Stud- or CBF in patients with alcoholism purchase flonase 50mcg otc allergy vs side effect, multiple studies have ies comparing the response to benzodiazepines between con- been done comparing regional brain metabolic and CBF trol subjects and patients with alcoholism showed a signifi- responses to various pharmacologic challenges between con- cantly lower response in the orbitofrontal cortex in patients trol subjects and patients with alcoholism order flonase overnight delivery allergy testing johnstown pa. Because most of with alcoholism than in controls (46 buy 50 mcg flonase with visa allergy medicine hydrochloride,53). The blunted re- the pharmacologic interventions were chosen to target a sponse to lorazepam in orbitofrontal cortex persisted after specific neurotransmitter system, we will discuss the find- detoxification, a finding suggesting that it was not the result ings from these studies under the neurotransmitter heading. Such studies showed that acute alcohol ad- in benzodiazepine receptors using PET and [11C]flumazenil ministration decreased brain glucose metabolism (Fig. When compared with controls, patients with alco- though there were no changes in the levels of receptor be- holism showed a significantly larger reduction in metabo- tween controls and patients with alcoholism, the latter had lism despite showing less subjective response to the intoxi- a significantly larger variability for Bmax (receptor concentra- cating properties of ethanol (55). In control subjects but tion) measures than controls (63). However, more recent not in patients with alcoholism, the subjective response to studies have consistently reported significant decreases in Chapter 103: Application of Imaging Technologies in Drug Addiction 1483 benzodiazepine receptors in patients with alcoholism, pre- trols. This study showed that mCPP-induced activation in dominantly in frontal brain regions including cingulate thalamus, orbitofrontal cortex, caudate, and middle frontal gyrus and orbitofrontal cortex (64,65), but also in cerebel- gyrus was significantly blunted in patients with alcoholism lum (66). The reductions in benzodiazepine receptors in when compared with controls (74). This finding was inter- patients with alcoholism reported by these imaging studies preted as reflecting a hyporesponsive striatothalamoorbito- are consistent with postmortem studies and may indicate frontal circuit in patients with alcoholism. The abnormal either a toxic effect of alcoholism on benzodiazepine recep- response to mCPP suggests an involvement of the serotonin tors or a vulnerability factor for developing alcoholism. The system in the abnormalities seen in this circuit in patients reductions in benzodiazepine receptors in the orbitofrontal with alcoholism. This study showed a significant reduction in the availability of brainstem serotonin transporters in patients with alcoholism Dopamine System that was significantly correlated with lifetime alcohol con- DA D2 receptors were evaluated in patients with alcoholism sumption and with ratings of depression and anxiety during with PET and [11C]raclopride and showed significant re- withdrawal (75). As for the prior study, this finding provides ductions in DA D2 receptor availability when compared evidence of a role for serotonin in alcoholism and in its with controls (67,68). No significant correlations were involvement with depressive symptoms during withdrawal. One of these studies also Opioid System measured DATs in a subgroup of the alcoholics in whom reductions in DA D2 receptors were detected and reported The effects of an oral naltrexone challenge on CBF in pa- no changes in DAT availability (68). This finding was inter- tients with alcoholism during detoxification was studied preted as evidence of GABAergic involvement in patients with SPECT and HMPAO. At baseline, patients with alco- with alcoholism because DA D2 receptors in striatum are holism showed lower CBF in left orbitofrontal cortex and mainly localized in GABA cells. After naltrexone, a signifi- DAT availability in patients with alcoholism has been cant regional CBF decrease was found in basal ganglia and measured by various PET and SPECT studies. The results the left mesial temporal region, which are structures rich in have not been consistent. These results were interpreted as support- reported that a group of violent patients with alcoholism ing the involvement of the opioid system in alcohol depen- had increases (8%) and nonviolent patients with alcoholism dence (76). SPECT studies in nonviolent patients with late-onset Spectroscopic Studies alcoholism have also reported a reduction in DATs (70). However, a PET study done with [11C]D-threo-MP and a Patients with alcoholism had a significant reduction of the SPECT study done with [123I] -CIT showed no changes cerebellar N-acetylaspartate–to-creatine ratio, which was in- in DATs in patients with alcoholism (71,68). These discrep- terpreted as reflecting neuronal loss and a reduction of the ancies are likely to reflect in differences in the time since choline-to-creatine ratio, which was interpreted as reflecting detoxification. One SPECT study showed that whereas cell membrane modification or myelin alterations (77). DAT levels were significantly reduced in patients with alco- holism within the first few days of last alcohol use, the levels Subjects at Risk of Alcoholism returned to normal 4 weeks after detoxification (72). PET studies with 6-[18F]-FDOPA (a marker for the DA synthesis The regional brain metabolic response to lorazepam was in the DA terminal) in patients late-onset (type 1) alcohol- evaluated in subjects with a positive family history of alco- ism showed higher striatal 6-[18F]-FDOPA uptake in the holism (FHP) and was compared with that of subjects with- patients with alcoholism than in the controls, a finding that out a family history of alcoholism (FHN) (78). At baseline, was interpreted as a compensatory mechanism to low post- FHP subjects showed lower cerebellar metabolism than synaptic DA function (73). FHN, and when challenged with lorazepam, they also showed a blunted response in cerebellum and in anterior cingulate gyrus. Lorazepam-induced changes in cerebellar Serotonin System metabolism were significantly correlated with motor impair- The effects of m-chlorophenylpiperazine (mCPP), a mixed ment. The blunted cerebellar sensitivity to benzodiazepines serotonin agonist-antagonist drug, on brain glucose metab- in FHP could account for the decreased sensitivity to the olism was compared in patients with alcoholism and in con- motor effects of alcohol and benzodiazepines in FHP sub- 1484 Neuropsychopharmacology: The Fifth Generation of Progress jects. The decreased cerebellar baseline metabolism in FHP in cerebral high-energy phosphates and in phospholipid me- subjects as well as the blunted cerebellar response to lora- tabolites. Marijuana Opiates Marijuana is the most widely used illicit drug of abuse in the United States. Despite its widespread use, the mecha- The effects of morphine on brain glucose metabolism were 9 nisms by which -tetrahydrocannabinol (THC) (the main evaluated in polydrug abusers (79). This study showed that psychoactive substance of marijuana) exerts its psychoactive morphine reduced glucose metabolism by 10% in whole effects are still not known. Relatively few imaging studies brain and by about 5% to 15% in telencephalic areas and have been done to assess the effects of acute and chronic the cerebellar cortex. Morphine-induced metabolic decre- marijuana use in the human brain. The effects of acute fentanyl, a synthetic opiate, on CBF were measured with PET and [15O]water. Fentanyl Brain Metabolism and Cerebral Blood Flow administration was associated with significant increases in regional CBF in cingulate, orbitofrontal, and medial pre- SPECT studies assessed the effect of THC intoxication on frontal cortices, as well as caudate nuclei, areas known to CBF in chronic marijuana users (84,85). Acute marijuana be involved in reward and addiction (80). In a more continuation and then retested 2 weeks later (81). The recent study, these investigators extended these findings to initial scans demonstrated significant CBF defects in the a larger groups of subjects and documented increases in frontal, parietal, and temporal cortices. Two weeks later, CBF in anterior cingulate gyrus and in the insula in mari- the SPECT scans showed improvement. Interpretation of the effects of THC on this study provide evidence that long-term use of opiates CBF is confounded by the vasoactive properties of THC results in perfusion abnormalities that are partially reversible (87). Thus, it is difficult to separate the effects of THC that with short-term abstinence. This problem is obviated when using deoxyglucose to measure brain glucose metabo- Dopamine System lism because this agent is insensitive to fluctuations in CBF Using PET and [11C]raclopride, opioid-dependent subjects (88). Naloxone-induced withdrawal in opioid-depen- lism have been evaluated in nonabusing controls (89) as well dent subjects did not change [11C]raclopride binding, a as in marijuana abusers (90). The whole-brain metabolic finding indicating that withdrawal does not alter synaptic response to the effects of THC was variable among individu- DA in the striatum as measured by this method (82). Despite these variable responses in whole-brain metabolism, there was a very consistent pat- Opioid System tern of metabolic activation by THC.
Blood pres- sure (BP) m edications m ay require adjustm ent buy flonase 50mcg overnight delivery allergy medicine generic list, depending on the m agnitude of the pregnancy-related changes in blood pressure buy flonase 50mcg online food allergy treatment guidelines. In the latter half of pregnancy order online flonase allergy medicine anxiety, close surveillance for early signs of preeclam psia increases the likelihood the condition will be diag- nosed before it progresses to a severe stage. FIGURE 10-42 ANTIHYPERTENSIVE THERAPY The overall treatm ent goals of chronic hypertension in pregnancy are to ensure a success- FOR CHRONIC HYPERTENSION ful full-term delivery of a healthy infant without jeopardizing m aternal well-being. The DURING PREGNANCY level of blood pressure control that is tolerated in pregnancy m ay be higher, because the risk of exposure of the fetus to additional antihypertensive agents m ight outweigh the ben- efits to the m other (for the duration of pregnancy) of having a norm al blood pressure. Methyldopa M ost antihypertensive agents have been evaluated only sporadically during gestation, and blockers (labetalol) careful follow-up of children exposed in utero to m any of the agents is lacking. The only antihypertensive agent for which such follow-up exists is m ethyldopa. Because no adverse Calcium channel blockers effects have been docum ented in offspring of exposed m others, m ethyldopa is considered Hydralazine to be one of the safest drugs during pregnancy. Diuretics can be used at low doses, particu- larly in salt-sensitive hypertensive patients on chronic diuretic therapy. Angiotensin-con- verting enzym e inhibitors are contraindicated in pregnancy because they adversely affect fetal renal function. Angiotensin II receptor antagonists are presum ed to have sim ilar effects but have not been evaluated in hum an pregnancy. Baylis C: Glom erular filtration and volum e regulation in gravid anim al 19. Sibai BM , Kusterm ann L, Velasco J: Current understanding of severe m odels. Lindheim er M D, Katz AI: The kidney and hypertension in pregnancy. Philadelphia: enzym es, and low platelet syndrom e, and postpartum acute renal W B Saunders Co; 1991:1551–1595. Davison JM , Shiells EA, Philips PR, Lindheim er M D: Serial evaluation 20. H ou S: Peritoneal dialysis and hem odialysis in pregnancy. Clin O bstet of vasopressin release and thirst in hum an pregnancy: role of chorionic G ynaecol (Balliere) 1994, 8:491–510. Davison JM : Pregnancy in renal allograft recipients: problems, prognosis, and practicalities. Lindheim er M D, Richardson DA, Ehrlich EN , Katz AI: Potassium hom eostasis in pregnancy. Douglas KA, Redm an CW : Eclam psia in the United Kingdom. Brown M A, Sinosich M J, Saunders DM , Gallery EDM : Potassium regulation and progesterone-aldosterone interrelationships in hum an 23. Chesley LC, Annitto JE, Cosgrove RA: Pregnancy in the sisters and pregnancy. Lim VS, Katz AI, Lindheim er M D: Acid-base regulation in pregnancy. Cooper DW , Brenneckes SP, W ilton AN : Genetics of pre-eclam psia. Khong TY, W F De, Robertson W B, Brosens I: Inadequate m aternal 7. Am J preeclam psia and sm all for gestational age infants. August P, M ueller FB, Sealey JE, Edersheim TG: Role of renin- 26. Zhou Y, Fisher SJ, Janatpour M : H um an cytotrophoblasts adopt a angiotensin system in blood pressure regulation in pregnancy. Zhou Y, Dam sky CH , Fisher SJ: Preeclam psia is associated with failure outcom e. H ayslett JP, Lynn RI: Effect of pregnancy in patients with lupus O ne cause of defective endovascular invasion in this syndrom e? Lüscher TF, Dubey RK: Endothelium and platelet=derived vasoactive erythem atosus. In H ypertension: Pathophysiology, D iagnosis and M anagem ent, edn 2. Im basciati E, Surian M , Bottino S, et al: Lupus nephropathy and aspirin for the prevention and treatm ent of preeclam psia am ong 9364 pregnancy. A study of 26 pregnancies in patients with system ic pregnant wom en. Arch Intern M ed 1982, analysis of random ized controlled trials. H ojo M , August P: Calcium m etabolism in norm al and hypertensive predictor of fetal distress on death in pregnant patients with system ic pregnancy. Chapm an AB, Johnson AM , Gabow PA: Pregnancy outcom e and its preeclam psia. Renal biopsy during pregnancy: developm ent of superim posed preeclam psia. In H em olytic Urem ic Syndrom e and Throm botic Throm bocytopenic Purpura. Gertz he word amyloid was first coined in 1838 by Schleiden, a German botanist, to describe a normal constituent of plants. Virchow Tobserved the similarity of the staining properties of the amyloid to those of starch and named it amyloid. All forms of amyloid appear homogeneous when viewed under a light microscope and are pale pink when stained with hematoxylin-eosin. Under polarized light, amyloid stained with Congo red dye produces the charac- teristic apple-green birefringence. The modification of alkaline Congo red dye by Puchtler and Sweat is used most often. The amorphous hyaline- like appearance of amyloid is misleading because it is a fibrous protein. On electron microscopy, amyloid deposits are composed of rigid, linear, non- branching fibrils 7. The deposits occur extracellularly and ultimately lead to damage of normal tissue. In primary amyloidosis (AL) the fibrils consist of the variable portions of monoclonal ( ) or ( ) immunoglobulin light chains or, very rarely, heavy chains. In secondary amyloidosis (AA) the fibrils consist of protein A, a non- immunoglobulin. In familial amyloidosis (AF) the fibrils are composed of mutant transthyretin (prealbumin) or, rarely, fibrinogen or apolipoprotein. In senile systemic amyloidosis the fibrils consist of normal transthyretin.
Arch dase activity in subgroups of alcoholics and controls: results Gen Psychiatry 1998;55:593–602 order flonase toronto allergy buster. Greater abundance of serotonin1A Alcohol Clin Exp Res 1998;22:598–604 generic 50 mcg flonase visa allergy medicine quercetin. Serotonergic and nora- pared to -nonpreferring (NP) rats order flonase without a prescription allergy forecast indianapolis. Pharmacol Biochem Behav drenergic dysregulation in alcoholism: m-chlorophenylpipera- 1993;46:173–177. Am J Psychiatry 1996;153:83– sumption in null mutant mice lacking 5-HT1B serotonin recep- 92. Serotonin2C receptors and sero- functional polymorphisms of the alcohol-metabolism genes in Chapter 98: Vulnerability Factors for Alcoholism 1411 protection against alcoholism. Meta-analysis of the effects of alcohol dehydro- 795–807. Prevalence, onset, Jewish men in Israel: a pilot study. J Stud Alcohol 1998;59: and risk of psychiatric disorders in men with chronic low back 133–139. Nu- tion is accepted as a pleasurable pastime and even an en- merous studies have shown that alcoholism is familial. In hancer of health and well-being, it has historically been ob- the National Comorbidity Survey of 5,877 individuals, it served that a sizable minority is unable to keep within safe was found that alcohol use disorders aggregate significantly limits of consumption. Such individuals may abuse alcohol in families with an odds ratio of 1. Alcoholism is today among the most holic parent is a significant risk factor for the development pervasive psychiatric disorders. In the United States, the of the disease; children of alcoholics are five times more lifetime prevalence of alcohol dependence, the severe form likely to develop alcohol-related problems than children of of alcoholism, is 8% to 14% (1). It has been shown that the transmission dence to abuse is 1. Individuals often maintain a pattern of the vulnerability to alcoholism from parents to their of alcohol abuse without dependence for many years (2). Serious drinking frequently begins in adolescence, and ap- Studies of heritability, a measure of the genetic compo- proximately 40% of alcoholics develop their first symptoms nent of variance in interindividual vulnerability, indicate of addiction between the ages of 15 and 19 years (3). As that genetic influences are substantially responsible for the discussed in this chapter, heritability studies suggest that an observed patterns of familiality. Comparative studies across populations suggest holism in children even when the child is reared by unre- that sociocultural factors determine differences in thresholds lated adoptive parents (7,8). Large, well-constructed twin above which an individual is likely to go beyond social studies (8–10) have demonstrated that genetic factors are drinking and slip into abuse or addiction. Is the develop- important in determining vulnerability to alcoholism, par- ment of alcoholism due to a unique set of biochemical and ticularly in the more severe forms of the disease (11). Are there preexisting behav- been performed using the population-based Virginia Twin ioral traits that predispose to alcoholism? Caucasian female twin pairs of the questions addressed by this chapter. Some of the environmental influences are uniquely nonshared environmental factors, which is most accurately experienced by the individual (nonshared) and some are labeled as 'other,' including as it does other sources of variance such as measurement error (12). The results of these two studies were confirmed in a recent analysis of 5,091 U. This study also added the information Health, Bethesda, Maryland. Compared recent evaluation of the co-inheritance of alcoholism and with the expected genetic correlations of 0. Female twins from the Virginia Twin dence interval (CI) 4% to 45%] for opposite-sex pairs. Registry were evaluated for alcoholism, MD, BN, phobia, Although the heritability value of approximately 0. Alcoholism cohol dependence in men and women was replicated in emerged as the one disorder with a large disease-specific an analysis of 2,685 male and female twin pairs from the genetic component: approximately 75% of the genetic vari- Australian twin registry (10), no evidence was found for sex ance. In addition, smaller components of the genetic liabil- differences in sources of genetic influence. It may be that ity to alcoholism also loaded onto a factor common to MD the relatively small number of opposite sex pairs—592—in and GAD as well as a factor common to phobia, panic, and the Heath et al. COMORBIDITY OF ALCOHOLISM WITH OTHER SUBSTANCE ABUSE: GENETIC GENETIC HETEROGENEITY IN ALCOHOLISM DIATHESES? Although there is good evidence for substantial heritability Alcohol, cocaine, opiate, and tobacco (nicotine) depen- for alcoholism, individual differences in clinical presenta- dency co-occur more often in the population than would tion suggest variation in origins of vulnerability. This raises the pos- vary in their drinking patterns, the severity of their symp- sibility that there may be substance-general, as well as sub- toms, and in behavioral, physical, and psychiatric sequelae. Vulnerability factors found in some, but by hol and drug dependence (22,23). Both studies found that no means all, alcoholics include attentional deficits reflected relatives of drug-disorder probands across a wide range of by low amplitude of the P300 event-related potential (14), substances, including opioids, cocaine, and cannabis, had a anxiety reflected by the low-voltage alpha EEG trait (15), greater rate of drug disorders themselves than relatives of and diminished subjective response to alcohol (16). However, this comorbidity occurred largely inde- pendently from cotransmission of alcoholism, suggesting that the transmission of alcoholism and other drug disorders COMORBIDITY OF ALCOHOLISM AND is largely independent. OTHER PSYCHIATRIC DISORDERS: GENETIC The strongest evidence of a shared, as well as a specific, DIATHESES? It has long been observed that there is a relationship between Alcohol dependence is often comorbid with other psychiat- smoking and alcoholism. More than 80% of alcoholics ric disorders, including drug abuse, major depression (MD), smoke cigarettes and 70% are heavy smokers, compared anxiety disorders (ADs), and bulimia nervosa (BN), or anti- with 30% of the general population who smoke and 10% social personality disorder (ASPD) (17,18). In a multivariate genetic analysis currence is more common among women than men and is of the use of tobacco and alcohol in 774 MZ and 809 DZ positively associated with the persistence of alcohol depen- male and female twin pairs from the Virginia Twin Registry, dence in both men and women (18). Population comorbid- the univariate heritability of alcohol consumption was 0. Tobacco use had epidemiologic studies is their ability to detect evidence of a stronger loading on this shared genetic factor (0. However, the precise level of coexist in the same individuals, usually male. The relative the co-inheritance is less certain than the existence of co- risk of alcoholism is significantly increased in males with inheritance, and the level of genetic sharing may depend either ASPD, attention-deficit/hyperactivity disorder, or on how the phenotypes are determined. In an analysis of childhood conduct disorder, and there is evidence of co- 2,220 MZ and 2,373 DZ U. These data notwithstanding, a alcohol genetic factor accounted for 0. A study opioids are enhanced by activation of (and possibly also of 3,356 male twin pairs from the U. Registry found a substantial genetic correlation (r 0. Of the total vari- paminergic, opioid peptide, and serotoninergic neurotrans- ance in risk for alcohol dependence, 0.
Moreover discount flonase on line allergy shots ulcerative colitis, repeated administration of most drugs of or not these glutamatergic afferents to the nucleus accum- abuse generic 50 mcg flonase with visa allergy testing tuscaloosa al, including psychostimulants order flonase 50 mcg without a prescription allergy forecast kerrville tx, opioids, alcohol, and bens influence the behavioral effects of drugs of abuse and nicotine, increases the capacity of subsequent drug adminis- play a role in the neuroplasticity associated with the develop- tration to release dopamine in the nucleus accumbens (2,63, ment and expression of addictive behaviors is a subject of 65). This neurochemical reverse-tolerance or sensitization is much recent interest (13,59). For example, antagonists of opposite to what typically occurs with repeated exposure to the NMDA subtype of glutamate receptors block the devel- motivationally relevant environmental stimuli, such as food, opment of behavioral neuroadaptations (e. Of note, the indirect tion of most drugs of abuse, including alcohol, psychostim- measurement of dopamine release using methylphenidate- ulants, and opioids (59,60). Moreover, it has been shown induced displacement of radiolabeled D2 receptor antago- that drug craving induced in addicts by environmental stim- nist revealed an apparent decrease in dopamine release in uli previously paired with the drug experience is associated cocaine addicts compared with control subjects (66). As- with metabolic activation of the anterior cingulate and suming the veracity of D2 ligand displacement as an in vivo Chapter 95: Neurocircuitry of Addiction 1361 measure of dopamine release (67), this indicates a poten- prefrontal cortex and amygdala. In general, in animal tially important distinction between data in animal models models the repeated administration of drugs of abuse, in- and human cocaine addicts. The enhanced releas- Motivational Circuitry as a Site of ability may result in part from increased excitability of dopa- Addiction Pathologies mine cells (24,78–80), but also clearly involves increased The circuit shown in Fig. Following repeated am- the transition from dopamine- to glutamate-dependent be- phetamine and cocaine administration the elevated pre- haviors. This circuit has been a focus for research aimed synaptic release of dopamine arises from enhanced at determining how the neuroplastic changes produced in presynaptic calcium signaling through calmodulin kinase II various nuclei by repeated drug action at a molecular level (83–85). A number of enduring changes in postsynaptic are integrated with environmental stimuli to form the mal- dopamine signaling have also been identified. Most of these adaptive behaviors characteristic of addiction. Studies in this changes can be traced to alterations in gene expression fol- regard are most numerous for psychostimulants; the find- lowing stimulation of the D1 receptor-signaling cascade (2, ings employing this class of addictive drugs provide the pri- 86). Interestingly, among the genes showing changed mary buttresses of the model. However, emerging data with expression are protein products, including preprodynor- other drugs of abuse are generally consistent with this view; phin, NAC-1, and delta-Fos-B, that appear to dampen en- moreover, there is an abundance of behavioral data support- hanced dopamine transmission and/or the expression of be- ing the possibility that the neuroplastic changes elicited by haviors potentially related to addiction, such as motor repeated administration of one drug impinge on circuitry sensitization and conditioned place preference (87–89). For example, the This poses the likelihood that many changes produced by repeated administration of some drugs of abuse promotes repeated drug administration are not necessarily promoting the acquisition of addiction-related behaviors to another addictive behaviors but may constitute homeostatic altera- mechanistically similar drug of abuse (68,69). Similarly, a tions to minimize the impact of pathologic neuroadapta- number of overlapping cellular neuroadaptations, such as tions elicited by repeated drug injection. In addition to changes in G proteins, tyrosine hydroxylase, and certain changes in gene expression in the nucleus accumbens that immediate early genes, have been identified after repeated affect dopamine transmission, repeated administration of exposure to different drugs of abuse (70–73). Also, a num- psychostimulants also increases or decreases the synthesis ber of studies indicate behavioral and neurochemical overlap of proteins affecting glutamate transmission that may alter between the effects of repeated drug administration and postsynaptic corticofugal neurotransmission (see the follow- motivationally relevant environmental stimuli (e. This includes drug-induced changes in glutamate re- sensitization and cross-tolerance to stress) (65,69,74,75). In addition to the nucleus accumbens, more recent stud- Drug-Induced Changes in Presynaptic ies have examined the effect of repeated drug administration and Postsynaptic Dopamine Transmission on dopamine transmission in the PFC. In general, repeated As described in the preceding, most addictive drugs produce systemic drug administration reduces the releasability of do- significant elevations in cortical and subcortical dopamine pamine in the PFC. Such a blunting of stimulus- or drug- transmission, and repeated drug-induced dopamine release induced dopamine transmission in the PFC has been most causes enduring alterations in presynaptic and postsynaptic clearly shown after repeated cocaine and phencyclidine ad- dopamine transmission. These changes have been character- ministration (50,92). Further implicating reduced cortical ized using animal models of addiction, including behavioral dopamine transmission, destruction of dopamine afferents sensitization studies involving repeated investigator admin- to or blockade of dopamine receptors in the PFC promotes istered drug, as well as studies in which the acquisition, behavioral sensitization and drug self-administration maintenance, and reinstatement of drug self-administration (93–95). Moreover, the blunting of PFC dopamine trans- is measured (9,76,77). The majority of studies have endea- mission may be related to the cognitive dysfunction and vored to identify changes in nucleus accumbens dopamine increased impulsivity often associated with drug addiction transmission. However, in light of evidence implicating cor- (96). Although the effect of repeated drug administration by cocaine in cocaine-pretreated subjects (13,112). Taken on dopamine release in the PFC and amygdala differs, the together with the imaging data in human cocaine addicts changes in dopamine transmission in both structures may showing an association between cocaine craving and meta- contribute to expression of addictive behavior. Although bolic activity in the anterior cingulate cortex (4,61), the reduced dopamine transmission in the PFC may contribute data to date point toward a critical role in addiction for to cognitive dysfunction in some addicts (see the preceding), neuroadaptations in glutamate transmission in the projec- enhanced release of dopamine in the amygdala may contrib- tion from the PFC to the mesoaccumbens dopamine system. Supporting this possibility, stimu- cleus accumbens, although a role for this projection has lation of dopamine transmission in the amygdala increases been more difficult to demonstrate for some drugs of abuse, stimulus-reward associations, whereas the inhibition of do- notably amphetamine (59). Thus, the sensitized re- Amygdala-Thalamo-Cortical Circuit lease of dopamine in the amygdala may contribute to cue- induced relapse, a conclusion directly supported by imaging There is substantial evidence for a role by the amygdala in studies showing that drug craving in addicts is associated mediating the conditioning of behavior to obtain a natural with metabolic activation of the amygdala (4,61,62), and or drug reward (99,113,114). Thus, pharmacologically in- in experimental animal models where drug-associated cues hibiting neurotransmission within the amygdala prevents have been shown to increase glucose uptake or c-fos synthe- the capacity of a cocaine cue to elicit drug-seeking behavior sis in the amygdala (101,102). There are two likely connections from the amygdala Prefrontal and Anterior Cingulate Cortex that are mediating the relationship between learned associa- As outlined above, there is an enduring change in dopamine tions and rewarding stimuli. The first is an interconnected transmission in the PFC associated with repeated adminis- relationship with the amygdala, mediodorsal thalamus, and tration of some drugs of abuse. Various data suggest that this subcircuit is critical for of dopamine transmission in the PFC have generally re- the formation of learned associations with rewarding stimuli vealed that the actions of dopamine are state-dependent. The second connection is among the amygdala, This is reflected by distinct electrophysiologic effects of do- VTA, and nucleus accumbens. Although this subcircuit is pamine when pyramidal cells in the cortex are relatively important in unconditioned responses to most drugs of active or inactive (e. Although the effects of dopamine tioned stimuli to obtain reward, as well as cue-induced drug are state-dependent, dopamine clearly has the capacity to relapse (114). Although both circuits probably contribute modulate excitatory glutamatergic projections to the nu- to stimulus-induced drug relapse, the relative role of each cleus accumbens and VTA (105–107). Thus, the long-term may depend on the type of stimulus. For example, relapse alterations in PFC dopamine transmission by repeated drug precipitated by a low dose of drug, especially a drug known use change corticofugal glutamate transmission. More- The last decade has witnessed the emergence of a number of over, the blockade of glutamate receptors in the nucleus seminal developments in our understanding of the circuitry accumbens inhibits the expression of behavioral sensitiza- mediating addiction. Primary among these is that there ex- tion to cocaine, as well as the capacity of systemic cocaine ists substantial overlap in the circuits mediating behavioral to elicit drug craving using a reinstatement model of craving responses to non-drug and drug reward (Figs. ACKNOWLEDGMENT The second critical development is that neuroplasticity to drug reward arises from an interaction between the molecu- This work was supported in part by USPHS grants MH- lar site of drug action and environmental stimuli associated 40817, DA-11809, and DA-03906. In this way, cortical and allocorti- cal circuitry important in learning and memory is recruited and undergoes neuroplastic alterations in response to drugs of abuse. The studies outlined in this chapter describe REFERENCES changes in neurotransmission and cell signaling that may 1. J be critical in changing the functional status of the circuit Neuropsychiatry Clin Neurosci 1997;9:482–497. Neuroadaptations involved in amphet- and neurochemical neuroadaptations, it is also important amine and cocaine addiction.
By M. Brontobb. New Mexico Institute of Mining and Technology.