Abstract:
Impulsive behaviour, defined as swift action without conscious judgement or adequate thought , is increasingly implicated in a wide range of recognised psychiatric conditions, including attentiondeficit hyperactivity disorder and substance-use disorders. This study aimed to identify structural and molecular markers of impulsivity in rats trained on the five-choice serial reaction time task (5- CSRTT), and to investigate the effects of chronic cocaine and methylphenidate treatment on impulsivity and dopamine D2/3 receptor availability using non-invasive imaging techniques. Rats were trained in the 5-CSRTT and low (LI), medium (MI) and high impulsive (HI) rats were identified. Subjects making >50 premature responses were considered HI. Magnetic resonance imaging (MRI) was used to identify changes in grey matter density between HI, MI and LI animals and changes in neuronal, glial and dendritic markers between HI and LI animals were then assessed using Western Blot. Levels of GAD65/67 were also assessed. A second experiment employed positron emission topography (PET) to measure D2/3 receptor availability in HI and LI animals before and after chronic self-administration of cocaine. Impulsivity was reassessed after exposure to cocaine using the 5-CSRTT. A third study investigated the effects of methylphenidate, using a similar protocol, to determine if the similar mechanisms of action of cocaine and methylphenidate could predict longterm effects on impulsivity and dopamine receptor binding. A lateralised reduction in structural integrity and concentration of GAD65/67 was observed in the left nucleus accumbens core of HI compared with LI animals. Additionally, HI animals exhibited lower levels of D2/3 receptor binding in the ventral striatum that increased after chronic self-administration of cocaine. Methylphenidate did not affect D2/3 receptor availability in HI animals however, but was associated with a significant reduction in binding in LI animals following chronic administration. Likewise, cocaine was associated with a significant reduction in impulsivity in HI animals, whereas methylphenidate induced a trend increase in impulsivity in LI animals following chronic treatment. These results provide new insight into the structural and functional deficits of impulsive subjects and confirm the involvement of the ventral striatum in impulsivity of this type and in the pharmacological response to cocaine and methylphenidate.
