ABSTRACT
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.
Subject(s)
Adrenergic alpha-2 Receptor Agonists/pharmacology , Behavior, Animal/drug effects , Cognition Disorders/physiopathology , Guanfacine/pharmacology , Impulsive Behavior/drug effects , Neostriatum/diagnostic imaging , Receptors, Dopamine/metabolism , Self-Injurious Behavior/physiopathology , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Animals , Attention/physiology , Carbon Radioisotopes , Cognition/physiology , Disease Models, Animal , Dopamine Antagonists , Guanfacine/therapeutic use , Impulsive Behavior/physiology , Macaca mulatta , Male , Neostriatum/metabolism , Neostriatum/physiopathology , Neuropsychological Tests , Positron-Emission Tomography , Raclopride , Random Allocation , Reaction Time , Self-Injurious Behavior/drug therapy , Severity of Illness IndexABSTRACT
Behavioral pharmacologists have enlisted Herrnstein's (1970) hyperbolic matching equation to understand the behavioral effects of drugs. Herrnstein's hyperbola describes the relation between absolute response rate and reinforcement rate. The equation has two fitted parameters. The parameter k represents the asymptotic response rate, and the parameter r(e) represents the reinforcement rate necessary to obtain half the asymptotic response rate. According to one interpretation of the equation, changes in k should reflect changes in response or motoric variables, and changes in r(e) should reflect changes in reinforcer or motivational variables, or changes in reinforcement from sources extraneous to the instrumental response. We review research that has applied Herrnstein's equation to distinguish the motoric from the motivational effects of drugs, and to identify additional independent variables responsible for drug effects, such as extraneous reinforcement. The validity of inferences about drug effects depends on the consistency of how k and r(e) respond to environmental manipulations: k should change only with response or motoric variables, and r(e) should change with reinforcer or motivational variables and with the rate of extraneous reinforcement. Empirical tests of these predictions, however, have produced inconsistent results. The review suggests that Herrnstein's theory has not fulfilled its promise of identifying the behavioral mechanisms of drug action. Modifications to the equation, known as bias and sensitivity, may explain some of these inconsistent results, and the modified equation may have utility in behavioral pharmacology.
Subject(s)
Behavior/drug effects , Models, Theoretical , Pharmacology , Animals , Humans , Motivation , Rats , Sensitivity and SpecificityABSTRACT
The physiological effects of gamma-hydroxybutyrate (GHB) are complex and not yet clearly defined. GHB has been labeled as a recreational drug and is reported to be frequently coabused with ethanol (ETH). Other studies have yielded discrepant results as to the interaction between GHB and ETH. Thus, the present study investigated extensively the discriminative stimulus of GHB and ETH and a mixture of the two compounds. Thirty male Long-Evans rats were divided into three groups and trained to discriminate doses of either 300 mg/kg GHB, 1000 mg/kg ETH, or a mixture (MIX: 150 mg/kg GHB+500 mg/kg ETH) from vehicle on a two-lever fixed-ratio (FR) 10 schedule of food reinforcement. Dose-response curves were attained in each group with its respective training drugs. GHB and ETH did not cross-generalize in the ETH- and GHB-trained rats, respectively. However, when the effects of the MIX were tested in the GHB- and ETH-trained rats, a greater than additive response was observed. Testing also revealed that the MIX-trained rats did not perceive a novel stimulus but a near-equal contribution from GHB and ETH. This study provides evidence of a complex relationship between GHB and ETH and opposes previous work reporting cross-generalization between GHB and ETH.
