Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations.

A role of the caudate nucleus in depression has been suggested from relevant clinical conditions, such as patients with Huntington's disease or caudate infarcts, as well as animal studies. Correlations of caudate nucleus disease with depressive symptoms have been limited to autopsy studies and cases of gross pathological disorder, such as large infarcts. We used serial axial high-field magnetic resonance images and an unbiased stereological technique to estimate the volumes of the caudate nuclei in 50 patients who met DSM-III criteria for major depression (23 men, 48.3 +/- 17 years old) in comparison with 50 age- and gender-matched normal controls free of major neurological and psychiatric disorders. Depressed patients had smaller caudate nucleus volumes (5.2 +/- 1.6 cm3) compared with controls (6.2 +/- 1.7 cm3). Right and left caudate nucleus volumes were smaller in depressed patients compared with controls. Age was negatively correlated with caudate nucleus volumes in depressed patients as well as in controls. Caudate nucleus volumes in depressed patients were inversely correlated with the bicaudate and bifrontal indices. These results may be the first demonstration of diminished caudate nucleus volumes in depression and suggest a role for the caudate nucleus in the pathogenesis of major depression.

Pituitary size in depression.

Magnetic resonance images centered at the pituitary stalk were used to measure pituitary gland size in 19 patients with major depression compared with that in age- and sex-matched controls. Depressed patients had significantly greater pituitary cross-sectional area (P = 0.0009) and volume (P = 0.007) than the controls. This difference was particularly prominent in elderly depressed patients compared to elderly controls. These results provide the first demonstration of structural alterations in the pituitary gland in major depression.

In vivo assessment of pituitary gland volume with magnetic resonance imaging: the effect of age.

We used sagittal and coronal T1 weighted magnetic resonance images, at 1.5 Tesla, to measure the height, width, length, and cross-sectional area and to generate two estimates of pituitary gland volume in 35 normal volunteers aged 26-79 yr (19 females and 16 males). Subjects over 50 yr of age had significantly smaller pituitary gland height (P = 0.03), area (P = 0.04), and volume (P = 0.04) than those under 50 yr (by two-tailed t test). Overall, age was negatively correlated with pituitary volume (V1: r = -0.51; P = 0.003; V2: r = -0.47; P = 0.008), area (r = -0.43; P = 0.009), and height (r = -0.46; P = 0.005), but not with pituitary length or width. There were no statistically significant differences in pituitary size between men and women (by two-tailed t test). These findings suggest that pituitary gland height provides a good single measure for the assessment of pituitary gland size and that age must be controlled for in studies of pituitary gland size.

Amphetamine stereotypy: the influence of environmental factors and prepotent behavioral patterns on its topography and development.

This report describes a series of experiments, all of which demonstrate a strong contribution of the behavioral pattern manifested at the time of initial amphetamine injection to the topography and development of the stereotypy that develops with chronic amphetamine intoxication. These initial behavioral patterns reflect (i) learned behaviors, (ii) species-specific behaviors, (iii) behaviors associated with amphetamine arousal, and (iv) novel behaviors reflecting unique environmental circumstances prevailing at the time of administration. In an experiment using eight dogs administered amphetamine in a situation which allowed interaction between the animals, the behavioral stereotypies that developed were comprised of the social interaction patterns ongoing at the time of initial drug effects. Experiments with rats have demonstrated that the configuration of the enclosure in which they are injected influences the initial behavioral reactions to amphetamine and thus modifies the stereotypy. In experiments with cats pressing a lever to self-administer amphetamine, investigatory behavior at the lever-press operandi becomes incorporated as does the learned behavior response into the stereotypy. The behavioral patterns originally associated with amphetamine arousal eventually supersede the learned response component of the stereotypy. Finally, monkeys incorporate components of the initial behaviors associated with amphetamine administration into a wider range of stereotype patterns over months of chronic intoxication, and eventually the stereotypy may evolve into a specific dyskinesia involving movements of the original behavioral component.

Fundamental mechanisms underlying altered behavior following chronic administration of psychomotor stimulants.

Psychomotor stimulant-induced abnormal behavior in man and experimental animals has provided a model for investigation of the biobehavioral basis of psychosis for the past decade. The altered behavior which occurs with chronic administration of psychomotor stimulants appears to be attributable to five major phenomena: One of these, conditioning, involves a global reorganization whose biological bases are little understood. Alterations reflecting kindling mechanisms represent changes in membrane mechanisms resulting in enhanced propagation of electrical signals. A third mechanism involves adaptation of drug metabolism systems, and the final two involve aminergic neuronal function, i.e., decreased levels of dopamine and possibly alterations in other amine systems and increased number of dopamine receptors. Evidence linking behavioral reorganization as a result of chronic administraton of psychomotor stimulants with these phenomena is presented.

Amphetamine behavioral toxicity: rotational behavior after chronic intrastriatal infusion.

The behavioral "reverse tolerance" to d-amphetamine in rats has not been clearly established for the high-dose, sustained d-amphetamine exposure relevant to human behavioral toxicity, especially the amphetamine psychosis. We have looked for alterations in the d-amphetamine response following pretreatment by a newer pharmacologic intervention, the continuous chronic unilateral infusion of highdose d-amphetamine into the caudate-putamen. We found that the circling response to a subsequent intraperitoneal injections of d-amphetamine is consistently ipsilateral compared to saline controls, suggesting tolerance development. This finding, and that of minimal apomorphine-induced rotation in these animals, is discussed in terms of a functional imbalance of right and left nigrostriatal dopamine activity, possibly due to dopamine depletion.

Behavioral analysis of chronic cocaine intoxication in the cat.

Modification of cocaine's stimulant and local anesthetic behavioral effects as a function of chronic treatment was evaluated in seven female cats. Video tape of behavior pre- and post-cocaine (iv) on days 1, 4, 7, 10, and 13 in seven cats, and in addition, on days 21, 28, and 35 for s subset of four cats, was rated for several scales of the Behavioral Rating Inventory for Drug-Generated Effects (BRIDGE), developed to quantify stimulant-induced behaviors. Preseizure events were measured using scales for Tremor Intensity and Preseizure-Seizure Intensity (PSI), developed to quantify local anesthetic-induced behaviors. Behaviors associated with cocaine's local anesthetic effects, i.e., Tremor Intensity and PSI levels, showed tolerance over the treatment period, while behaviors associated with cocaine's psychomotor stimulant effects, i.e., the BRIDGE measures, showed augmentation, or reverse tolerance. These data are discussed in terms of catecholamine supersensitivity, kindling mechanisms, and stimulant models of psychosis.

gamma-Butyrolactone effects on behavior induced by dopamine agonists.

gamma-Butyrolactone (GBL) potently inhibits stereotyped behavior induced by indirect (amphetamine and methylphenidate) and direct (apomorphine) dopamine agonists. Amphetamine induces a dose-response partial reversal of the GBL effect. The GABA antagonist, bicuculline, only partially reverses the GBL inhibition of apomorphine activity, indicating that GBL may be acting through mechanisms in addition to effects on GABA.

Effects of single and repeated alcohol withdrawal on kindling.

It has been hypothesized that an electrophysiological reorganization of the limbic system takes place with repeated episodes of alcohol withdrawal which leaves the individual more susceptible to withdrawal effects, including delirium tremens and seizures. We examined the effects of two alcohol-dosing paradigms on the rate of kindling. Levels of ethanol below 300 mg/dl clearly did not accelerate the rate of kindling nor appear to affect the afterdischarge threshold, in spite of the fact that these levels have produced short-term withdrawal symptoms in other studies. Higher levels appeared to accelerate kindling. In the second experiment kindling was accelerated in animals with blood alcohol levels between 300 and 500 mg/dl. These findings are discussed in relation to clinical studies of alcohol withdrawal.

Dopamine blocking activity of clomipramine in patients with obsessive-compulsive disorder.

While many data suggest that Obsessive-Compulsive Disorder (OCD) is an illness accompanied by dysregulation of the serotonergic system, interesting clinical evidence and animal studies also suggest possible dysregulation of the dopaminergic (DA) system. In order to determine whether clomipramine (CMI), an antiobsessional agent, is capable of altering DA function, we performed a neuroleptic radioreceptor assay (NRRA) on plasma samples from OCD patients before and after treatment in a double-blind, placebo controlled trial of CMI. CMI produced mild but significant DA D-2 receptor binding activity in an in vitro assay. The degree of dopamine binding activity did not correlate with clinical response to clomipramine. Because it has been suggested that another drug with antiobsessional efficacy, fluoxetine, may also have dopamine blocking properties, it may be speculated that antidopaminergic activity in combination with serotonergic effects is involved in antiobsessional activity of effective agents for some patients.

Cerebral atrophy in bulimia.

The extent of cerebral atrophy in 8 consecutively chosen unmedicated bulimics and 8 normal controls was determined by magnetic resonance imaging. There was no history of anorexia nervosa or alcoholism in either group. Measures obtained included the ratio of cerebral to cranial area at the midsagittal section, as well as maximum ventricle/brain ratio in the axial plane. Sagittal cerebral/cranial ratio was significantly less in the bulimic group than in controls [0.82 +/- 0.04 (SD) versus 0.90 +/- 0.03, Z = -2.74, p = 0.006, two-tailed Mann-Whitney U-test], whereas ventricle/brain ratio was not significantly different between groups. Implications for the occurrence of cortical atrophy in normal-weight bulimics, as well as for the relative absence of ventricular enlargement in these patients, are discussed.

A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia.

Magnetic resonance imaging (MRI) of the brain was used to examine the morphology and dimensions of the pituitary gland in 18 patients with eating disorders (8 anorectics and 10 bulimics), in comparison with 13 healthy volunteers. None of the 18 patients with anorexia or bulimia had any radiological evidence suggestive of pituitary macroadenoma, cyst, or empty sella. Measurements revealed that the anorectics and bulimics had smaller pituitary gland cross-sectional areas (p less than 0.05) and smaller pituitary gland heights, compared with healthy controls. These preliminary findings in anorectics and bulimics are suggestive of pituitary atrophy secondary to nutritional or endocrine alterations, rather than a primary pituitary pathology.

Abnormalities in the response of plasma arginine vasopressin during hypertonic saline infusion in patients with eating disorders.

We examined the response of plasma arginine vasopressin (pAVP) to intravenous 5% hypertonic saline in patients with anorexia nervosa (AN) and bulimia nervosa (BN). Patients did not differ from controls in their subjective response for the onset of thirst; however, only 5 patients (3 AN and 2 BN) showed pAVP levels that were within the normal range (0.5-11.0 pg/ml) for this test. With the exception of two eating disorder (ED) patients, all others showed some nonlinear irregularities in the pattern of their secretion of pAVP in response to the hypertonic saline infusion. Seven of the ED patients showed an irregular abnormally high pAVP secretion, and three patients showed abnormally low pAVP responses. Both of these pAVP secretion abnormalities occurred in underweight and weight-recovered AN patients, as well as in BN patients. The cause and pathophysiological consequences of these abnormalities remain unresolved.

Assessment of posterior fossa structures with midsagittal MRI: the effects of age.

Midsagittal magnetic resonance (MR) images of 36 normal volunteers, ranging in age from 26 to 79 years, were used to evaluate the effects of age on the size of posterior fossa structures (cerebellar vermis, midbrain, pons, medulla and fourth ventricle). Our results demonstrate a highly statistically significant age-related decline in the cross-sectional area of the midbrain (r = -.44, p less than 0.007), a less prominent decline in the area of the anterior cerebellar vermis (r = -.33, p less than 0.05) and striking intercorrelations between the dimensions of the pons, medulla and cerebellar vermis. To the best of our knowledge, this is the first MRI demonstration of midbrain atrophy during aging in normal adults.

Onset of peak impairment after diazepam and after alcohol.

Single doses of diazepam induced peak impairment of performance on cognitive and psychomotor tasks early (20 min after ingestion), when blood levels had reached less than two thirds of their eventual plateau. Alcohol did not have this effect. Early peak impairment and the acute tolerance that follows it contribute greatly to the lack of correlation between diazepam plasma level and performance impairment.

Effects of oral contraceptives on diazepam-induced psychomotor impairment.

Eight young women taking oral contraceptives and 10 young men each received three different doses of diazepam, 0.07, 0.14, and 0.28 mg/kg. The women also received each dose both on days 10 and 28 of an oral contraceptive cycle. Performance based on both a psychomotor and cognitive-encoding task was significantly impaired after a 0.28-mg/kg dose of diazepam in women taking oral contraceptives and in men. In general, however, impairment in performance was less on day 10 than on day 28 of the oral contraceptive cycle. The onset of behavioral impairment was also slower on cycle day 10 than on day 28; peak impairment was reached at 20 min after dosing for men and women on day 28, but at 60 min for women on day 10. The cycle phase effects are potentially dangerous because of their unexpected nature. Individuals may obtain an expectation of intoxication based on the 21-day OC period yet experience capriciously greater acute impairment during their 7-day menstrual pause.

Tricyclic-induced akathisia in patients taking conjugated estrogens.

Three patients taking conjugated estrogens developed akathisia induced by tricyclic antidepressants. The interaction between tricyclic antidepressants and conjugated estrogens could play a role in the development of akathisia.

Effect of cocaine on dopamine transporter receptors depends on routes of chronic cocaine administration.

Investigation of residual behavioral states produced by withdrawal from different routes of cocaine administration indicates that depending on the mode of intake, chronic cocaine produces either tolerance or sensitization to subsequent challenge doses of cocaine. We studied the effect of routes of cocaine administration on the dopamine transporter receptors (DATR), the presumed neuronal mediator of cocaine reward, using the diphenyl substituted piperazine derivative, [3H]GBR 12935 and the cocaine analogue [3H]WIN 35,428. Alzet osmotic mini-pumps filled with either cocaine (100 mg/ml) or saline were surgically implanted on rats into a subcutaneous pocket at the dorsal midline, continuously infusing cocaine at the rate of 40 mg/kg/day. The pumps were removed 14 days later, and the rats were killed 7 days after the removal of pumps. For the intermittent administration, two groups of rats were injected daily either with 40 mg/kg of cocaine or saline for 14 days. Rats were killed 7 days following the last injection. Continuous infusion of cocaine did not alter the [3H]GBR 12935 dopamine transporter (DAT) binding either in the caudate nucleus or in the prefrontal cortex, but it enhanced the density of [3H]WIN 35,428-labeled DAT receptor sites in the caudate putamen. In contrast, intermittent administration of cocaine resulted in a selective alteration of [3H]GBR 12935 binding in the prefrontal cortex but not in the caudate; the cocaine-injected rats had a 48% decrease in [3H]GBR 12935, Bmax (p < .05), without changing the KD. The contrast between the lack of effect of cocaine on [3H]GBR 12935-DATR and the increased binding of [3H]WIN 35,428-DATR highlights the differential sensitivities of the two binding sites to the continuous presence of cocaine.

Altered activity of midbrain dopamine neurons following 7-day withdrawal from chronic cocaine abuse is normalized by D2 receptor stimulation during the early withdrawal phase.

Using in vivo single-unit recording in rats, we compared the effects of continuous cocaine infusion via minipump or single daily injections (both 40 mg/kg/d x 14 days, S.C.) on the activity of putative dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA). On days 1-5 after cocaine withdrawal, animals were further treated with single daily injections of DA agonists. On withdrawal day 7 continuous cocaine caused a reduction in spontaneously active neurons in the SNC and reduced bursting in the VTA. In contrast, intermittent cocaine resulted in an increase in the number of active neurons in the VTA. These changes were all reversed by apomorphine or quinpirole given during the first 5 withdrawal days. The D1 antagonist SCH 39166 did not antagonize the effects of apomorphine in either region. The role of D2 receptors in modulating baseline DA activity during intermediate cocaine withdrawal is discussed.

Alterations in baseline activity and quinpirole sensitivity in putative dopamine neurons in the substantia nigra and ventral tegmental area after withdrawal from cocaine pretreatment.

Using in vivo single-unit recording, we compared in rats the-effects of continuous infusion and once-a-day injections of cocaine on the activity of single putative dopamine neurons in the substantia nigra and ventral tegmental area. After a 7-day withdrawal, we determined: (1) the number of spontaneously active neurons and their bursting patterns and (2) sensitivity of these neurons to intravenous quinpirole. In the substantia nigra, continuous cocaine infusion reduced the number of neurons without affecting the bursting patterns; daily injections were without effects. In the ventral tegmental area, continuous infusion reduced the bursting activity without affecting the number of neurons, whereas injections increased number of neurons without changes in the bursting pattern. Acute sulpiride normalized all the changes in both cell body areas. The quinpirole sensitivity was selectively increased in the nigral neurons following withdrawal from continuous infusion. Possible role of D2/autoreceptor mechanisms in these changes is discussed.