Clifford M. Knapp

Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 μA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder.

Increased aggressive behavior can occur in association with posttraumatic stress disorder (PTSD). This study tested the hypothesis that low-dose risperidone reduces aggression and other PTSD-related symptoms in combat veterans. Subjects were male combat veterans with PTSD who scored 20 or higher on cluster D (hyperarousal) of the Patient Checklist for PTSD–Military Version (PCL-M). Subjects were randomly assigned to either risperidone or placebo treatment groups. Drugs were administered over a 6-week treatment period in a double-blind manner. Subjects received either risperidone (0.5 mg/day; n = 7) or matched placebo (n = 8) tablets during the first 2 weeks of the treatment period. The dose of risperidone could then be increased up to 2.0 mg/day on the basis of response. Prerandomization psychotropic regimens were continued. Subjects were evaluated with the PCL-M and the Overt Aggression Scale–Modified for Outpatients (OAS-M). In comparison with placebo treatment, reductions in scores between baseline and the last week of treatment were significantly greater for OAS-M irritability and PCL-M cluster B (intrusive thoughts) subscales and on the PCL-M total scale. These results suggest that low-dose risperidone administration reduces irritability and intrusive thoughts in combat-related PTSD.

Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats.

Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat.

Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration

Administration of the adenosine antagonist caffeine will facilitate the reinstatement of cocaine self-administration responding. This suggests that adenosine receptors may play a role in the motivational systems that regulate cocaine-seeking behaviors. If so then adenosine agonists may act to block cocaine self-administration. To test this hypothesis, the effects of the nonselective adenosine agonist NECA and of the A2A selective agonist, CGS 21680 on the self-administration of cocaine were determined. In these experiments, rats were allowed to obtain intravenous cocaine infusions (0.6 mg/kg/infusion) delivered under a Fixed Ratio 5 schedule. Treatment with either NECA or CGS 21680 in comparison to vehicle administration reduced the number of infusions received per session. This, primarily, was due to a marked increase in the latency for delivery of the first cocaine infusion. Responding after drug-induced delays tended to be at control levels. Adenosine agonists are known to have sedative effects and these actions might play a role in NECA and CGS 21680-induced increases in latencies for cocaine delivery. These results indicate that the administration of adenosine agonists may inhibit cocaine-seeking behaviors. The degree to which these actions are on motivational systems as opposed to involving less specific effects remains to be fully elucidated.

Frontal lobe GABA levels in cocaine dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy study.

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93+/-0.27 mM/kg in cocaine-dependent subjects and 1.32+/-0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.

Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials.

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4–24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration‐time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose‐adjusted Cmax for both tablet formulations and for the dose‐adjusted AUCs for the buprenorphine‐naloxone tablets. For both formulations, the maximal buprenorphine‐induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats.

The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.

Concealment and fabrication by experienced research subjects

Background Subjects who enroll in multiple studies have been found to use deception at times to overcome restrictive screening criteria. Deception undermines subject safety as well as study integrity. Little is known about the extent to which experienced research subjects use deception and what type of information is concealed, withheld, or distorted. Purpose This study examined the prevalence of deception and types of deception used by subjects enrolling in multiple studies. Methods Self-report of deceptive behavior used to gain entry into clinical trials was measured among a sample of 100 subjects who had participated in at least two studies in the past year. Results Three quarters of subjects reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. Health problems were concealed by 32% of the sample, use of prescribed medications by 28%, and recreational drug use by 20% of the sample. One quarter of subjects reported exaggerating symptoms in order to qualify for a study and 14% reported pretending to have a health condition in order to qualify. Limitations Although this study finds high rates of lifetime deceptive behavior, the frequency and context of this behavior is unknown. Understanding the context and frequency of deception will inform the extent to which it jeopardizes study integrity and safety. Conclusion The use of deception threatens both participant safety and the integrity of research findings. Deception may be fueled in part by undue inducements, overly restrictive criteria for entry, and increased demand for healthy controls. Screening measures designed to detect deception among study subjects would aid in both protecting subjects and ensuring the quality of research findings.

Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment

RationaleThere is evidence that prefrontal lobe GABA levels are low in cocaine-dependent (CD) individuals, and treatment with GABA agonists decreases cocaine self-administration.ObjectivesThe aim of the study is to measure changes in GABA levels in CD subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo.MethodsCD subjects enrolled in a treatment trial for cocaine dependence were recruited for this proton (1H) magnetic resonance spectroscopy (MRS) study. GABA levels in the prefrontal lobe were measured before and after treatment.ResultsMean percentage changes in GABA levels were as follows: pramipexole +17.0±28.0%, venlafaxine +13.0±11.0%, and placebo −2.1±19.5%. Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Venlafaxine treatment was nonsignificantly associated with increased GABA levels compared to placebo (p=0.16). The overall statistical model for the effect of drug treatment vs placebo on brain GABA levels, including adjustment for baseline levels, was highly significant (p=0.002). Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites.ConclusionsThis study demonstrates that 1H MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used.

The Type IV Phosphodiesterase Inhibitors, Ro 20-1724 and Rolipram, Block the Initiation of Cocaine Self-Administration

The hypothesis that the selective activation of cyclic AMP (cAMP) signal transduction pathways will suppress the initiation of cocaine self-administration was examined in this investigation. To test this hypothesis, the effects of the administration of the cAMP-specific (type IV) phosphodiesterase inhibitors, rolipram and Ro 20-1724, on cocaine self-administration were determined. The effects of Ro 20-1724 treatment on operant responding for food also were examined. Both cocaine and food were delivered following a fixed-ratio 5 schedule. A significant increase in the latency for the delivery of the first cocaine infusion and a reduction in the number of infusions obtained per session were produced by treatment with either rolipram or Ro 20-1724. Similar effects on responding for food were seen with Ro 20-1724 administration. Responding after drug-induced delays tended to be at control levels. These results suggest that cAMP-specific phosphodiesterase inhibitors may inhibit the initiation of operant responding for either cocaine or food. However, the extent to which these actions involve specific effects on central motivational systems as opposed to other mechanisms remains to be determined.