Mark P. Bree

Buprenorphine self-administration by rhesus monkey

Intravenous injections of buprenorphine, a partial opiate agonist and antagonist, maintained operant responding under second order schedule control (FR 3 VR 16:S) across a dose range of 0.005 to 0.10 mg/kg/inj. A drug naive monkey and four monkeys with a history of morphine self-administration all self-administered buprenorphine at all doses studied. Four monkeys showed dose-related increases in the total amount of buprenorphine (mg/kg) self-administered each day as the available dose increased from 0.01 to 0.10 mg/kg/inj. Injections per day remained equivalent to the number of injections at the lowest dose studied or increased significantly (p less than 0.05, 0.01), as the dose per injection increased in three monkeys. Even at high buprenorphine doses, there was no evidence of sedation. Monkeys consistently self-administered significantly more buprenorphine than saline in control studies (p less than 0.01). Buprenorphines agonistic effects appear to persist for 24 to 48 hours. When saline and buprenorphine were available on alternate days, monkeys did not distinguish between them, but when 3 days of saline were alternated with 1 day of buprenorphine (0.03 mg/kg/inj), monkeys took significantly more buprenorphine than saline (p less than 0.02--0.001). Abrupt discontinuation of buprenorphine (0.10 mg/kg/inj) did not result in discernible withdrawal signs. The effects of buprenorphine on food intake were inconsistent, but there were no significant changes in body weight as a function of chronic buprenorphine self-administration or withdrawal. These data indicate that buprenorphine is a positive reinforcer in rhesus monkeys and maintains behavior leading to its administration on second order schedules over a wide dose range. Despite its opiate agonist properties, there was no evidence of physical dependence.

Desipramine effects on cocaine self-administration by rhesus monkeys

The effects of desipramine treatment (0.56-10.0 mg/kg per day) on cocaine self-administration were compared to saline treatment in five rhesus monkeys. Cocaine (0.050 or 0.100 mg/kg per inj) and food (1 g banana pellets) self-administration were maintained on an FR 4 (VR 16:S) reinforcement schedule. Desipramine (or an equal volume saline control solution) was infused over 1 h each day through the second lumen of an intravenous catheter. After 5 days of baseline saline treatment, seven doses of desipramine each were administered for 5 days in an ascending order. Cocaine self-administration increased (P less than 0.01) or remained equivalent to base-line levels in 4 of 5 subjects during the first 15 days of desipramine treatment (0.56 to 1.78 mg/kg per day). Three monkeys continued to self-administer cocaine equivalent to or significantly above base-line levels (P less than 0.01) during days 16-30 of desipramine treatment (3.2-7.86 mg/kg per day). The highest desipramine dose (10 mg/kg per day) significantly suppressed cocaine self-administration in only one of these three monkeys (P less than 0.01). Desipramine treatment (3.2-10.0 mg/kg per day) suppressed cocaine self-administration (P less than 0.01) without a concomitant suppression of food-maintained responding in one of five subjects. A generalized suppression of both cocaine and food-maintained responding (P less than 0.01) during desipramine treatment occurred in one monkey that took the highest base-line levels of cocaine (6.3 +/- 1.03 mg/kg per day). Food-maintained responding remained equivalent to or significantly above (P less than 0.01) base-line levels in four of five monkeys during desipramine treatment. A transient decrease in food self-administration at desipramine doses of 1.78-5.62 mg/kg per day occurred in one monkey (P less than 0.01). Thirty days of desipramine treatment at the highest doses (5.62, 7.86 and 10.0 mg/kg per day for 10 days each) also did not suppress cocaine self-administration in a monkey that took an average of 4 mg/kg per day of cocaine during saline base-line treatment. These primate data are concordant with the extant clinical literature on the inconsistent effects of desipramine treatment; i.e., both stimulation of cocaine use and inconsistent or incomplete attenuation of cocaine abuse during desipramine maintenance have been reported.

Alcohol and food self-administration by female Macaque monkeys as a function of menstrual cycle phase ☆

Female Macaque monkeys were trained to self-administer food (1 g banana pellet) and alcohol (0.12 g/kg/inj IV) in an operant paradigm. Alcohol and food-maintained responding were controlled by a second order schedule of reinforcement FR 4 (VR 16:S) that required an average of 64 responses for delivery of one food pellet or alcohol injection. Alcohol self-administration at average dose levels of 0-1.5, 1.5-3.0, 3.0-4.0 and 4.0 to 5.5 g/kg/day did not vary systematically as a function of menstrual cycle phase in a sample of 30 menstrual cycles. But alcohol self-administration was significantly lower during menstruation (p less than 0.002) in comparison to mid-cycle or the late luteal phase. Monkeys that self-administered high doses of alcohol (3.0-5.5 g/kg/day) also showed stable patterns of food self-administration across the menstrual cycle. Monkeys that self-administered low to moderate doses of alcohol (0-3.0 g/kg/day) showed a consistent decrease in food self-administration at mid-cycle. The implications of these data for hypotheses concerning estrogen modulation of food intake and the influence of the premenstruum on alcohol self-administration are discussed.

Blood alcohol levels as a function of menstrual cycle phase in female Macaque monkeys

Female Macaque monkey were given a low (1.5 g/kg), moderate (2.5 g/kg) and high (3.5 g/kg) dose of alcohol via nasogastric intubation. Integrated plasma samples for blood alcohol analysis were collected at 30 minute intervals over 210 minutes. Peak blood alcohol levels measured at the premenstruum, menstruation, the periovulatory and mid-luteal phase of the menstrual cycle did not differ significantly after a standard dose of alcohol. Average peak blood alcohol levels, independent of menstrual cycle phase after low, moderate and high doses of alcohol were 139, 238 and 335 mg/dl. Menstrual cycle phase was verified by calendar and radioimmunoassay of levels of luteinizing hormone and 17-beta estradiol. We conclude that in alcohol-naive female Macaque monkeys studied under controlled conditions, peak blood alcohol levels after a standard dose of alcohol do not vary as a function of phase of the menstrual cycle.

Buprenorphine effects on food-maintained responding in Macaque monkeys

The effects of acute and chronic administration of buprenorphine, an opioid mixed agonist-antagonist, on food-maintained responding were compared in Macaque monkeys. Low acute doses of buprenorphine (0.01 and 0.03 mg/kg) did not change the number of food pellets earned or response rates on an FR 4 (VR 16:S) schedule of reinforcement from saline pre-treatment levels. Acute administration of 0.10 and 0.30 mg/kg buprenorphine significantly suppressed food-maintained responding (p less than 0.01). Chronic buprenorphine self-administration (0.01-0.10 mg/kg/injection) did not significantly suppress food intake, even at total daily doses that were 3 to 9 times higher than the highest dose (0.03 mg/kg) studied in the acute pre-treatment paradigm. Decreases in daily buprenorphine intake to 30 to 40 percent of control levels were not associated with increased food self-administration. Similarly, chronic heroin self-administration (0.01, 0.05, and 0.10 mg/kg/injection) was not associated with significant changes in food self-administration. These data suggest that during chronic self-administration of buprenorphine. Macaque monkeys developed tolerance to its acute suppressive effects on food-maintained responding.

Naltrexone effects on pituitary and gonadal hormones in male and female rhesus monkeys

The long-acting opioid antagonist, naltrexone, stimulates LH and FSH in women during the early follicular phase of the menstrual cycle and is a new provocative test of hypothalamic-pituitary function (42,63). The acute effects of naltrexone (0.25, 0.50 and 1.0 mg/kg IV) on anterior pituitary (LH, FSH, PRL) and gonadal steroid (T or E2) hormones were studied in 7 female and 4 male rhesus monkeys (Macaca mulatta). Integrated plasma samples were collected at 20 min intervals for 60 min before and for 300 min after intravenous infusion of naltrexone over 10 min. In females studied during the early follicular phase (cycle days 1-3), naltrexone did not stimulate LH and significantly suppressed E2 (p less than 0.0003-0.0001) and FSH (p less than 0.006-0.0001). Naltrexone (0.50 and 1.0 mg/kg) also did not stimulate LH release in late follicular phase females (cycle days 10-12) when estradiol levels were in the peri-ovulatory range. FSH and E2 were significantly suppressed (p less than 0.01-0.05) after 1.0 mg/kg naltrexone, but not after 0.5 mg/kg naltrexone. However, in males all doses of naltrexone significantly stimulated LH (p less than 0.003-0.0001) and T (p less than 0.001-0.0001) but not FSH. LH increased significantly above baseline within 20 to 40 min and T increased significantly within 60 min. These gender differences in naltrexones effects on pituitary gonadotropins and gonadal steroid hormones were unanticipated. These data are not concordant with clinical studies which report significant naltrexone stimulation of LH in men and in women during the early follicular phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential tolerance development to buprenorphine-, Diprenorphine-, and heroin-induced disruption of food-maintained responding in Macaque monkeys

Single daily subcutaneous injections of buprenorphine (1.0 mg/kg), diprenorphine (1.0 mg/kg), or heroin (1.0 mg/kg) were given over 25 consecutive days to examine the degree and the rate of tolerance development to drug-induced suppression of food maintained responding. One gram food pellets were available on a second order schedule (FR 4 VR 16: S) during the 1-hr sessions three times a day. All drug and saline control injections were given at 10:00 a.m., 1 hr before a food session. During the first three days of treatment all three drugs produced marked suppression of food-maintained performance. Recovery from buprenorphine- and diprenorphine-induced suppression of food-maintained responding occurred within four and eight days, respectively. By the 25th day of buprenorphine and diprenorphine treatment, operant responding for food increased significantly above control levels (p less than 0.01). In contrast, the significant heroin-induced disruption of food-maintained responding (p less than 0.01) persisted throughout the 25-day treatment period. Saline substitution for all three drugs resulted in a gradual return to control levels of food pellets earned. Linear regression analysis of the linear portion of the time-effect curve revealed significant differences in both the rate and the degree of tolerance development to these three drugs. These differences in tolerance development may reflect pharmacokinetic differences between the relatively short-acting heroin and the longer-acting diprenorphine and buprenorphine.

Lack of acute alcohol effects on estradiol and luteinizing hormone in female macaque monkey

The effects of alcohol (1.5, 2.5, 3.5 g/kg) on 17-beta estradiol and LH were evaluated in adult female Macaque monkeys. Integrated plasma samples were collected prior to and following nasogastric intubation of alcohol or isocaloric sucrose control solutions. Samples were collected at 30 minute intervals over 240 minutes. Each alcohol dose and control was studied at menstruation, the peri-ovulatory and mid-luteal periods and the premenstruum. After low, moderate and high doses of alcohol, blood alcohol levels (BAL) averaged 140, 260 and 344 mg/dl at the peak of the ascending BAL curve. Despite high blood alcohol levels, there was no evidence of alcohol dose-related suppression of LH or 17-beta estradiol at any phase of the menstrual cycle. These data are consistent with our findings in human females that acute alcohol intoxication did not suppress LH or estradiol. The apparent resiliency of human and Macaque females to acute alcohol effects on reproductive hormones contrasts sharply with data obtained in males that alcohol significantly suppresses testosterone in all species studied.

Acute venous catheterization for integrated plasma sample collection in monkey

A method is described which permits acute percutaneous venous catheterization for continuous blood collection over a period of several hours. This procedure can also be used for collection of repeated bolus samples without additional venipunctures. Potential applications include collection of integrated plasma samples for neuroendocrine analysis of discrete plasma samples for pharmacokinetic studies.