Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Cognitive development in macaques: attentional set-shifting in juvenile and adult rhesus monkeys.

In humans and nonhuman primates, the structure and function of frontal cortical regions of the brain are not completely developed until early adulthood. How this cortical development affects cognitive function continues to be elucidated. To that end, this experiment tested the ability of juvenile and adult rhesus monkeys to perform a cognitive task that is dependent upon intact frontal cortical function for optimal performance. Twenty-four juvenile (mean age 2.3 years) and 16 adult (mean age 10.3 years) rhesus monkeys were tested on the Cambridge Neuropsychological Test Automated Battery intradimensional/extradimensional set-shifting (ID/ED) task. Performance on the ID/ED task has been shown to be dependent upon frontal cortical function in both humans and nonhuman primates. Compared with adults, juveniles were impaired on the reversal of simple discrimination, intradimensional shift, reversal of intradimensional shift, and the extradimensional shift stages of the task. These results indicate juveniles committed more perseverative errors and more errors on the set-formation and set-shifting components of the ID/ED task. The developmental stage of the juvenile monkeys corresponds to roughly 5 to 6-year-old children, and these results are consistent with performance of human children and adults on similar ID/ED tests and on several other tests of attentional set-shifting or attentional flexibility. Furthermore, these results are consistent with the ongoing development of frontal cortical structures relating to ongoing cognitive development in nonhuman primates.

Functional consequences of repeated (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys.

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus-infected monkeys.

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions.

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

Scopolamine alters rhesus monkey performance on a novel neuropsychological test battery.

Rhesus monkeys (6) were trained on a test battery including cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CeNeS, Cambridge, UK) as well as a bimanual motor skill task. The complete battery included tests of memory (delayed non-match to sample, DNMS; self-ordered spatial search, SOSS), reaction time (RT), motivation (progressive ratio; PR) and fine motor coordination (bimanual). The animals were trained to asymptotic performance in all tasks and then were administered two of the four CANTAB tasks on alternate weekdays (PR/SWM; DNMS/RT) with the bimanual task being administered on each weekday. The effect of acute administration of scopolamine (3-24 microg/kg, i.m.) on performance was then determined. Although performance on DNMS was impaired there was no interaction of drug treatment with retention interval, suggesting that scopolamine does not increase the rate of forgetting in this task. Scopolamine administration produced a decrement in SOSS performance that was dependent on task difficulty as well as dose. Scopolamine also impaired motor responses, resulting in increased time required to complete the bimanual motor task and increased movement time in the RT task. Performance in the PR task was decreased in a dose-dependent fashion by scopolamine. The results suggest that scopolamine interferes with memory storage and motor responses but not memory retention/retrieval or vigilance. The findings demonstrate that the test battery is useful for distinguishing the effects of neuropharmacological manipulation on various aspects of cognitive performance in monkeys.

Early physiological abnormalities after simian immunodeficiency virus infection.

Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction.

Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata.

Several phenyl-benzazepine compounds, putatively selective dopamine D1 receptor agonists, have been used to study the effects of dopamine D1 receptor stimulation in rodents and nonhuman primates. However, the dopamine receptor selectivities of these compounds have not been established in nonhuman primates. Accordingly, the relative selectivities of six phenyl-benzazepines for dopamine D1-like and D2-like receptors were assessed in rhesus monkey and, for comparison, rat striata. The compounds tested had higher affinity for D1 than D2 receptors in both species; however, their selectivity varied by up to three orders of magnitude. GTP (100 microM) reduced agonist binding at the high-affinity state of the dopamine D1 receptor, but the magnitude of the effect of GTP did not reliably predict a compound's efficacy. Furthermore, a history of cocaine self-administration did not appear to influence dopamine receptor binding characteristics in the rhesus monkeys in this study. The present results will aid the comparison of dopamine receptor binding characteristics and behavioral effects of D1 dopamine receptor agonists.

Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys.

A model is proposed in which a neurovirulent, microglial-passaged, simian immunodeficiency virus (SIV) is used to produce central nervous system (CNS) pathology and behavioral deficits in rhesus monkeys reminiscent of those seen in humans infected with human immunodeficiency virus (HIV). The time course of disease progression was characterized by using functional measures of cognition and motor skill, as well as neurophysiologic monitoring. Concomitant assessment of immunological and virological parameters illustrated correspondence between impaired behavioral performance and viral pathogenesis. Convergent results were obtained from neuropathological findings indicative of significant CNS disease. In ongoing studies, this SIV model is being used to explore the behavioral sequelae of immunodeficiency virus infection, the viral and host factors leading to neurologic dysfunction, and to begin testing potential therapeutic agents.

The effects of dopaminergic agents on reaction time in rhesus monkeys.

Many CNS pathologies, including Parkinson's, Alzheimer's and Huntington's diseases, as well as AIDS dementia complex, involve some degree of movement dysfunction. Reaction time (RT) performance has been shown to be a sensitive measure of motor function for these disorders. Useful models of RT performance exist in a variety of species, but few are performed in the same manner as with humans. To facilitate species comparisons, the present RT task was developed from a human RT task. Dopaminergic drugs were then used to characterize the sensitivity of the model to CNS changes and to investigate their effects on RT performance in intact rhesus monkeys. With cumulative dosing, the selective dopamine receptor antagonists (D1) SCH 39166 and (D2) raclopride produced dose-dependent slowing of RT performance. Results following bolus administration of these drugs were consistent with the cumulative dosing procedure, although of smaller magnitude and higher variability. Amphetamine had no significant effect on group RT performance with either dosing scheme, but RT performance in individual monkeys was either speeded or slowed by d-amphetamine. The present results suggest that blockade of either D1-like or D2-like dopamine receptors can slow RT performance in rhesus monkeys and that this paradigm may be useful to study movement dysfunction in non-human primates.

Choice between cocaine and food in a discrete-trials procedure in monkeys: a unit price analysis.

In behavioral economics, the unit price (UP) model of drug consumption defines UP as the ratio of the response requirement to the dose of drug. This model makes two predictions: increasing UP will decrease consumption, and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. The present experiment was designed to test the UP model in rhesus monkeys allowed to choose between an IV injection of cocaine and food in a discrete-trials choice procedure. Both response requirement/injection and dose of cocaine were varied in such a way as to yield UPs from 40 to 10,000 responses per mg/kg. The response requirement for food was always 30 and there was a 30-min time-out between trials to allow the direct effects of cocaine on responding to dissipate. Consistent with the UP model, cocaine consumption decreased as UP increased. However, at a given UP, cocaine consumption was usually higher at the higher dose. Thus, under the conditions of the present experiment an important component of the UP model of drug consumption was not supported. It may be that UP is not a reliable predictor of consumption under conditions in which the direct effects of a drug on responding are minimized.

The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys.

The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission and stimulation of central nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been found to function as positive reinforcers. The present experiments were designed to examine why some, but not all, D1 receptor agonists can function as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) schedule until stable responding was established. Various doses of D1 agonists, previously reported to function as positive reinforcers, were then made available for self-administration. Stimulation of cAMP production in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive reinforcers in monkeys (SKF 38393, SKF 77434 and S(-)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR schedule and did not differ significantly in efficacy as positive reinforcers; SKF 81297 was less potent than the other two agonists. SKF 81297, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP production in rhesus striata than did SKF 38393, SKF 77434 and S(-)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing efficacy among D1 agonists increases with efficacy in stimulating D1 receptors.

The reinforcing effects of dopamine D1 receptor agonists in rhesus monkeys.

Central dopaminergic systems have been implicated in the reinforcing effects of a number of stimuli, including drugs of abuse; however, the role of dopamine D1 receptors remains controversial. The present study evaluated the reinforcing effects of six reportedly selective D1 agonists of differing intrinsic efficacies. Rhesus monkeys with chronic intravenous catheters lever pressed on a fixed-ratio 10 schedule maintained by a base-line cocaine dose of 0.03 mg/kg/inj in daily 1-hr sessions. Periodically, D1 agonists were substituted for the cocaine base-line. All monkeys (n = 4) self-administered the high-efficacy D1 agonists SKF 81297, SKF 82958 and R(+) 6-Br-APB at rates above those maintained by vehicle; therefore, each of these compounds functioned as a positive reinforcer (maxima: SKF 81297: 55-172 inj/hr, 0.01 mg/kg/inj; R(+) 6-Br-APB:103-165 inj/hr, 0.001 mg/kg/inj; SKF 82958: 110-149 inj/hr, 0.01 mg/kg/inj). In contrast, no monkeys self-administered the lower-efficacy D1 agonists SKF 38393 (N = 4), SKF 77434 (N = 4) or the S(-) enantiomer of 6-Br-APB (N = 2). Additionally, two stimulant-naive monkeys acquired self-administration of SKF 81297. The finding that selective D1 receptor agonists can function as positive reinforcers implicates D1 receptors in the reinforcing effects of psychomotor stimulants and of other drugs that stimulate D1 receptors.

Reinforcing and discriminative stimulus effects of beta-CIT in rhesus monkeys.

beta-CIT (also designated RTI-55) is one of a series of 2 beta-carbomethoxy-3 beta-phenyltropane cocaine analogues that have recently been synthesized for characterizing the dopamine transporter and its function. The present study was designed to examine the behavioral effects of beta-CIT in rhesus monkeys. Two monkeys were allowed to self-administer cocaine (0.01 or 0.03 mg/kg/inj, IV, fixed-ratio 10, 1 h/day) in baseline sessions. When behavior was stable, beta-CIT (0.0007-0.003 mg/kg/inj, IV) was made available for self-administration for several consecutive sessions. beta-CIT maintained responding above saline levels in both monkeys. Two other monkeys were trained to discriminate cocaine (0.2 or 0.4 mg/kg, IM) from saline in a two-lever, food-reinforced drug discrimination paradigm. beta-CIT (0.012-0.025 mg/kg, IV) fully substituted for cocaine as a discriminative stimulus. In both preparations, beta-CIT was at least eightfold more potent than cocaine and had a longer duration of action. Thus, beta-CIT has cocaine-like behavioral effects indicative of a functional interaction with the dopamine transporter.

Reinforcing effect of the D1 dopamine agonist SKF 81297 in rhesus monkeys.

Rhesus monkeys with IV catheters were allowed to self-administer cocaine for 1 h/day. When responding was stable, saline or the D1 dopamine agonist SKF 81297 (SKF; 0.001-0.3 mg/kg/inj) was substituted for cocaine. At least two doses of SKF maintained responding above saline levels in all monkeys. The D1 antagonist SCH 39166 (0.001-0.03 mg/kg, IM) was then administered 30 min before sessions of self-administration of the lowest dose of SKF that maintained behavior (0.01 mg/kg/inj). SKF-maintained responding decreased in a dose-related manner, suggesting antagonism of the reinforcing effect. These results suggest that stimulation of D1 receptors can initiate a reinforcing effect and further implicate D1 receptors in the reinforcing effects of drugs that increase dopamine neurotransmission.