Cannabis use in teenagers can result in the development of drug dependence and has the potential to trigger psychosis and schizophrenia in vulnerable individuals. Aiming to investigate the age-specific responses in the brain following cannabinoid exposure, we treated adolescent and adult rats with a synthetic cannabinoid for 14 days.
Comparing the levels of the cannabinoid CB1 receptor (the main target of both synthetically produced cannabinoids as well as marijuana) by using in vitro autoradiography, we found that adult rats adapted to excess cannabis exposure. Interestingly, in adolescent rats this adaptation was smaller.
The reduced adaptive response to cannabinoid drug treatment that we observed in adolescent rats may account in part for the behavioural effects, decreased response to other drugs and adverse psychological consequences following cannabinoid exposure during
Effects of cannabis use during adolescence
Cannabis is one of the most widely used street drugs worldwide by adolescents, but cannabis use during teenage years is linked to the development of drug dependence, impairments in memory and thought processing, and psychoses including schizophrenia in later life.
Adolescence is an important time for brain maturation when many connections between nerve cells are being made as well as eliminated and fluctuations are occurring in levels of brain chemicals. It is likely that cannabis use, which can alter levels in brain chemicals and affect the formation of connections between nerve cells [1], may adversely influence the developmental processes taking place in the adolescent brain.
Behavioural studies in animal models show that adolescent and adult rodents respond differently to cannabinoids in the short and long term with adolescents showing less anxiety, more movement and deficiencies in memory and attention which mirror some aspects of schizophrenia.
Despite these studies though, new groups have examined the underlying changes that take place in adolescent brain chemical systems that drive the different agespecific behavioural responses to cannabinoid exposure.
Age-specific difference in response to cannabinoid exposure
We observed age-specific differences in the adaptive, compensatory response to long–term cannabinoid drug treatment in the adolescent and adult rat brain.
In brain regions involved in movement, memory, anxiety and drug response, for example, adolescents showed a smaller adaptive response than adults (i.e. a smaller reduction in cannabinoid CB1 receptor number compared to adults).
These age-specific differences may account in part for the different short term behavioural responses to cannabinoids seen in adolescent and adult animals in this study [2,3,4] and reported by others [5,6]. We also noted a decreased compensatory response to treatment in adolescents in brain areas such as nucleus accumbens and amygdala, which are important in producing the rewarding effects or “high” associated with drugs of abuse.
This decreased response may in turn encourage further drug consumption to achieve the desired high, may account in part for the decreased adolescent reaction to other drugs of abuse such as morphine, cocaine and amphetamine [7] and perhaps increase the risk of drug dependence in later life.
In the long term, the lessened compensatory response in adolescents, in brain regions important in memory (hippocampus), thought processing and attention (cortex) may have an adverse impact on the developmental changes taking place in various neurochemical systems in these brain areas during adolescence.
The consequences of disrupting these developmental changes may include problems in learning, memory and attention, and the development of psychosis in later life.
Methods: Treatment of adolescent and adult rats with the synthetic cannabinoid, HU210.
We treated groups of adult [2] and adolescent [3,4] rats with a potent synthetic cannabinoid, HU210, which binds to the naturally occurring cannabinoid receptor in the brain, the CB1 receptor. We examined the effect of HU210 treatment on levels of the CB1 cannabinoid receptor.
Adolescent and adult male rats were treated daily with low, medium or high doses of HU210 for 14 days. CB1 receptor numbers (densities) were investigated in brain regions that are important in functions such as cognition (cortex), control of movement (basal ganglia), drug response (nucleus accumbens) and memory (hippocampus).
A technique called in vitro autoradiography was used whereby a radioactively labelled molecule, [3H] CP55,940, targeted towards the receptor of interest (CB1) is applied to the brain tissue and binding of the labelled molecule is visualised using photographic film (Figure 1) and quantified.
HU210 treatment caused a region specific, dosedependent decrease in CB1 receptor levels in the adult and adolescent brains (Figure 1 and 2). In the adult brain, decreases ranged from 35- 90%, with the highest dose of HU210 causing the greatest decline in receptor number (Figure 1).
Regions where the largest reductions (78-88%) in binding took place included the hippocampus and hypothalamus (Figure 1). Smaller reductions (51-76%) were seen in the basal ganglia and a major information integration centre of the brain, the thalamus (Figure 1).
The compensatory responses (i.e. alterations in receptor levels) to HU210 treatment were different however in the adolescent and adult brain (Figure 2). The treatment caused a dosedependent decrease in CB1 receptor levels which was smaller by up to 28% in adolescents than in adults (Figure 2).
What is next?
Future studies will focus on the effects of cannabis in animal models of psychosis (e.g. animals made vulnerable to develop psychosis like behaviour due to environmental or genetic manipulations) using in vitro and in vivo imaging techniques.
This research will provide an insight into the mechanisms by which cannabis is involved in triggering psychosis in vulnerable individuals. Furthering our understanding of these processes will aid in identifying targets for treatment of both drug dependence and psychosis.
Authors
Victoria S. Dalton1,2 and Katerina Zavitsanou1,2.
1 ANSTO and 2 Schizophrenia Research Institute, Sydney, Australia
Reference
[1] Schlicker E, Kathmann M, Modulation of transmitter release via presynaptic cannabinoid receptors. Trends in Pharmacological Sciences, 22(11), (2001) 565-572.
[2] Dalton VS, Wang H, Zavitsanou K; HU210-induced downregulation in cannabinoid CB1 receptor binding strongly correlates with body weight loss in the adult rat. Neurochemical Research, 34(7), (2009)1343-1353.
[3] Dalton VS, Zavitsanou K. Cannabinoid effects on CB1 receptor density in the adolescent brain: an autoradiographic study using the synthetic cannabinoid HU210. Synapse (2010), in press (DOI: 10.1002/syn.20801).
[4] Dalton V S, Zavitsanou K. Adolescent rats show a reduced neurochemical reaction compared to adults in response to cannabinoid administration. Schizophrenia Research 117(2010) 388.
[5] Schramm-Sapyta N.L, Cha Y.M, Chaudhry S, Wilson W.A, Swartzwelder H.S, Kuhn C.M Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats, Psychopharmacology (Berlin) 191: (2007) 867-77.
[6] Quinn H.R, Matsumoto I, Callaghan P.D, Long L.E, Arnold J.C, Gunasekaran N, Thompson M.R, Dawson B, Mallet P.E, Kashem M.A, Matsuda-Matsumoto H, Iwazaki T, McGregor I.S Adolescent Rats Find Repeated Delta(9)-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure. Neuropsychopharmacology 33, (2008) 1113-26.
[7] Pistis M, Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL; Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biological Psychiatry 56 (2), (2004) 86-94
Published: 15/07/2009