry does not lead to natri- uresis, despite high levels of M CT cGM P. AR— AN P receptor; GC— guanylyl cyclase; K— potassium ; V2— receptors. Peritonitis Pancreatitis Small bowel obstruction Rhabdomyolysis, crush injury Bleeding into tissues Venous occlusion FIGURE 2-20 In volum e expansion, total body sodium (N a) content is increased. In prim ary renal N a retention, volum e expansion is m odest and edem a does not develop because blood pressure increases until N a excretion m atches intake. In secondary N a retention, blood pres- sure m ay not increase sufficiently to increase urinary N a excretion until edem a develops. FIGURE 2-23 FIGURE 2-24 Clinical signs of volum e depletion. N ote that laboratory test results for volum e expansion and contraction are sim ilar. Serum sodium (N a) concentration m ay be increased or decreased in either volum e expansion or contraction, depending on the cause and intake of free water (see Chapter 1). Acid-base disturbances, such as m etabol- ic alkalosis, and hypokalem ia are com m on in both conditions. The sim ilarity of the lab- oratory test results of volum e depletion and expansion results from the fact that the “effective” arterial volum e is depleted in both states despite dram atic expansion of the extracellular fluid volum e in one. Unifying Hypothesis of Renal Sodium Excretion from a reduction in m ean arterial pressure M yocardial ↓ Extracellular (M AP). Som e disorders decrease cardiac dysfunction fluid volume output, such as congestive heart failure owing to m yocardial dysfunction; others – – High output decrease system ic vascular resistance, such AV fistula Cirrhosis Pregnancy failure as high-output cardiac failure, atriovenous – – fistulas, and cirrhosis. Because M AP is the – – product of system ic vascular resistance and cardiac output, all causes lead to the sam e Cardiac output × Systemic vascular resistance = M ean arterial pressure result. As shown in Figures 2-3 and 2-4, sm all changes in M AP lead to large changes + in urinary N a excretion. Although edem a- tous disorders usually are characterized as Sodium excretion resulting from contraction of the effective (pressure natriuresis) arterial volum e, the M AP, as a determ inant of renal perfusion pressure, m ay be the cru- cial variable (Figs. The m echanism s of edem a Sum m ary of m echanism s of sodium (N a) retention in volum e contraction and in depletion in nephrotic syndrom e are m ore com plex of the “effective” arterial volum e.

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The rationales have broadly whether the mechanism is DA release cheap prometrium master card treatment jones fracture, direct effects on DA involved mechanisms such as sensitization and kindling as receptors cheap 200 mg prometrium otc medications guide, or DA reuptake blockade is unclear buy prometrium 100mg lowest price symptoms lymphoma. One study well as neurotransmitter systems that are indirectly affected examined the effects of acute amantadine (200 or 400 mg) by cocaine such as the opioid, excitatory amino acid/gluta- and chronic amantadine (100 mg twice daily for 4 days) mate, and GABAergic systems. For most of these ap- followed by insufflation of cocaine 0. Al- proaches, outpatient clinical trials have been quite limited. Finally, stress responses and the associ- The effectiveness of amantadine was evaluated in a double- ated elevation of cortisol have been considered as potentially blind, placebo-controlled trial in which 42 patients in a day important in cocaine craving induction and as a therapeutic treatment program were randomized to amantadine 100 mg agent. However, a cocaine administration study showed no twice daily (n 21) to be taken over 10 days or placebo reduction in cocaine effects or self-administration with the (n 21). Urine toxicology screens showed that those who cortisol synthesis inhibitor ketoconazole in spite of signifi- had received amantadine were significantly more likely to cant reductions in cortisol levels (59). A double-blind, placebo- human volunteers examined the effects of 10 mg L-deprenyl controlled, crossover study of the interaction of 400 mg of alone and in combination with cocaine, but found no atten- CBZ daily for 5 days with cocaine found no effects on uation of cocaine effects (54). More recently, it was found subjective response to cocaine (60). A double-blind, pla- to attenuate some subjective effects of cocaine, and an out- cebo-controlled study in outpatients included a 20-day, patient trial showed reduced cocaine use reported in com- controlled, fixed-dose (CBZ 200 mg or 400 mg or placebo) Chapter 102: Pathophysiology and Treatment of Cocaine Dependence 1467 trial in 30 volunteers and found that cocaine use was un- caine 'high,' it decreased craving for cocaine. Another study in 183 cocaine abusers ran- cocaine concentration following cocaine administration was domized to CBZ 400 or 800 mg daily or placebo showed significantly greater while on disulfiram, and this may have that CBZ at 400 mg was associated with a significant de- contributed to the decreased craving and increased dys- crease in cocaine-positive urines and a reduction in cocaine phoria observed in some subjects. However, three other double-blind, placebo- that cocaine use was significantly reduced in the disulfiram controlled studies with CBZ treatment in over 150 subjects group compared to psychotherapy alone, with patients who found no significant difference in cocaine use, cocaine-posi- abused both alcohol and cocaine. The patients reported a tive urine samples, or depressive symptoms measured by the significantly lower percentage of cocaine use days and fewer Beck Depression Inventory (63–65). Plasma CBZ levels of days of cocaine use, and fewer positive urine screens for 5. In surveys of cocaine abusers, 65% have reported signifi- Naltrexone is an opioid antagonist that has been exam- cant problems in concentration and 57% reported memory ined as a treatment agent for cocaine abuse. One study ex- problems, and formal testing suggests some sustained abnor- amined the effects of cocaine after 10 days of treatment with malities in memory and concentration among abusers (3, naltrexone 50 mg or placebo in a double-blind, randomized, 16). Initial studies of recovering cocaine-dependent patients within-subjects design (66). Some cocaine-induced subjec- have revealed impairments of short-term memory, atten- tive effects were less during naltrexone than placebo admin- tion, and complex psychomotor and simple motor abilities, istration. A placebo-controlled outpatient study of naltrex- but the data are limited (16,77). The calcium channel antago- functional brain damage caused by cocaine including strokes nist nifedipine has been studied and shows some promise (16). Structural imaging using computed tomographic scan- (68). Nimodipine showed a reduction in the effects of intra- ning and magnetic resonance imaging (MRI) have shown venous cocaine as well as reductions in acute cocaine-related enlarged ventricles and sulci in cocaine abusers (79). Func- cardiovascular toxicity, but lamotrigine did not reduce co- tional neuroimaging studies have shown focal reductions in caine effects in a similar placebo-controlled crossover study regional cerebral blood flow(rCBF) among chronic cocaine (69,70). Memantine, a glutamate inhibitor, showed no effi- abusers (15–17). These defects also appear to be persistent cacy in reducing cocaine effects acutely (71). Outpatient for several weeks of abstinence at least, and can be associated placebo-controlled studies have not been done with these with neuropsychological deficits (15–17,80). Unfortu- normally high levels of phosphomonoesters and lowlevels nately, this agent is not available in the United States, and of nucleotide triphosphates compared to normals (81). However, baclofen, which is a involve vasoconstriction (82) and platelet abnormalities. Abnormal platelets may produce thrombosis No other controlled trials have been published with this or in cerebral vessels and produce blood flowalterations (18). One study in six cocaine-dependent nary test of 4 weeks of aspirin therapy led to a 50% improve- volunteers examined the effect of disulfiram 250 mg on ment in cerebral perfusion (16). In a placebo-controlled responses to intranasal cocaine (2 mg/kg) using a random- study that has just been completed, aspirin significantly re- ized double-blind, placebo-controlled design (75). Al- duced perfusion defects on single photon emission com- though disulfiram induced no significant differences in co- puted tomography (SPECT) imaging (84,85). It was a large, multisite psychother- apy clinical trial for outpatients who met the DSM-IV crite- Although the simplest peripheral blocking approach of pas- ria for cocaine dependence. For 480 randomized patients, sively injecting polyclonal antibodies to cocaine into a four treatments were compared over an 18-month period. One treat- ies would not last very long and might be of limited use as ment also added cognitive therapy, one added supportive- a sustained treatment. For any type of relapse prevention, expressive psychodynamic therapy, and one added individ- the immune response elements must remain at relatively ual drug counseling. The final group had drug counseling high levels for periods of several weeks or months, which alone. Two specific interaction hypotheses, one involving is best done by active immunization (86). However, three psychiatric severity and the other involving degree of antiso- other approaches using catalytic antibodies, monoclonal cial personality characteristics, were examined, but no major passive antibodies, or injections of butrylcholinesterase have findings related to these hypotheses have been found (88, some promise (87). Either of these was intensive, including 36 possible individual sessions and effects can cause a very significant reduction in the high or 24 group sessions for 6 months. All four of these approaches can also be monthly during active treatment and at 9 and 12 months combined and used together with the pharmacotherapies after baseline. Primary outcome measures were the Addic- described above. The only approach that has been tested tion Severity Index–Drug Use Composite score and the in humans is active immunization (86). The initial animal number of days of cocaine use in the past month. Compared studies showed excellent production of a highly specific an- with the two psychotherapies and with group drug counsel- tibody to cocaine. With active immunization the amount ing (GDC) alone, individual drug counseling plus GDC of inhibition of cocaine entering the brain ranged from 30% showed the greatest improvement on the Addiction Severity to 63% at 30 seconds after cocaine injection in rats. Individual group coun- amount of inhibition was sufficient to extinguish cocaine seling plus GDC was also superior to the two psychothera- self-administration in the rat model. In the initial human study of this vaccine, it was well Hypotheses regarding the superiority of psychotherapy to tolerated with virtually no side effects using a dose of 1,000 GDC for patients with greater psychiatric severity and the g given with two booster injections over a 3-month period superiority of cognitive therapy plus GDC compared with (88). The vaccine produced substantive quantities of anti- supportive-expressive therapy plus GDC for patients with body that was related to both the dose of vaccine and the antisocial personality traits or external coping style were not number of booster injections. Thus, compared with professional psychother- potential efficacy in relapse prevention for abstinent cocaine apy, a manual-guided combination of intensive individual abusers appear warranted.