Serotonin 5-HT2 receptor availability in chronic cocaine abusers

Life Sciences,

Vol. 56, No. 16 pp. PL 299-303, Copyright 0 1995 Elsetier Science 1995 Lid Prmted in the USA. All rights resewed

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PHARMACOLOGY LETTERS Accelerated Conmwicatiot~

SEROTONIN

5HT2 RECEPTOR AVAILABILITY COCAINE ABUSERS

IN CHRONIC

Gene-Jack WangI.3, Nora D. Volkowl~‘t, Jean Logan2, Joanna S. Fowlerz, David Schlyerz, Robert R. MacGregor2, Robert J. Hitzemann4, Albert Gjeddes and Alfred P. Wolfz

Medical1 and Chemistry2 Departments, Brookhaven National Laboratory, Upton, New York, 11973, USA; Department of Radiology3 and Psychiat#, SUNY, Stony Brook, New York, 11794, USA; PET Centers, Aarhus University Hospital, Aarhus, Denmark. (Submil~cd Dcccmbcr 9, 199% acceplcd January 19. 1995; received in linal form January 27, 1995)

Abstract: Serotonin 5-HT2 receptor availability was evaluated in chronic cocaine abusers (n=19) using positron emission tomography and F-18 N-methylspiperone and was compared to control subjects (n=19). 5HT2 Receptor availability was measured in frontal, occipital, cingulate and orbitofrontal cortices using the ratio of the distribution volume in the region of interest to that in the cerebellum which is a function of B ,,,ax/&. 5-HT2 Receptor availability was significantly higer in cingulate and orbitofiontal cortices than in other frontal regions or occipital cortex. The values were not different in normal subjects and cocaine abusers. These results did not show any changes in S-HT2 receptor availability in cocaine abusers as compared to the control subjects.

Key Words:

serotonin

SHT,,

chronic

cocaine

abuse,

receptor

availability

Introduction Cocaine is a psychostimulant that has a considerable influence on monoaminergic neurotransmission in the brain. Behavioral, biochemical and eletrophysiological studies indicate that acute cocaine directly affects serotonergic activity (1,2). Repeated administration of cocaine is reported to modify ~-HT~A receptor-mediated behavior and neuroendocrine responses (3,4). In humans continued abuse of high doses of cocaine has been reported to be associated with anhedonia and dysphoria during withdrawal which may perpetuate cocaine self-administration (5). Because decreased function of serotonergic neurons is considered to be one of the causes of endogenous depression (6), disrupted serotonergic activity from cocaine could contribute to postwithdrawal dysphoria. In animals, chronic cocaine administration has been shown to enhance serotonin autoregulation and serotonin uptake binding in some regions of the rat brain (7). To our knowledge, changes in 5-HT2 receptor properties in long-term cocaine abusers has not been reported. N-Methylspiperone (NMS) is a ligand which binds predominantly to dopamine D2 like receptors in the striatum and to 5-HT2 receptors in the cerebral cortex and can therefore be used to evaluate D2 and 5-HT2 receptors in the same individual (8). We evaluated 5-HT2 receptor availability Corresponding Author: G-J Wang, M.D. Medical Department, Brookhaven National Laboratory, Upton, New York, 11973 USA. TEL: (516) 282-3608, FAX: (516) 282-5311

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with F-18 NMS in a group of 19 chronic cocaine abusers for whom we had previously documented significant decreases in dopamine D2 receptors (9). A group of 19 age-matched healthy subjects was used as control.

The patient group comprised of 19 male cocaine abusers (mean age 35.2 f 9.8 years, range 1854 years old) who met DSM III-R diagnostic criteria for cocaine dependence, had at least a 6 month history of continuous use of free-base cocaine or crack and had used at least 4 gm of cocaine per week over the past 6 months. Subjects with a history of cardiovascular, psychiatric, neurological, metabolic, or endocrinological disease; history of dependence on any substance other than cocaine, nicotine, or caffeine were excluded from the study. Patients were kept in the hospital during the evaluation and were tested 2-4 weeks after last use of cocaine. The characteristics of cocaine abusers have been previously reported (9). The control subjects comprised of 19 healthy male volunteers (mean age 33.3 f 10.6 years, range 21-49 years old). Exclusion criteria were as for cocaine abusers except for cocaine abuse. As part of the evaluation all subjects received a complete medical, neurological, and psychiatric evaluation. Urine toxicological studies were performed in all the subjects prior to the study to ensure absence of drug use. The consent forms and protocol were approved by the Human Subjects Research Committee of Brookhaven National Laboratory and the institutional review boards of the Northport Veterans Administration Medical Center. The scans were obtained using a high-resolution positron emission tomograph (CTI-931, 15 slices, 6.5x6.0x6.0 mm FWHM). Positioning, preparation for the study and attenuation scans were carried out as previously described (9). The emission scans were started immediately after intravenous injection of 4-6 mCi of F-18 N-methylspiperone (NMS) and sequential scans were obtained for a total of 3 hours. Preparation of F-18 NMS (specific activity l-2 Ci/umol) and measurement of arterial input function were performed as described (9). Regions of interest (ROIs) for the frontal cortex (4 slices at level of the basal ganglia, 6 regions per slice), occipital cortex (2 slices at level of the basal ganglia, one region per slice), cingulate gyrus (4 slices at level of the basal ganglia, one region per slice), orbito-frontal gyri (right, left orbital and rectal gyri, one region in each area) and cerebellum (2 slices, 2 regions per slice) were drawn directly on the PET images obtained at 11 minutes postinjection. To minimize errors in the values due to partial volume effects, small ROIs were used (average 0.7 cm3 each for ROIS ). A template with the location of these regions has been published (10). Values for the frontal, occipital, cingulate, and orbitofrontal cortices and for cerebellum were computed using the weighted average from the different slices where the regions were obtained. Quantitation of 5HT2 receptor availability was obtained using the ratio of the distribution volume in the region of interest to that in the cerebellum which corresponds to Bmax’/Kd’ +l (11). Bmax’ is Brmx- L (L = Kd’ is G/f2 (f2 = free fraction in tissue). concentration of endogenous neurotransmitter). Distribution volumes were obtained using a graphical analysis technique for reversible systems (11). This can be done since NMS binding in 5-HT2 receptor dissociates within the time of the experiment. Comparisons of regional 5-HT2 receptor availability between cocaine abusers and controls was done using a repeated measure ANOVA with regions (frontal, cingulate, orbitofrontal and occipital cortices) as within factors and diagnosis as between factor. Separate paired t tests were then done to determine differences between the brain regions. The level of significance was set at p 5 0.05. In addition, Pearson product moment correlation analyses was used to evaluate the relationship of 5-HT2 receptor availability (Bin, ‘/I&$ +l) and age as well as the relation between the four cortical regions, These relations were evaluated separately for the normal subjects and

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for the cocaine abusers. Difference in correlations between the group were tested using the Olkin and Finn method (12).

5HT2 Receptor availability was significantly different between brain regions (F = 35, p c 0.0001). Receptor availability was higher in the cingulate (CC) and orbitofrontal (OF) cortices than in other frontal (CC: p I 0.0001, OF: p 5 0.0001) regions and occipital (CC: p I 0.002, OF: p 5 0.05) cortex. There were no differences m the values for K1 which represents the transfer of NMS from blood to brain nor in the DV values in cortex and cerebellum between cocaine abusers and controls. The regional values for the model parameter used to estimate receptor availability @VR&DVCB) did not differ between cocaine abusers and controls (Table 1). There was a significant decrease of 5-HT2 receptor availability with age in controls (r = 0.92, p 5 0.0001) and cocaine abusers (r = 0.72, p < 0.0007) (Figure 1). Table 1 Mean value of plasma to tissue transport (Kl: ml cm-3 mini), distribution volume (DV) and ratio of DV of regions to cerebellum [DV(ROI/CB)] in normal subjects and cocaine abusers. Region C &i OF OC CB

K1 OlWO5 0’2U0’05 0:2&06 0.26zkO.06 0.20.05

Normal subiects DV DVROL/DVCB 84X20 2.0.3 9’4f2.4 2.W.4 9:0?2:2 2. W.3 8.51t2.3 2.W.3 4.3k1.2 1

Cocaine abusers DV DVROI/DVCB 0.17% 04 1.9IhO.3 0. 18ti:OS ;‘%: 2.1zhO.3 0.18A10.05 7:8&l 2.EO.3 0.23ti.07 7.5k1.7 2.W.2 0.17rto.05 3.8kl.l 1

The Kt and DV values were not significantly different, except DV in FC (p < 0.037), in cocaine abusers from that in normal subjects. (FC: frontal cortex, CC? cingulate cortex, OF: orbitofiontal cortex, OC: occipital cortex, CB: cerebellum).

15 20 25

30 35 40 Age (years)

45 50

55

Fig. 1 Serotonin 5-HT2 (ratio of distribution volume of frontal cortex to cerebellum, DVFR/DV& receptor availability in normal subjects (--0---, y = -.026x + 2.872) and cocaine abusers (..*O...v y = -.023x + 2.677).

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Discud 5-HT2 Receptor availability in the cocaine abuser was not different from that in the controls. This lack of a change did not appear to be due to an insufficient length of drug use since dopamine D2 receptor availability was decreased in this group of abusers (9). This data is consistent with animal studies where chronic cocaine failed to affect 5-HT2 receptor concentration (13-15), despite the fact that it enhances their sensitivity (3, 15) and causes regionspecific alteration in 5-HT levels (14). The extent to which there are changes in the functional responsivity of 5-HT2 receptors after chronic cocaine would require an experimental paradigm where these receptors are acutely challenged and the responses (i.e. brain metabolism, cerebral blood flow, or neurotransmitter release) are compared with that in normal subjects. Failure to observe changes in 5-HT2 receptor availability after chronic cocaine in spite of changes in D2 receptor availability is intriguing because cocaine binds with higher affinity to 5-HT than dopamine transporters (16). This difference in response to chronic cocaine could reflect differences in adaptation responses between 5-HT2 and dopamine D2 receptors. For example chronic administration of dopamine antagonist leads to a consistent up-regulation of dopamine D2 receptors (17) whereas most studies administrating 5-HT2 antagonist chronically fail to reveal receptor up-regulation (18). However because the decrements in D2 receptors in the cocaine abusers may have predated the use of cocaine, these changes may not represent differences in receptor adaptation. The serotonergic system has been shown to be involved with addictive behaviors. For example, decreases in serotonergic activity increase the drive for cocaine self-administration (19). The fact that we were unable to document difference in 5-HT2 receptor availability in cocaine abusers does not exclude the possibility of changes in other elements of the semtonergic system. This study did not detect changes in 5-HT2 receptor availability in chronic cocaine abusers. The extent to which chronic cocaine use affect other 5-HT receptors, 5-HT transporters and/or the responsivity of the serotonergic system requires further investigation. Acknowle@&Rt This work was supported by NIDA Grant No. 5ROl-DA06891 and by U.S. Department of Energy under contract DE-AC02-76CHO16. The authors thank T. Johnson, P. King, N. Netusil, N. Pappas, C. Redvanly, D. Warner for their participation in various aspects of this work.

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