Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

Abstract

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P ¼ 0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…In the design of this study, we have explicitly set the aim to investigate CB 1 receptor network alterations by using both absolute and relative [ 18 F]MK-9470 measurements. It is known that there is a higher physiologic interindividual variability of absolute regional [ 18 F]MK-9470 determinations in the human brain, in the order of several tens of per cent [14,57]. Relative measurements have the advantage of being much more sensitive, allowing changes of 5-10% to be measured using SPM [58], as proven here.…”

CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

“…There are more convincing results on the association of the CNR1 gene and substance abuse disorders (Zhang et al, 2004;Zuo et al, 2007;Chen et al, 2008), although there is a negative replication study (Herman et al, 2006). Regarding depression, two studies with significantly smaller sample sizes failed to find any association with depression using the (AAT) n polymorphism (Barrero et al, 2005;Tsai et al, 2001), although the former found that a significant association emerged when only the depressed patients with Parkinson's disease were considered (Barrero et al, 2005).…”

Prevalência de depressão na doença de Parkinson

“…Em relação à estratégia de avaliação e/ou obtenção de informações a respeito da presença de depressão nos pacientes com DP (Tabelas 2 e 3), os estudos foram organizados de acordo com o emprego de: a) entrevista clínica 8,13,14,[18][19][20][21][22] ; b) instrumentos estruturados de auto-avaliação [8][9][10]14,17,[23][24][25] ; c) entrevista clínica e instrumentos de auto-avaliação 11 ; e d) consulta em banco de dados 12,15,16,26 .…”

“…Dos estudos selecionados, 11 10,11,13,14,17,18,[21][22][23][24]27 descrevem a relação entre a presença de depressão ou sintomas depressivos e os sintomas motores. Em todos os estudos, constatou-se correlação positiva entre piora do quadro motor, medida por escalas neurológicas específicas, e presença de depressão, corroborando a hipótese de que, ao comparar pacientes deprimidos e não deprimidos, o quadro motor é mais grave na presença de sintomas depressivos.…”

“…Entrevista clínica e instrumentos de auto-avaliação Além disso, Schrag et al 23 e Barrero et al 13 verificaram maior prevalência de depressão em quadros acinéticos, quando há predomínio de rigidez motora, do que naqueles que predominavam tremores ou sintomas mistos. Wichowicz et al 22 constataram que os pacientes com DP com depressão apresentaram maiores pontuações em uma escala para discinesias.…”