Biobehavioral effects of extended salt loading and conflict stress in intact baboons.

Behavioral stressors may inhibit sodium excretion, potentially increasing plasma volume and elevating blood pressure during chronic exposure. Blood pressure regulation may be especially deranged during manipulations that further challenge the kidney, such as a diet high in salt content. The effects on blood pressure and other variables of combined behavioral stress (food/shock conflict) and dietary salt (12 g NaCl per day; 218 mEq Na+ per day) were examined in adult male baboons over the course of 1 year. Mean arterial pressure was not significantly elevated over baseline after 5 months of high dietary salt alone (6 +/- 5 mmHg) but was maximally elevated by an average of 17 (+/- 3 SEM) mmHg after 5 months of combined salt and conflict stress. Control baboons showed no significant trends in mean arterial pressure across the same time period. Individual subjects whose blood pressure was "salt+stress resistant" or "salt+stress sensitive" were differentiated by their degree of pressure diuresis and natriuresis, urinary free cortisol, and a behavioral index of stress sensitivity. The data indicate additive effects of chronic high dietary salt intake and behavioral stressors on blood pressure in nonhuman primates that are dependent on renal function and pituitary-adrenocortical activity.

General activity in baboons measured with a computerized, lightweight piezoelectric motion sensor: effects of drugs.

A small, 1-oz activity-monitoring device is described for measuring motor activity continuously for periods of up to 42 days. The monitor employs a piezoelectric sensor that detects extremely small accelerations induced by movements. The monitor can be placed on collars or harnesses (e.g., for rabbits, cats, dogs, nonhuman primates, etc.). The use of the monitor is described within numerous laboratories studying the behavioral pharmacology of drugs in individually caged laboratory baboons. Patterns of daily activity were reliably recorded over periods of several months, and reflected the normal activity patterns of animals. The activity monitor recorded reliable, drug-induced changes in general activity that paralleled the known effects of the same drugs on learned behaviors. Low doses of the stimulants cocaine and d-amphetamine both increased general activity. Marked reductions in general activity were observed following both the administration of delta-9-tetrahydrocannabinol and an antihypertensive drug combination of diuretic and verapamil.

Beta-blocker effects on 24-h activity in normotensive and renovascular hypertensive baboons.

Spontaneous motor activity of normotensive and renovascular hypertensive baboons was measured during oral dosing with the beta-adrenergic antagonists atenolol HCl (2.6 mg/kg/day) and d,l-propranolol HCl (6.8 mg/kg twice daily) in separate studies. Each study administered active drug for 21 consecutive days. Piezoelectric monitors sensitive to movement were worn continuously by the baboons. Propranolol decreased overall 24-h average activity during the third week of dosing in normotensive baboons but not in renovascular hypertensive baboons. The greatest reductions in activity averaged 20% at those times of day corresponding to the second daily drug dose both in normotensive baboons and, at this time of day only, in the majority of hypertensive baboons. Activity decreases reversed to baseline levels when propranolol was discontinued. For atenolol, most normotensive but no hypertensive baboons showed decreases in activity at the time of day corresponding to the daily drug dose.

Behavioral performance effects of verapamil in normotensive and renovascular hypertensive baboons.

Behavioral performances of normotensive and hypertensive adult male baboons were tested before, during, and following chronic oral dosing with verapamil. Performances during a five-color simultaneous match-to-sample task were measured for two doses (2.0, and 3.2 mg/kg/day) and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Choice reaction times increased by 9% during the lower dose of verapamil, compared to vehicle; choice reaction times were unchanged at the higher dose. At baseline and during vehicle administration, the yellow and white stimuli were the most difficult to discriminate correctly; discrimination of these colors was slightly impaired by the lower, but not the higher dose of verapamil. Verapamil's behavioral effects were not modulated by blood pressure changes since both baboon groups showed equivalent changes in behavioral performance, but only renovascular hypertensive baboons showed blood pressure decreases. Verapamil appears to be an effective hypotensive and does not produce profound psychomotor impairment at clinically used doses during the first weeks of treatment.

Chronic hydrochlorothiazide and verapamil effects on motor activity in hypertensive baboons.

Spontaneous motor activity was measured in six baboons during chronic oral dosing with a diuretic (hydrochlorothiazide/triamterene), a calcium channel blocker (verapamil), and a combination of the two drugs. Piezoelectric monitors sensitive to movement were attached to leather collars and were worn continuously by the baboons throughout the protocol. Baboons were made hypertensive during a preexperimental period by either 1) chronic administration of deoxycorticosterone acetate (DOCA)-salt or 2) surgical renal artery stenosis. Total inactive periods/day increased over baseline levels during diuretic alone and increased further during diuretic + verapamil combined. The total number of inactive periods/day returned toward baseline levels in the subsequent conditions of verapamil alone and baseline recovery. Activity levels decreased during combination dosing mainly during morning hours (0700-1100 h). Overall changes in activity occurred in the second week of dosing; this time period was found earlier to maximally decrease blood pressure and to impair behavioral performances.

Performance of baboons under a repeated acquisition procedure during chronic oral exposure to atenolol and propranolol.

Repeated acquisition behavioral performances of normotensive and renovascular hypertensive baboons were tested before, during, and following chronic oral dosing with the beta-adrenergic antagonists atenolol HCl (2.6 mg/kg/day PO), and d,l propranolol HCl (6.8 mg/kg twice daily PO) in separate studies. Each study administered active drug for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Animals pressed five keys in sequence for food reinforcement during daily experimental sessions which consisted of alternating acquisition (new sequence learning) and performance (previously learned) task components. Atenolol increased response latencies during acquisition in comparison to performance components, and during early portions of sessions. Propranolol also increased response latencies during acquisition components in early periods of sessions, but fewer dependent measures were affected, and the magnitude of increases in response latencies was smaller (12% +/- 5 SEM) as compared with atenolol (47% +/- 13). Test doses of phencyclidine HCl (PCP) increased latencies to the same degree as atenolol. PCP markedly reduced accuracy, while atenolol or propranolol did not. Blood pressures remained stable under atenolol, and decreased by approximately 10-15 mmHg under propranolol. No differences between renovascular hypertensive and normotensive baboons were found as a function of drug conditions. Drug effects were not dependent on plasma propranolol concentration.

Chronic effects of high salt intake and conflict stress on blood pressure in primates. A progress report.

The effects of combined behavioral stress and high dietary salt on blood pressure were examined in baboons (N = 4) over the course of 1 year. Either high salt diet (240 mEq Na+/day) or conflict stress were administered for 8 to 16 weeks, followed by high salt intake and stress combined. Mean arterial pressure (MAP) increased by 8 mmHg during high dietary salt alone, by 4 mmHg during stress alone, and increased further to 14 mmHg above baseline during combined salt and stress. Control baboons (N = 2) had no change in MAP across 47 weeks. The data indicate additive effects of chronic high dietary salt intake and behavioral stress on blood pressure in non-human primates.

Stress and sodium hypertension in baboons: neuroendocrine and pharmacotherapeutic assessments.

Behavioral stress and high dietary salt have been reported to increase blood pressure additively in non-human primates. This study was designed to replicate this phenomenon and to assess neuroendocrine correlates and responses to two commonly used antihypertensives, a beta-adrenoceptor blocker and a thiazide diuretic. High-salt intake (240 mmol sodium per day) and stress were administered for 9 weeks in adult baboons. Oral atenolol hydrochloride (50 mg, twice daily) or hydrochlorothiazide (25 mg/day) was administered for 2 weeks each. In all four baboons, salt loading and stress increased systolic blood pressure (SBP) chronically by 14 mmHg, with increases in water intake, urine osmolality and excretion of sodium, decreases in levels of serum sodium, plasma renin activity and plasma vasopressin and no changes in urinary excretion of norepinephrine or epinephrine. Neither drug decreased SBP during ongoing high salt and stress. The results confirm the additive chronic effects of high-dietary salt intake and behavioral stress on blood pressure in non-human primates. The hypertension in this model is resistant to two antihypertensive drugs commonly used clinically.

Familial density of alcoholism: effects on psychophysiological responses to ethanol.

Recent research findings suggest that the patterning of familial alcoholism may critically determine ethanol sensitivity and severity of alcohol-related problems in the offspring. The present study examined the effects of familial alcoholism density on psychophysiological responses to ethanol administration in college males. Subjects with a positive family history of alcoholism were classified into affected biological father only (LD-FHP) versus both father and at least one second-degree affected relative (HD-FHP), and were compared to family history negative (FHN) subjects. Subjects received 1 g/kg ethanol or placebo in a double-blind procedure. A battery of subjective, physiological and psychomotor measures were collected once prior to and four times following drink administration. HD-FHP subjects showed significantly greater subjective effects, body sway and skin conductance after alcohol ingestion than either FHN or LD-FHP subjects; in contrast, there was no difference on any measure for LD-FHP versus FHN subjects. Our findings of increased ethanol sensitivity as a function of familial density of alcoholism strongly suggest the importance of carefully defining family history characteristics in all studies examining potential markers or risk factors for alcoholism.

Blood pressure hyperreactivity in non-human primates during dietary sodium combined with behavioral stress.

The potential for behavioral stress alone or combined with dietary salt to augment pressor reactivity to the onset of daily experimental sessions was examined in normotensive, intact baboons over the course of four months. During twice daily experimental sessions, adult male baboons experienced food/shock conflict such that lever pulling not only served to earn food, but was also occasionally punished with cued mild electric shock. Blood pressure and heart rate were measured during a baseline period of fixed-ratio food reinforcement (3 weeks), during conflict stress (2 weeks), and after dietary salt was added to the daily conflict protocol (CONFLICT + SODIUM, 3 weeks). Reactivity, i.e., acute changes in blood pressure and heart rate to the daily experimental sessions, was not evident during food reinforcement sessions nor during the CONFLICT stress alone condition. The addition of a high salt diet virtually doubled blood pressure increases and heart rate decreases to the onset of experimental sessions. Average reactivities during CONFLICT + SODIUM periods were 11.2/7.9% delta for SBP/DBP (systolic/diastolic blood pressure, mmHg), and -5.65% delta for HR (heart rate, BPM). Neither atenolol nor hydrochlorothiazide diuretic significantly altered cardiovascular reactivity during CONFLICT + SODIUM in comparison to a preceding non-drug CONFLICT + SODIUM period. When atenolol and diuretic effects were directly compared, atenolol mildly augmented, while diuretic mildly decreased DBP but not SBP reactivity during CONFLICT + SODIUM. Reactivity was eliminated after salt loading and behavioral sessions were terminated. These findings provide evidence that enhanced salt ingestion may synergistically act with behavioral stress to produce pressor hyperresponsiveness to otherwise benign environmental events.

Alcohol and secobarbital effects as a function of familial alcoholism: extended intoxication and increased withdrawal effects.

Response differences following administration of alcohol between adult males with a positive (FHP) versus negative (FHN) family history of alcoholism have been demonstrated in previous research and are thought to be related to risk for developing alcoholism. If this is so, the pharmacological breadth of addiction risk conferred by a positive family alcoholism history might be studied by determining whether FHP subjects show different responses than FHN to drug classes other than alcohol. We have previously reported on the acute effects of ethanol as compared with secobarbital in FHP and FHN subjects and found that FHP subjects showed greater sensitivity across a variety of subjective measures than FHN subjects for both drug classes. The data reported here are based on an extended data collection period of 3 to 18 hr postingestion, following completion of the acute laboratory portion of the study. Specifically, in the present study, dose-effect timecourse functions for a variety of physiological (heart rate, blood pressure, and breath alcohol level), subjective (analog mood, drug effect, and withdrawal, Subjective High Assessment Scale (SHAS], and psychomotor measures (Digit Symbol Substitution Test and numeric recall) were examined in FHP and FHN college-aged males for secobarbital (0, 100, 200 mg daily) and ethanol (1 g/kg daily). FHP and FHN subjects were matched on light-to-moderate drinking patterns, anthropometric dimensions, age, years of schooling, and drug use. FHP subjects reported more extended intoxication and greater withdrawal effects following both ethanol and the high dose of secobarbital than did FHN subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral effects of chronic, orally administered diuretic and verapamil in baboons.

Behavioral performances of six baboons were tested during chronic oral dosing with diuretic (hydrochlorothiazide/triamterene), a calcium channel blocker (verapamil), and a combination of the two drugs. Reaction times and color matching-to-sample performances as well as physiological measures were obtained in deoxycorticosterone acetate (DOCA)-salt baboons and in renovascular hypertensive baboons. Combined diuretic and verapamil impaired color matching to a small degree in comparison to baseline performance, while drug administered alone had no effect. Weekly systolic and diastolic blood pressures decreased maximally from baseline during the drug combination period, and were accompanied by maximal increases in serum sodium. The largest behavioral impairments during combination dosing were observed for colors that were most difficult to discriminate during baseline. Significant positive correlations were found between systolic blood pressure and color matching accuracy. No differences between the animal hypertension groups were found as a function of drug condition either in physiological or behavioral responses. Only the combination of diuretic and verapamil produced a deleterious effect on color discrimination, which suggests further study of commonly administered drug combination therapies in hypertension.

Alcohol and secobarbital effects as a function of familial alcoholism: acute psychophysiological effects.

Previous research has demonstrated response differences following administration of alcohol between adult males with a positive (FHP) versus negative (FHN) family history of alcoholism. These response differences are thought to reflect differences in vulnerability to dependence on alcohol. Thus, the role of positive family alcoholism history in increasing risk of addiction to a variety of drug classes might be studied by determining whether FHP subjects show different responses to drug classes other than alcohol. This was done in the present study by determining dose-effect functions for a variety of physiological (heart rate, skin conductance, skin temperature), subjective (analog mood and drug effect, Subjective High Assessment Scale), and psychomotor measures (hand tremor, body sway, Digit Symbol Substitution Test, eye-hand coordination, and numeric recall) in FHP and FHN college-aged males for secobarbital (0, 100, 200 mg by mouth) and ethanol (1 g/kg). FHP and FHN subjects were matched on light-to-moderate drinking patterns, anthropometric dimensions, age, years of schooling, and drug use. At equivalent blood alcohol levels family-history positive subjects reported greater effects of ethanol than did family-history negative subjects on almost all subjective measures. Following the high dose of secobarbital, FHP but not FHN subjects showed elevated subjective effects; these effects were substantially less and were evident in fewer measures than following ethanol. In contrast to effects on the subjective measures, ethanol and secobarbital produced comparable impairment in both groups of subjects for most psychomotor responses. Group differences were not obtained on any physiological measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol and drug use by college males as a function of family alcoholism history.

Family history of alcoholism increases the risk for development of alcoholism in male offspring. The present questionnaire study examined self-reported alcohol and drug use in 744 college males as a function of DSM-IIIR alcohol dependence diagnoses in first- and/or second-degree biological relatives. Substance use was most prevalent and most frequent in students with both first- and second-degree alcohol-dependent family members, was intermediate in students with only first-degree affected relatives, and was least in students with no affected relatives. Students with both first- and second-degree alcohol-dependent relatives reported: more alcohol, marijuana, sedative, and cocaine ingestion; a younger age at first alcohol intoxication and first marijuana use; experience with less commonly used drugs; and more personal substance-related problems as well as more family mental health care. These data have significant prevention implications for targeting at-risk youth.

New methodology for measuring blood pressure in awake baboons with use of behavioral training techniques.

Adult male baboons were behaviorally conditioned to extend an arm outside of the living cage and to accept repeated cuff inflations for manual auscultatory blood pressure measurements. Frequency distributions of systolic and diastolic blood pressure for both normotensive and renovascular hypertensive baboons generally were normally distributed. The procedure accurately tracked rapid changes in blood pressure after oral administration of antihypertensive drugs. Advantages over direct arterial cannulation for blood pressure measurement during extended, chronic experiments are discussed.

Behavioral performance effects of nifedipine in normotensive and renovascular hypertensive baboons.

Behavioral performances of normotensive and hypertensive adult male baboons were tested before, during, and following chronic oral dosing with nifedipine. Performances during a five-color simultaneous match-to-sample task were measured during three dosing schedules (0.20, 0.68, and 1.14 mg/kg/day) and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Choice reaction times increased by 191 ms over baseline at the 0.68 mg/kg dose. Choice reaction times above the 95th percentile (i.e., the slowest reaction times) were the most slowed by nifedipine. Accuracy of color matching was decreased at 0.20 and 0.68 mg/kg by an average range of 2-4%. The yellow and white stimuli were the most difficult to discriminate correctly, and were also the most impaired by nifedipine. Nifedipine's behavioral effects were not modulated by blood pressure changes because daily changes in choice reaction time and systolic blood pressure were not correlated, and hypertensive status did not determine the behavioral effects. Potential sources of nifedipine's behavioral performance effects are discussed, with blood pressure changes excluded as a probable mechanism.

Matching to sample, blood pressure and hormonal effects of chronic enalapril in baboons.

Sensory and behavioral performance of three normotensive and one renovascular hypertensive baboon was tested before, during and following chronic oral dosing with the angiotensin converting enzyme (ACE) inhibitor enalapril. Performance measurements during a five-color simultaneous matching to sample task were obtained during enalapril dosing of 0.18 and 0.61 mg/kg/day, and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14 baseline and recovery periods, respectively. BP from awake animals as well as serum ACE activity were measured. Systolic BPs decreased by a maximum of 6-8% (8 mmHg). ACE activity was decreased in a dose-dependent fashion by 54.01% and 81.63% for 0.18 mg/kg and 0.61 mg/kg doses, respectively. At 0.61 mg/kg, the duration of simple key-press motor behavior increased by 15% in the first week and then progressively returned to baseline levels. Systematic changes in choice reaction times or color discrimination accuracy were not observed. Although the renovascular hypertensive baboon displayed greater hypotension and ACE inhibition, behavioral effects were not significantly different from normotensive baboons. The present study extends to sensory functions the lack of adverse behavioral side-effects of enalapril.

Conditioned opponent responses: effects of placebo challenge in alcoholic subjects.

The present study continues a series of studies examining a number of variables that contribute to the demonstration of conditioned responses to alcohol in alcoholics. We pursued here the hypothesis that subjects receiving placebo in an environment previously associated with alcohol ingestion would exhibit conditioned responses as compared with subjects who had only received placebo in the environment. Further, we predicted that these conditioned responses would be opposite in direction to responses obtained during active drink sessions. Twelve subjects received active alcohol during session Days 1 through 4 and a placebo challenge on Day 5; the second group received placebo throughout sessions 1 through 5. On Day 1, heart rate and skin conductance were elevated following active alcohol ingestion as compared with placebo. On Day 5 following the placebo challenge, these physiological responses were significantly lower in the alcohol group as compared with the placebo group; the reversal of effects on Day 5 is suggestive of conditioned compensatory responses. Also, following the placebo on Day 5, desire to drink scores of the alcohol group were greater than those of the placebo group. The present data suggest that subjects exhibit conditioned compensatory responses when the environment signals alcohol availability. Results are consistent with Siegel's model of conditioned compensatory responses to repeated drug administration, and may help to account for some aspects of tolerance development and conditioned withdrawal.