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2022 JUL 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Biotechnology - Gene Therapy is the subject of a [...]

The current study examined possible interactions between genetic factors and prolonged drug access by testing the Fischer (F344), Lewis (LEW), and Wistar rat strains in a prolonged access cocaine self-administration (SA) procedure. Before prolonged access, the strains did not differ in breakpoints for food or cocaine with progressive ratio (PR) testing. The LEW and Wistar rats acquired cocaine SA faster than the F344s. With prolonged access to cocaine SA, the LEW and Wistar rats showed comparable within-session patterns that were higher at the outset of each session and decreased to a stable baseline. Alternatively, the F344 rats began sessions with lower intake and increased their rate of intake during the session. The F344 and Wistar rats took more drug per session than the LEW rats but did not differ from each other. Following prolonged access, the strains did not differ in breakpoints for food, but the Wistar rats had higher breakpoints for cocaine than the F344 rats. Possible underpinnings for the observed strain differences are discussed. Keywords: Fischer, Lewis, Wistar, cocaine, self-administration

Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine. Keywords: growth factors, neural plasticity, viral-mediated gene transfer, drug addiction, behavioral sensitization

Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty's impact when cocaine exposure was discontinued. The identical procedures were used except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward. Keywords: reward competition, novelty seeking, sensation seeking, conditioned place preference, natural rewards

Neurodevelopmental abnormalities of temporal--limbic structures may underlie both adult psychiatric syndromes and increased addiction vulnerability, leading to high frequencies of 'dual diagnosis' disorders. Although the amygdala is implicated in various mental disorders and drug addiction, no studies have explored the impact of early developmental damage to the amygdala on pbenotypes relating to mental illness and addictions as co-occurring processes. We tested rats with neonatal amygdala lesions (NAML) vs. SHAM-operated controls in a battery of tests--novel field activity, elevated plus maze (EPM), and social interaction (SI) at baseline and after odor and restraint stress--followed by measures of cocaine sensitization (15 mg/kg vs. saline x 5 days + challenge session 2 weeks later) and remeasurement of SI. NAMLs showed increased novelty-related locomotion, less fear responding in the EPM, and resistance to predator-odor- but not to restraint-induced suppression of SI. NAMLs also had elevated cocaine sensitization profiles, and cocaine history differentially affected subsequent SI in NAMLs compared with SHAMs. NAMLs may provide models for understanding a shared neurobiological basis for and complex interactions among psychiatric symptoms, drug exposure history, and addiction vulnerability. Keywords: amygdala, cocaine, neurodevelopment, dual diagnosis, social interaction.

In experiments examining the potential reconsolidation of drug-associated contextual memories, rats were given a single pairing of cocaine with a specific context, and the ability of the protein synthesis inhibitor anisomycin administered following a context-only memory retrieval trial to impair conditioned locomotor sensitization was tested. Rats receiving 150 mg/kg anisomycin immediately following a 5-min reexposure to the cocaine-conditioned context showed decreased activity compared with the vehicle control group in response to a low-dose cocaine challenge during a subsequent test for conditioned sensitization. This effect was not seen when anisomycin was administered following a 30-min reexposure to the context or when anisomycin was administered 25 min after a 5-min reexposure. These results are consistent with a growing literature suggesting that following retrieval, associative contextual memories may undergo a transient protein synthesis-dependent reconsolidation phase that normally serves to maintain memory. Keywords: reconsolidation, cocaine, sensitization, memory

Serotonin 5-HT2A receptor antagonists have been shown to attenuate the locomotor stimulant effects of cocaine in rats. The present study used the expression of c-Fos protein as a marker to identify brain areas through which 5-HT2A receptors may modulate cocaine-induced behaviors. Significant correlations were observed between cocaine-induced hyperactivity and c-Fos expression in the nucleus accumbens core (NAcC), caudate-putamen (CPu), and subthalamic nucleus. In a separate experiment, a low, behaviorally relevant dose of cocaine was found to increase c-Fos immunoreactivity in the medial CPu, NAcC, and nucleus accumbens shell (NAcSh). The selective 5-HT2A receptor antagonist M100907 significantly attenuated cocaine-induced c-Fos expression in the medial CPu and in the NAcSh. These data suggest that 5-HT2A receptors in the NAcSh and CPu or in afferents to these regions may contribute to genomic responses to cocaine in the brain as well as to cocaine-induced locomotor activity. Keywords: cocaine, 5-HT2A receptor, c-Fos, striatum, nucleus accumbens

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) [D.sub.1] receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions.

The spatial memory of adult rats prenatally exposed to cocaine and that of control offspring was assessed using the Morris water maze. Offspring were derived from Sprague Dawley dams that received subcutaneous injection of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. After acquisition, the platform was moved to a new location (reversal phase). Probe trials were conducted at the end of acquisition and reversal training. On the 1st acquisition day, adult male and female offspring prenatally exposed to cocaine required significantly more time and traversed a greater distance to find the hidden platform than did control offspring. Despite these initial differences observed in C40 offspring performance, all of the rats were performing at equivalent levels at the time probe trials were conducted.

Rat fetuses were exposed to cocaine, lidocaine, or saline on Gestational Day 20 or 21 to provide information about cocaine effects on behavior during prenatal development. Cocaine was administered into the cisterna magna of individual fetal subjects to restrict effects to the CNS. Behavioral effects of cocaine were compared with lidocaine to help distinguish the effects of cocaine on monoamine systems in the brain from its properties as a local anesthetic. Cocaine promoted 3-5-fold increases in fetal motor activity in the absence of explicit sensory stimulation, in contrast to the slight suppressive effects of lidocaine. Cocaine and lidocaine also reduced coordinated behavioral responses to an artificial nipple. The behavioral effects of cocaine administered into the CNS of fetal subjects suggest specific mechanisms of action on developing neural and behavioral systems in the late prenatal period.

Objective: Unrecognized stimulant use could lead to the misdiagnosis of schizophrenia or the misunderstanding of its course and prognosis. This study was conducted to determine the prevalence of unrecognized stimulant use among patients with a clinical diagnosis of schizophrenia. Method: The subjects were 108 schizophrenic patients admitted consecutively to a Veterans Affairs psychiatric hospital. Admitting psychiatrists supplemented routine clinical evaluations with a semistructured interview regarding recent and lifetime use of alcohol, cocaine, amphetamine, marijuana, and opiates. A urine specimen was assayed for the four illicit drugs. Results: Of the 103 patients who provided a urine specimen, 37 (36%) used cocaine during the 6 months before admission, including 31 who used the drug in the week before admission. Because of the poor reliability of negative self-reports of recent cocaine use, clinicians failed to recognize cocaine use in one-third of the patients with a urine toxicology positive for cocaine metabolites. Two other groups of patients were identified; schizophrenic patients without substance abuse (including alcohol) and schizophrenic patients with substance abuse other than stimulants. Both substance-abusing groups were younger than the nonabusing group, but the three groups had similarly high rates of recent psychotic symptoms, homelessness, and unemployment. Conclusions: Among schizophrenic patients who require hospitalization, clinicians should not rely solely on self-reported stimulant use. Recognition of stimulant use could be improved through routine urine toxicologies for all psychotic patients. The authors suggest that recognition of stimulant use among schizophrenic patients may identify a population with a better prognosis for schizophrenia and different treatment needs. (Am J Psychiatry 1993; 150:758-762)

In normal subjects, high doses of cocaine have been found to induce acute psychiatric symptoms such as paranoia, hallucinations, agitation, assaultiveness, and severe depression. To explore associations between schizophrenia and cocaine, 51 hospitalized schizophrenic patients were studied. Subjects ranged in age from 19 to 56 years, and 48 were male. All subjects were stabilized on the same medication (chlorpromazine). Subjects were divided into two groups - those with and those without a history of cocaine use. Patients who had used drugs over the past three months, who had major psychiatric disorders or neurological conditions other than schizophrenia, or were mentally retarded, were excluded from the study. Symptoms, depression and overall severity of illness were assessed. Attention deficits were tested and evaluated, and behavioral manifestations during hospitalization were assessed by nursing staff. Results indicated that schizophrenics with a history of cocaine abuse were significantly more depressed, less socialized, and had more memory defects than schizophrenics without such a history. Contrary to expectations, those with a history of cocaine abuse displayed better temporal lobe attention span, were neater in appearance, and had better aggression control. Groups did not differ in severity of illness or in types of schizophrenic symptoms displayed. History of substance abuse was obtained primarily from the patient's themselves and, in most cases, was not substantiated by any other source. There was no urine monitoring for cocaine use during the study. (Consumer Summary produced by Reliance Medical Information, Inc.)

Although clinical and laboratory evidence indicates that people who use alcohol and other psychoactive drugs are at risk for psychotic experiences (delusions, hallucinations), epidemiological studies of real populations have not been carried out. To address this issue, a prospective study of 4,994 adults (aged 18 to 49) was performed to identify subjects who reported at least one psychotic experience during the first year of the study. A positive response to one or more of the 12 questions on the Diagnostic Interview Schedule constituted a self-reported psychotic experience. Slightly more than 11 percent of the group (507 'cases') met this criterion, and they were matched to 'noncases' in the same census tract of the general population. Cases and noncases were then compared with respect to drug use habits. Results showed that habitual drug use was associated with psychotic experience, with different drugs having different risk factors. Thus, daily use of marijuana was associated with a 2.4-fold elevated risk (cases versus controls), while daily cocaine use (involving 11 people in the entire study) was associated with a 7-fold higher risk. Alcohol disorder (but not heavy use of alcohol) carried a risk for cases that was 2.6 times that for controls, with a much higher risk for men than women. Overall, the findings suggested that regular use of alcohol, marijuana, and cocaine is associated with a considerably elevated risk of psychotic experience, while occasional use of these substances is not. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: During early abstinence, many cocaine-dependent individuals experience symptoms such as anhedonia, craving, fatigue, insomnia, and dysphoria. While several studies have shown an association between depressive symptoms and negative treatment outcome, the reasons for this association are unclear. The authors conducted this study in order to determine the association between severity of depressive symptoms during early abstinence and subjective effects of experimentally administered cocaine. Method: Seventeen cocaine-dependent individuals achieved 5 days of abstinence in a hospital setting. Forty mg of cocaine was given intravenously on the fifth day of abstinence, and participants were asked to rate the subjective effects produced by the cocaine. The relationship between the subjective high produced by cocaine and the symptoms experienced during the 5 days of abstinence was evaluated. Results: Individuals experiencing more intense depressive symptoms experienced a significantly greater high from the 40-mg cocaine infusion than individuals who did not. Conclusions: These data suggest that the severity of depressive symptoms experienced during initial abstinence is associated with the intensity of the subsequent high produced by cocaine. This finding could help explain why individuals who experience greater levels of depression-like symptoms during abstinence appear to be at greater risk for unsuccessful treatment outcome.

Objective: The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies. Method: [123I][Beta]-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender. Results: Results showed a significant (approximately 20%) elevation in striatal [V.sub.3][double prime] values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed. Conclusions: These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.

Objective: Although suicidal behavior is frequent among cocaine-dependent patients, it has been little studied. Therefore, the author examined the characteristics of cocaine-dependent patients who had attempted suicide. Method: Cocaine-dependent patients who had attempted suicide (N=84) were compared with cocaine-dependent patients who had never attempted suicide (N=130) on clinical, personality, psychiatric, and physical variables. Results: Significantly more of the patients who had attempted suicide were female and had a family history of suicidal behavior; they reported significantly more childhood trauma and were significantly more introverted, neurotic, and hostile. They had also had significantly more comorbidity with alcohol and/or opiate dependence, major depression, and physical disorders. Conclusions: The clinical implications are that family, childhood, personality, psychiatric, and physical risk factors contribute to suicidal behavior in cocaine-dependent patients. Comorbidity appears to be an important determinant of suicidal behavior. (Am J Psychiatry 2001; 158:1215-1219)