The effects of inhaled L-methamphetamine on athletic performance while riding a stationary bike: a randomised placebo-controlled trial.

OBJECTIVE: L-methamphetamine (the non-abused isomer of methamphetamine) is banned in athletic competition because it may improve athletic performance, but there are no studies assessing its effects on performance. In the United States L-methamphetamine is formulated in the non-prescription Vick's Vapor Inhaler (VVI) nasal decongestant. VVIs sold elsewhere (we used ones from the UK) contain similar inactive ingredients (menthol, camphor and Siberian pine oil) but no L-methamphetamine. This study tested the effects of inhaled L-methamphetamine delivered from a widely available non-prescription product on athletic performance. DESIGN: In a 2-session double-blind placebo-controlled study 12 participants (ages 14-17) were dosed with 4 (session 1) and 12 (session 2) inhalations from VVIs with (USA) or without (UK) L-methamphetamine and then performed two 20 minute rides on a stationary bike with rides separated by a 30 minute rest. OUTCOME MEASURE: The main outcome measure was miles travelled during each 20 minute ride. Secondary outcome measures included postride urine toxicology; heart rate and blood pressure before, 1, 5 and 10 minutes postride; energy, performance, endurance, and ability to breathe; and VVI preference. Data were analysed using Excel statistical macros. RESULTS: After approximately 16 microg L-methamphetamine distance travelled was 5.26 (SD 0.53) miles vs 5.30 (0.55) with placebo; p = 0.81. After approximately 48 microg L-methamphetamine distance travelled was 5.30 (0.51) vs 5.35 (0.43) with placebo; p = 0.85. The approximately 16 microg dose increased systolic blood pressure from 72.6 (4.3) to 79.6 (6.6) mm Hg (p = 0.03) at 5 minutes postride but there were no other differences in outcomes. CONCLUSIONS: Modest doses of inhaled L-methamphetamine probably do not improve athletic performance but do minimally raise diastolic blood pressure.

Enhanced spatial ability in aged dogs following dietary and behavioural enrichment.

We examined the benefits of a broad spectrum antioxidant diet and enrichment comprised of physical exercise, environmental stimulants and cognitive testing, on spatial memory performance in beagle dogs. Both aged (N=48) and young (N=16) beagle dogs (Canus familiaris) were tested yearly on a three-component delayed non-match to position spatial task for three consecutive years. The results showed that young enriched animals acquired the task in fewer sessions, made fewer errors, responded slower and made fewer positional responses, compared to aged enriched animals. An analysis restricted to aged animals revealed that antioxidant administration and enrichment resulted in fewer errors, slower responses and decreased positional responses, particularly in Year 3. Finally, cohort differences emerged, which exemplify the significance of early environmental intervention. Aged dogs that were housed with other animals and exposed to an outdoor environment in early development displayed greater benefits from both interventions. These findings indicate that long-term dietary intervention and enrichment can buffer age-associated cognitive decline.

Acute effects of nalmefene on LH, prolactin, and testosterone in male rhesus monkeys.

The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4, 5-alpha-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min (p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min (p < 0.05). Although nalmefene antagonizes opioid agonists for 6-8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance.

This study evaluated cerebral phosphorus metabolites in opiate-dependent polydrug abusers in methadone maintenance therapy (MMT) and determined whether metabolite profiles differed based on treatment duration. Phosphorus magnetic resonance spectroscopy (31P-MRS) data were acquired with the ISIS volume localization method from a 50-mm thick axial brain slice through the orbitofrontal and occipital cortices. Study subjects included 15 MMT subjects, seven having undergone treatment for an average of 39 +/- 23 weeks (mean +/- S.D.) and eight having undergone treatment for 137 +/- 53 weeks, as well as an age matched comparison group (n = 16). The methadone dose administered on the study day averaged 70.5 +/- 17.1 mg and was statistically equivalent in short- and long-term subgroups. MMT subjects (n = 15) differed from control subjects in percent phosphocreatine (%PCr) levels (-13%), and in both phosphomonoester (%PME, +13%) and phosphodiester (%PDE, +10%) levels, which likely reflect abnormalities in energy and phospholipid metabolism, respectively. There were no sex effects or group by sex interaction effects on these measures. In short-term MMT treatment subjects, abnormal %PCr (-18%), %PME (+20%) and %PDE (+17%) levels were found compared with control subjects. The only metabolite abnormality detected in long-term MMT subjects was decreased %PCr (-9%), in spite of continued illicit drug abuse. From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.

Functional topography of cat primary auditory cortex: response latencies.

Minimum onset latency (Lmin) of single- and multiple-unit responses were mapped in the primary auditory cortex (AI) of barbiturate-anesthetized cats. Contralateral Lmin for multiple units was non-homogeneously distributed along the dorso-ventral/isofrequency axis of the AI. Responses with shorter latencies were more often located in the central, more sharply tuned region while longer latencies were more frequently encountered in the dorsal and ventral portions of the AI. For single units, a large scatter of Lmin values was found throughout the extent of the AI including cortical depth. The relationship between Lmin and previously reported spectral, intensity and temporal parameters was analyzed and revealed statistically significant correlations between minimum onset latency and the following response properties in some but not all studied animals: sharpness of tuning of a frequency response area 10 dB above threshold, broadband transient response, strongest response level, monotonicity of rate/level functions, dynamic range, and preferred frequency modulation sweep direction. This analysis suggests that Lmin is determined by several independent factors and that the prediction of Lmin based on relationships with other spectral and temporal response properties is inherently weak. The spatial distribution and the functional relationship between these response parameters may provide an important aspect of the time-based cortical representation of specific features in the animal's natural environment.

Buprenorphine treatment of opiate and cocaine abuse: clinical and preclinical studies.

Buprenorphine, an opioid mixed agonist-antagonist, is a potent analgesic that appears to be effective for the treatment of opiate abuse. Recent preclinical studies have shown that buprenorphine also significantly reduces cocaine self-administration by rhesus monkeys for periods up to 120 days. This unexpected finding has led to clinical trials to evaluate buprenorphine's effectiveness for the treatment of dependence on both cocaine and opiates, as defined by DSM-III-R criteria. Buprenorphine's safety in combination with cocaine and opiates and its effects on electroencephalographic sleep patterns and regional cerebral blood flow were evaluated during inpatient studies. Buprenorphine (4 or 8 mg/day given sublingually) did not accentuate the cardiovascular and respiratory changes induced by an acute challenge dose of cocaine (30 mg given intravenously) or morphine (10 mg given intravenously) alone. In an outpatient open trial, buprenorphine significantly reduced both opiate and cocaine abuse by patients who had abused these drugs for more than 10 years. Most of these patients had failed in other drug abuse treatment programs. Reports of needle sharing also decreased significantly, and no patient tested positive for human immunodeficiency virus (HIV). The apparent safety and effectiveness of buprenorphine, combined with a high level of patient acceptance, led the Food and Drug Administration to grant a compassionate extension of the approved period for outpatient buprenorphine treatment from 26 to 52 weeks. Clinical trials of buprenorphine are ongoing. Possible mechanisms underlying buprenorphine-cocaine interactions are now under investigation.

Functional topography of cat primary auditory cortex: responses to frequency-modulated sweeps.

The spatial distribution of neuronal responses to frequency-modulated (FM) sweeps was mapped with microelectrodes in the primary auditory cortex (AI) of barbiturate-anesthetized cats. Increasing and decreasing FM sweeps (upward- and downward-directed FM sweeps, respectively) covering a range of 0.25-64.0 kHz were presented at three different rates of frequency change over time (i.e, sweep speed). Using multiunit recordings, the high-frequency domain (between 3.2 and 26.3 kHz) of AI was mapped over most of its dorsoventral extent (as determined by the distribution of the excitatory bandwidth, Q10dB) for all six cases studied. The spatial distributions of the preferred sweep speed and the preferred sweep direction were determined for each case. Neuronal responses for frequency sweeps of different speeds appeared to be systematically distributed along the dorsoventral axis of AI. In the dorsal region, cortical cells typically responded best to fast and/or medium FM sweeps, followed more ventrally by cells that responded best to medium--then slow--, then medium-speed FM sweeps. In the more ventral aspect of AI (which in some cases may also have included cells located in the dorsal region of the second auditory field, AII), neurons generally preferred fast FM sweeps. However, a comparison of maps from different animals showed that there was more variability in the distribution of preferred speed responses in the ventral region of the cortex. The directional preference of units for FM sweeps was determined for the sweep speed producing the strongest response. Direction selectivity appeared to be nonrandomly distributed along the dorsoventral axis of AI. In general, units that responded best to upward-directed FM sweeps were located in the more dorsal and ventral aspects of AI while units that responded best to downward-directed FM sweeps were usually located in the mid-region of AI. Direction selectivity was also determined for multiunit responses at each of the three FM sweep speeds. In general, there was a relatively close agreement between the spatial distributions of direction selectivity determined for the strongest response with those calculated for the fast and medium speeds. The spatial distribution of direction selectivity determined for slow FM sweeps deviated somewhat from that determined for the strongest response. Near the dorsoventral center of the mapped areas, the distribution of units that responded best to downward sweeps tended to overlay the distribution of units that responded best to slow speeds, suggesting some spatial covariance of the two parameters.(ABSTRACT TRUNCATED AT 400 WORDS)

Neural selectivity for interaural frequency disparity in cat primary auditory cortex.

Single-unit responses to interaural frequency disparities (IFDs) were examined in 74 neurons in cat primary auditory cortex (AI). Thirty-three of these cells were classified as EE (binaural facilitators), 39 were classified as EI (binaural inhibitors), and 2 were classified as EO (binaural occluders). The best frequency (BF) was presented to the dominant (usually the contralateral) ear while tones of the same or different frequency (either higher or lower than BF) were presented simultaneously to the nondominant (usually the ipsilateral) ear. Most cells displayed sensitivity to IFDs and thus were classified according to the IFD condition that elicited the strongest facilitatory or inhibitory response. The stimulus condition which evoked the strongest binaural response is referred to as the best IFD. For 50 cells (68%), the best IFD response was obtained when tones of different frequency were presented to each ear. Across the entire sample, binaural IFD responses of cortical neurons were categorized into one of three groups: Those preferring a lower frequency than BF in the ipsilateral ear (referred to as the 'lower IFD group'), those preferring a frequency equal to BF (the 'zero IFD group'), or those preferring a frequency higher than BF (the 'higher IFD group'). Among EE cells, approximately one third were maximally facilitated when the ipsilateral ear frequency was lower than BF, one third when it was equal to BF, and one third when it was higher than BF. Among EI cells, 50% exhibited deepest inhibition for higher IFDs with relatively fewer cells showing inhibition for zero or lower IFDs. Overall, EI cells responded over a broader range of IFD conditions than EE cells. Finally, approximately 50% of all units exhibited bimodal responses such that cells classified as EE displayed some inhibitory response characteristics when stimulated with certain IFD conditions and vice versa.

Functional topography of cat primary auditory cortex: representation of tone intensity.

The neuronal response to tones as a function of intensity was topographically studied with multiple-unit recordings in the primary auditory cortex (AI) of barbiturate-anesthetized cats. The spatial distribution of the characteristics of rate/level functions was determined in each of three intensely studied cases and their relationship to the distribution of spectral parameters (sharpness of tuning and responses to broadband transients) in the same animals was determined. The growth of the high-intensity portion of rate/level functions was estimated by linear regression. Locations with monotonically growing high-intensity portions were spatially segregated from locations with nonmonotonic rate/level functions. Two noncontiguous areas with a high degree of nonmonotonicity were observed. One was located at the dorsoventral center of AI, and a second in the dorsal third of AI. The more ventral aggregate of high nonmonotonicity coincided with the region of sharp frequency tuning. The stimulus levels that produced the highest firing rate (strongest response level, SRL) at any sampled location ranged from 10 to 80 dB sound pressure level (SPL). Several spatial aggregates with either high or low SRLs were observed in AI. The region of sharpest tuning was always associated with a region of low SRLs. The response threshold to contralateral tones at the characteristic frequency (CF) ranged from -10 dB SPL to 85 dB SPL with the majority between 0 and 40 dB SPL. The spatial distribution of response thresholds indicated several segregated areas containing clusters with either higher or lower response thresholds. The correlation of response threshold with integrated bandwidth and transient responses was only weak. Low- and high-intensity tones of the same frequency are represented at different locations in AI as judged by the amount of evoked neuronal activity and are largely independent of the frequency organization. The spatial distribution of locations with high monotonicity and low strongest response levels were aligned with the organization of the integrated excitatory bandwidth and covaried with the response strength to broadband stimuli.

Buprenorphine and naltrexone effects on cocaine self-administration by rhesus monkeys.

The effects of daily treatment with buprenorphine (0.237-0.70 mg/kg/day), naltrexone (0.32-3.20 mg/kg/day) and saline on cocaine self-administration were compared in rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellets) self-administration were maintained on a fixed-ratio 4 (variable ratio 16:S) schedule of reinforcement. Buprenorphine, naltrexone or an equal volume saline control solution were infused slowly over 1 hr through one lumen of a double lumen i.v. catheter at the same time each day. Saline and each dose of buprenorphine (0.237, 0.40 and 0.70 mg/kg/day) or naltrexone (0.32 and 3.20 mg/kg/day) were studied for 60 sessions over 15 consecutive days. Buprenorphine significantly suppressed cocaine self-administration (P less than .001-.0001) in comparison to saline in all monkeys. Cocaine self-administration decreased by 49 to 95% in five of six monkeys on the 1st day of buprenorphine administration (0.237 and 0.40 mg/kg/day) and remained suppressed by an average of 72 to 93% during buprenorphine treatment. After abrupt termination of buprenorphine treatment (0.237 and 0.70 mg/kg/day), cocaine self-administration remained suppressed for an average of 16 +/- 4.4 and 28 +/- 6.6 days, respectively. Buprenorphine (0.237 and 0.40 mg/kg/day) initially suppressed food self-administration in some monkeys (P less than .01), but tolerance developed to buprenorphine's effects on food-maintained responding whereas cocaine self-administration remained significantly suppressed. During treatment with 0.70 mg/kg/day of buprenorphine, food self-administration returned to or significantly exceeded (P less than .01) base-line levels in three animals. Daily patterns of food self-administration were not disrupted by buprenorphine treatment. Naltrexone (0.32 mg/kg/day) initially suppressed cocaine self-administration by an average of 28% over 15 days (P less than .0009). During high-dose naltrexone treatment (3.20 mg/kg/day), cocaine-maintained responding was suppressed by 25% over 15 days (P less than .01). Cocaine-maintained responding was not significantly changed by naltrexone in one of the five subjects. Food self-administration decreased by 24% (P less than .05) after 5 days of 0.32 mg/kg of naltrexone administration, then exceeded baseline levels during 3.20 mg/kg of naltrexone administration. These data suggest that buprenorphine decreases cocaine's reinforcing properties more effectively than naltrexone across the dose-range studied. Buprenorphine may be an effective pharmacotherapy for treatment of cocaine abuse as well as dual abuse of cocaine plus heroin.

Use of naltrexone as a provocative test for hypothalamic-pituitary hormone function.

Naltrexone (50 mg) administration to normal adult women during the early follicular phase of the menstrual cycle (day 1 to day 4 following onset of menstruation) induced a significant elevation in plasma LH, prolactin, ACTH and cortisol levels. Orally administered naltrexone appears to be a safe and effective compound for assessing function of the hypothalamic-anterior pituitary axis in women.

Effects of EMG and thermal feedback training on tinnitus: a case study.

This case report describes a patient who exhibited the usual complaints of frustration, annoyance, and lack of sleep associated with severe tinnitus. After 2 months of weekly biofeedback sessions along with home training with a portable thermal biofeedback unit, the patient was relieved of the psychological symptoms associated with the tinnitus. A 1-year follow-up demonstrated that the patient remained complaint-free of psychological symptoms although the subjective loudness of the ringing was judged to be the same as at the onset of the tinnitus. The results indicate that biofeedback is a useful procedure in the treatment of severe tinnitus.

Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor sites on T lymphocytes.

Street opiate addiction produces a significant depression in the absolute number of total T lymphocytes in peripheral blood as measured by the ability of the lymphocytes to rosette sheep red blood cells (SRBC). Associated with the decrease in T cells, there is an increase in the absolute number of null lymphocytes but no significant changes in B lymphocytes or total white blood cell count. The T cell values for 2 different populations of addicts (n = 12 and 32) are 31.8% and 23.1%, whereas the null cell values are 51.1% and 57.6%, respectively. The values for comparable control populations (n = 18 and 10) are: T% = 70.7% and 67.4%, and null % = 9.2% and 14.5%. Self-reported use of marihuana does not significantly alter the distribution of cell populations. A 1- to 3-hr incubation of addicted-derived lymphocytes with 10(-6) to 10(-7) M Naloxone reverses both T cell depression and null cell increase by allowing the null cells to express SRBC receptors. Cyclic AMP and dibutyryl cyclic AMP can also convert the null cells to T cells. The conversion of null to T lymphocytes has additionally been measured by monitoring the increase in PHA-stimulated growth in 72-hr cultures as determined by tritiated thymidine incorporation into DNA. These results support the hypothesis that opiates can alter T lymphocyte number and function in vivo, and that this alteration may produce a significant degeneration in the immune competence of street opiate addicts.