Stress Vulnerability, Substance Abuse, and Schizophrenia
Stress is important to the etiology of schizophrenia as well as craving for abused substances. Studies examining cumulative non-illness-related stressors have reported increased number of stressors a few weeks or months prior to the onset of relapse in schizophrenia, as well as in other psychiatric disorders (73-75). However, Norman and Malla (73) reported that the number of stressful life events in schizophrenia within the defined study period was not different from that in other psychiatric patients. Several clinical and preclinical studies suggest enhanced sensitivity to stress in schizophrenia. For example, patients with schizophrenia have been reported to have enhanced plasma homovanillic acid (HVA) (76), the major metabolite of DA, and greater adrenocorticotropine hormone (ACTH) (77) responses following metabolic stress compared to normal controls. Furthermore, various studies indicate abnormal regulation of the hypothalomic-pituitary-adrenal (HPA) axis in schizophrenia. Patients with schizophrenia, especially inpatients, have higher basal cortisol levels, than normal controls do (78,79). About one-third of schizophrenics show nonsuppression during the overnight 1-mg dexametha-sone suppression test (78,80). Recently, we (81) and Mokrani et al. (82) have reported the blunted HPA axis response to challenge with apomorphine, a direct-acting DA-agonist.
A leading hypothesis concerning the pathophysiology of schizophrenia is the contributing neurodevelopmental abnormalities in DA function leading to decreased DA activity in the prefrontal cortical DA system and increased
DA function in the mesolimbic DA system (83). Animal studies have reported that prefrontal dysfunction produced enhanced hormonal and neurochemical responses to stress. Animals with lesions in the medial prefrontal cortex (cingulate gyrus) responded with greater HPA-axis response to restraint stress (84). In addition, in rodents, prefrontal cortical DA depletion has been reported to enhance the responsivity of mesolimbic DA neurons to stress (85). Similarly, birth complications, which have been reported to be significantly more frequent in patients with schizophrenia (86), have been reported to produce enhanced nucleus accumbens DA neuronal responses to repeated stress during adulthood in rodents (87). These clinical and preclinical studies suggest that patients with schizophrenia may have heightened HPA axis and DA responsiveness to stress.
Patients with schizophrenia also showed enhanced sensitivity to psychostimulants. Recent neuroimaging studies (88,89) have reported significantly greater reduction of D2-receptor binding in the striatum after amphetamine challenge in patients with schizophrenia compared to normal controls, suggesting enhanced DA efflux following amphetamine in schizophrenia. This is consistent with the report by Lieberman et al. (72), who reported greater sensitivity to psychostimulant (becoming psychotic with low dose) in patients with schizophrenia compared to normal controls. In addition, schizophrenics who had a transient activation of psychotic symptoms following the psychostimulant challenge had a significantly shorter time to relapse than patients who did not have a symptom exacerbation (90,91). Similarly, substance-abusing schizophrenics have a higher relapse rate than non-substance-abusing schizophrenics (20,23,25,27,28). This enhanced sensitivity to psychostimulants and stress may have a common biological substrate.
Behavioral sensitization also develops following intermittent repeated exposure to stress, which is also mediated via the mesolimbic DA system (92-94). Furthermore, there is cross-sensitization between stress and psychostimulants (and other drugs) (92-94), and the HPA axis appears to mediate this interaction (93,94). Repeated exposure to stress has been reported to increase the behavioral response to psychostimulants and other drugs in rodents (92-94). This stress-induced enhanced sensitivity to addictive drugs is mediated via stress-induced glucocorticoids secretion, which increases the sensitivity of mesolimbic DA neurons to drugs (93,94). For example, metyra-pone, an inhibitor of corticosterone, suppressed stress-induced sensitization of the increase of DA in nucleus accumbens induced by cocaine and sensitization of cocaine-induced locomotion (94). Similarly, suppression of stress-induced corticosterone secretion by adrenalectomy abolished stress-induced sensi-tization of the locomotor effects of amphetamine and morphine (93).
Glucocorticoids at concentrations produced by stress have state-dependent stimulant effects on mesolimbic DA transmission. In rodents, they further enhance DA activity in situations that increase DA activity (e.g., in a dark phase, while eating, and in high responders to novelty), but have little effect in situations with low-normal DA activity (e.g., in a light phase and in low responders to novelty) (95). In summary, patients with schizophrenia may have enhanced HPA axis and DA responses to stress, which may increase the sensitivity to addictive drugs and contribute to the high rate of substance abuse.
Cannabis Abuse and Schizophrenia: Genetic and Environmental Influence
The possibility that substance abuse is a precipitating factor for the psychotic phase of schizophrenia has received considerable attention. Substance abuse may precede the onset of schizophrenia (96,97). Several reports relate cannabis use to the development of schizophrenia (98-102); a summary of the association is presented in the Table 2. Swedish conscripts with a history of cannabis use at age 20—the age of beginning military service—developed schizophrenia 2.4 times more frequently than nonusers (98). The rate was six times higher in heavy users (98). Furthermore, Tien and Anthony (99) examined quantitative relationships between substance use and psychotic diagnosis in a 4994-adult sample from the ECA study. They reported that the risk of developing a psychotic illness in daily users of marijuana was double that for nonusers, after controlling for daily cocaine use and alcohol disorder. Similarly, Linszen et al. (28) have reported significantly more and earlier psychotic relapses in canna-bis-abusing schizophrenics, especially in heavy abusers, compared to schizophrenics who did not abuse cannabis, after controlling for other substance abuse. In addition, cannabis abuse was reported to start before the onset of schizophrenia in 69-96% of patients abusing cannabis (28,100). Kovasznay et al. (38) have compared substance abuse in patients during early schizophrenia and affective psychosis. Cannabis was the only substance that showed a difference between groups; more schizophrenics used cannabis than did patients with affective psychosis (69.1% vs. 46.2%; p = 0.03). A high comorbid rate of schizophrenia in cannabis abusers, but not in cocaine or amphetamine abusers, was also found in the ECA study (1). Furthermore, Fried (103) has reported that prenatal exposure to marijuana was associated with impairment in verbal ability, memory, and attention in children at age 5 and 6. These areas of cognitive deficit are also present in patients with schizophrenia. The association between cannabis abuse and schizophrenia may be via genetic and/or environmental as well as direct pharmacological effect of cannabis.
Table 2. The Relationship of Cannabis Abuse to Schizophrenia
Prevalence of schizophrenia in cannabis abusers
Familial risk for cannabis abuse and schizophrenia
Effects of cannabis on psychosis
The higher rate of development of schizophrenia in cannabis abusers compared to nonabusers. The rate was six times higher in heavy abusers.
Cannabis abuse started before the onset of schizophenia in 69-96% of patients abusing cannabis.
The higher rate of cannabis abuse in patients with schizophrenia compared to patients with affective psychosis.
Significantly greater familial morbid risk of schizophrenia in patients with acute psychosis abusing cannabis compared to nonabusing patients.
Increased morbid risks for cannabis abuse in the first-degree relatives of schizophrenics compared to controls.
Administration of tetrahydrocannabinol (THC) transiently worsens psychosis in neuroleptic-treated schizophrenics and produces transient psychotic state in controls.
Source: Refs. 28,38,98-102,108.
McGuire et al. (101) examined lifetime morbid risk of psychiatric disorders in the first-degree relatives of 23 patients with acute psychosis and positive cannabis urine screen and sex-matched psychotic controls with negative urine drug screen. They reported significantly greater familial morbid risk of schizophrenia in the positive urine cannabis group (7.1%) than the controls (0.7%), while the risks of other psychoses and nonpsychotic conditions were similar. The same pattern of familial risk was present when the analysis was repeated in patients with DSM-III schizophrenia. In addition, Verma and Sharma (102) reported increased morbid risks for cannabis-use disorder as well as schizoid-schizotypal personality disorder, and paranoid personality disorders in the first-degree relatives of 162 schizophrenics compared to 106 controls. Cannabis abuse has been reported to have a genetic and/or family environmental influence. For example, Kendler and Prescott (104) reported that genetic risk factors have a strong impact on the risk of heavy use, abuse, and probably dependence on cannabis in a population-based sample of female twins. Tsuang et al. (19) reported, in 3372 male twin pairs, influence of a specific family environmental factor for marijuana abuse. Similarly,
Merikangas et al. (105) have reported familial aggregation of cannabis abuse in 231 probands, 61 control probands, and their 1267 first-degree relatives. These studies suggest that cannabis abuse may be a risk factor for the development of schizophrenia, and this association has a genetic as well as a specific family environmental influence.
In contrast with cannabis, the risk in relatives of schizophrenics for alcoholism was reported not to be increased (106). This is in contrast to the study by Lin et al. (107), who reported that association between major depression and alcohol abuse/dependence was influenced by familiar factors. Similarly, intravenous administration of tetrahydrocannabinol (THC), the active ingredient of marijuana, transiently worsens psychosis in neuroleptic-treated schizophrenics and produces transient psychotic state in controls (108). However, ethanol has inconsistent effects on psychosis in schizophrenics (109). Thus, the relationship between cannabis abuse and schizophrenia appears to have some specificity.
Preclinical studies have reported interactions between the cannabinoid and DA system. For example, D1 and D2 antagonists block turning behavior induced by cannabinoid agonists injected into the mouse striatum (110). Giuffrida et al. (111) have reported that quinpirol, a D2-receptor agonist (but not SKF 38393, a D1-receptor agonist), increased release of anandamide, an endogenous cannabinoid, in the dorsal striatum in rats. They have also reported that the cannabinoid antagonist SR 141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole. On the other hand, Castellano et al. (112) have reported antagonism of the effects of anandamide-induced impairment of memory consolidation by pretreatment with either D1 (SKF 38393)- or D2 (quinpirole)-receptor agonists at doses that were ineffective when given alone. Thus, interaction between the cannabinoid and the DA system may differ in different regions of the brain and needs further study. In addition, studies on interactions between the cannabinoid and various other neurotransmitter systems are needed to understand the biological underpinnings involved in cannabis abuse and schizophrenia.
Similar to other psychostimulant abuse, nicotine addiction involves the meso-corticolimbic DA mechanism. Pich et al. (68) have reported that cocaine and nicotine produced specific overlapping patterns of activation in the shell and the core of the nucleus accumbens, medial prefrontal cortex, and medial caudate areas in rats trained to self-administer intravenous cocaine and nicotine. Similarly, Pontieri et al. (71) have reported that intravenous administra tion of nicotine to the rat stimulated local energy metabolism and DA transmission in the shell of the nucleus accumbens.
Nicotinic receptors are divided into high- and low-affinity receptors for nicotine. Nicotinic receptors contain alpha and beta subunits (113). However, the low-affinity nicotinic receptor, which also binds alpha-bungalotoxin, the snake neurotoxin, is composed exclusively of alpha7 subunits (114). Freedman et al. (115) have reported that alpha-bungalotoxin binding in the hippocampus of schizophrenics was significantly decreased in both the dendate gyrus and CA3 region of the hippocampus as compared to matched controls. Another piece of evidence suggesting the alpha7 nicotinic receptor abnormality in schizophrenia comes from the study of sensory gating (116). The regulation of gating of auditory stimulation has been reported to be mediated via hippocam-pal alpha7 nicotinic receptors (117). Normally, the evoked response to the second auditory stimulus (P50) is lower than the response to the first auditory stimulus because of inhibitory circuits activated by the first stimulus. However, this inhibitory gating effect was impaired in 91% of the schizophrenics (118) as well as 50% of their first-degree relatives who did not have the illness (117). Thus, the P50 deficit may be a risk factor for schizophrenia. Interestingly, prenatal exposure to nicotine produced impairment in auditory processing in children between 1 and 11 years old (103). Nicotine transiently reversed the auditory gating deficit in smoking schizophrenics (118) as well as nonsmoking relatives of schizophrenia (119). Treatment with clozapine has been reported to normalize the P50 deficit (120) as well as decreasing smoking (121,122) in schizophrenics, but typical neuroleptic treatment did not improve either P50 deficit (123) or smoking (124). Whether this abnormality in the nicotinergic neurotransmission is related, in part, to the high rate of smoking in patients with schizophrenia requires further study.
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