Psychopharmacology (2010) 210:521–531 DOI 10.1007/s00213-010-1851-6 ORIGINAL INVESTIGATION Zolmitriptan and human aggression: interaction with alcohol Joshua L. Gowin & Alan C. Swann & F. Gerard Moeller & Scott D. Lane Received: 13 October 2009 /Accepted: 25 March 2010 /Published online: 21 April 2010 # Springer-Verlag 2010 Abstract Specifically, compared to placebo, zolmitriptan decreased Rationale The serotonin 1B/D (5-HT1B/D) receptor has the aggressive/monetary ratio at the 0.4- and 0.8-g/kg shown potential as a target for decreasing aggression. The alcohol doses. 5-HT1B/D agonist zolmitriptan's ability to reduce aggressive Conclusions A 5-mg dose of zolmitriptan effectively behavior in humans and its interaction with the well-known reduced alcohol-related aggression in an acute dosing aggression-enhancing drug alcohol were examined. protocol, demonstrating an interaction of 5-HT and alcohol Objectives Our objective was to investigate zolmitriptan's in human aggressive behavior. potential to modify human aggression in a laboratory paradigm across a range of alcohol doses. Alcohol has Keywords Serotonin . 5-HT1B/D receptors . Agonist . been consistently associated with aggression and violence, Human behavior . PSAP thus we hoped to expand current understanding of alcohol's role in aggressive behavior via manipulation of the serotonin (5-HT) system. Introduction Methods Eleven social drinkers, seven male, were recruited to participate in a research study lasting 3–4 weeks. Serotonin (5-HT) has a longstanding relationship with Aggression was measured using the point-subtraction aggression and violence that has been demonstrated across aggression paradigm (PSAP), a laboratory model widely gender and species (Westergaard et al. 1999; Miczek et al. used in human aggression studies. Subjects were adminis- 2002). For example, cerebrospinal fluid (CSF) levels of 5- tered 5-mg zolmitriptan and placebo capsules along with hydroxy-indolacetic acid (5-HIAA), a 5-HT metabolite, alcohol doses of 0.0, 0.4 and 0.8 g/kg in a within-subject, have been negatively correlated with lifetime history of counterbalanced dosing design. Data were analyzed as the aggression in an inpatient population who had demonstrat- ratio of aggressive/monetary-earning responses, to account ed past antisocial behavior (Brown et al. 1979). Although for possible changes in overall motor function due to not all studies have found a negative correlation (Moller et alcohol. al. 1996), a meta-analysis found a significant mean effect Results There was a significant alcohol by zolmitriptan size of −0.45 for increased aggressive behavior as 5-HIAA interaction on the aggressive/monetary response ratio. decreases (Moore et al. 2002). Further, individuals with conduct disorder, a personality disorder typified by extreme aggression, have lower 5-HT profiles than healthy controls Electronic supplementary material The online version of this article (Cappadocia et al. 2009). In consequence, the 5-HT system (doi:10.1007/s00213-010-1851-6) contains supplementary material, has shown potential as a target for the therapeutic treatment which is available to authorized users. : : : of aggression (Siever 2008). J. L. Gowin A. C. Swann F. G. Moeller S. D. Lane (*) One established laboratory assessment for human ag- Department of Psychiatry and Behavioral Sciences, gression, the point-subtraction aggression paradigm The University of Texas Health Science Center Houston, Houston, USA (PSAP), is a free-operant measure of aggressive behavior e-mail: [email protected] that allows subjects to subtract money (represented on a 522 Psychopharmacology (2010) 210:521–531 computer screen), later to be exchanged for real money, to regulate inhibitory control of aggression (New et al. from a (non-existent) confederate in a computer task 2004). In mice, the injection of a 5-HT 1B agonist into the (Cherek 1992). Subjects are provoked throughout the ventral orbitofrontal cortex (VO PFC) caused reductions in session by subtractions from their counter (attributed to species-typical aggressive behavior without significantly the confederate) and can freely choose the aggressive altering non-aggressive behaviors (de Almeida et al. 2006). option throughout the course of the task, but they are never Notably, a 5-HT 1B agonist injected into the VO PFC forced to use it. The primary measure of interest is the reduced aggression in socially provoked male mice, demon- frequency with which the individual uses the aggressive strating the potential external validity of 5-HT 1B anti- response option. Thus, the PSAP indexes the frequency of aggressive effects (Centenaro et al. 2008). Studies of human aggressive behavior. By comparison, another common task, 5-HT1B receptors have been inconclusive, as some reports the Taylor aggression procedure (or TAP), measures the link genetic polymorphisms of the 5-HT1B receptor to intensity of aggressive behavior (McCloskey and Berman comorbid alcoholism and ASPD (Lappalainen et al. 1998), 2003;Tayloretal.1976; Parrott and Giacola 2007). while other reports have found no relationship (Huang et al. Previous studies in subjects with histories of frequent 1999). In alcohol-dependent men, a single-nucleotide poly- aggressive behavior, criminal violence and disorders asso- morphism (SNP) of the 5-HT1B receptor predicted a blunted ciated with aggression (substance abuse, antisocial person- growth-hormone response to sumatriptan, a 5-HT1B agonist, ality and borderline personality disorders) have documented suggesting a relationship between 5-HT1B receptor function the external validity of the PSAP (Cherek et al. 1997, 1999; and the development of alcoholism (Moss et al. 2007). Gerra et al. 2004; Golomb et al. 2007; Moeller et al. 1998). Investigating the role of 5-HT1B agonists in humans remains The PSAP has also established sensitivity to 5-HT important, especially given their pre-clinical anti-aggressive manipulation, as one study demonstrated that acutely indications and the evolutionary diversity of aggressive lowering serotonin levels via tryptophan depletion can behavior and 5-HT receptor sub-types. increase aggressive responding (Moeller et al. 1996). When Zolmitriptan, one of numerous triptans, is indicated for tryptophan depletion accompanied alcohol administration, migraine relief by acting as an agonist at the 5-HT 1B/D the effects on aggression were additive and aggressive receptor, causing intracranial blood vessels to contract and responding increased to higher levels than following reduce pressure (Peterlin and Rapoport 2007). Second- alcohol administration or tryptophan depletion alone generation triptans, such as zolmitriptan, appear more (Dougherty et al. 1999). Aggressive responding on the selective for cerebral blood vessels than peripheral blood PSAP was also decreased following acute administration of vessels, and thus pose less ischemic risk than first the non-specific 5-HT releasing agents D-fenfluramine and generation triptans such as sumatriptan (Silva et al. 2007). D,L-fenfluramine (Cherek and Lane 1999; Cherek and Lane Unlike releasing agents such as D- and D,L-fenfluramine or 2001), and chronic administration of the SSRI paroxetine reuptake inhibitors like paroxetine, zolmitriptan is a direct (Cherek et al. 2002). Notably, paroxetine was also recently agonist. Therefore, it represents a potentially unique found to reduce aggression measured via the Taylor mechanism of action with regard to effects on aggressive aggression procedure (Berman et al. 2009). behavior. Research supporting a general serotonin deficiency is Behavioral research using a mouse model demonstrated robust, but receptor function and local 5-HT levels may that zolmitriptan effectively reduced both alcohol- reveal a more precise mechanism through which 5-HT heightened and species-typical aggressive behavior via its alters aggression as opposed to systemic changes. For actions at the post-synaptic 5-HT 1B/D receptor (de Almeida example, Cherek et al. (1999)demonstratedthatviolent et al. 2001). Although zolmitriptan shows efficacy at parolees showed less response to a biochemical challenge by targeting 5-HT receptors in the brain and potential to the 5-HT receptor type 1A (5-HT1A) agonist buspirone mitigate aggression, to date few studies have examined compared to non-violent parolees, and thus may have lower zolmitriptan's behavioral effects in humans. Indeed, this expression or decreased function of 5-HT1A receptors rather experiment represents, to our knowledge, the first explora- than lower levels of 5-HT in general. Research exploring tion of any of the triptans to potentially modify human serotonin receptor expression and pharmacologic manipula- aggression or impulse control. tions targeting specific receptors has pointed to serotonin The γ-amino butyric acid A (GABA-A) receptor also receptors 1A,B and D as well as 2A, B and C as targets for plays an important role in the modulation of aggression (see modulating aggressive behavior (Miczek et al. 2002). de Almeida et al. 2005 review). Both epidemiological and For over a decade, the 5-HT 1B receptor has received experimental data document a well-established relationship attention as a target for anti-aggressive modulation, partic- between alcohol use, via action at the GABA-A receptor ularly due to its high concentration in the orbitofrontal (Harris et al. 2008) and aggression (Bushman 1997; Taylor et cortex (OFC; Boschert et al. 1994), a brain region proposed al. 1976; Martin and Bryant 2001). Although not all people Psychopharmacology