Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats

J of Comparative Neurology

et al. 2018

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Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1‐ or D2‐expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein‐tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.

Section: Discussionmentioning

confidence: 99%

Section: Prelimbic and Infralimbic Cortices Of The Medial Prefrontamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Cullity

Madsen

J of Comparative Neurology

et al. 2018

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“…Increasingly complex variants of extinction reinstatement have been developed that tease out the importance of contextual (Kim et al ) and discrete drug‐associated cues (Torregrossa et al , ) in driving drug seeking. Indeed, preclinically at least, it is possible to create resistance to relapse by pharmacological manipulation of what is learned during the extinction phase (Perry et al ; Zbukvic et al ). Cognitive aids such as metabotropic glutamate 5 (mGlu5) receptor positive allosteric modulators (PAMs) show potential in this regard (Cleva et al ; Gass & Olive ; Olive ; Perry et al ).…”

Section: Animal Models and Treatment Research: A Movement From Decreamentioning

confidence: 99%

Addiction, cognitive decline and therapy: seeking ways to escape a vicious cycle

Genes Brain and Behavior

Lawrence

2016

Any type of behavioral change is an effortful process. Thus, the process of behavioral therapy, where clients seek to change maladaptive behavioral patterns, requires high-level cognitive engagement. It is unfortunate, then, that cognitive impairment is a feature of substance use disorders (SUDs), and especially because the domains that tend to be impaired are the very ones involved in the process of therapeutic behavioral change. In this review, we compare the cognitive profile that is frequently observed with chronic SUD with the skills that are required to initiate and sustain behavioral change during rehabilitation. Furthermore, we look to new therapeutic developments that seek to improve cognitive function. We propose that the use of these cognitive enhancing agents as adjuncts to behavioral therapy should help to overcome some of the cognitive barriers imposed by the disorder itself, and hence reduce the chance of relapse.Keywords: Abstinence, addiction, animal models, behavioral therapy, cognition, cognitive enhancement, cognitive impairment, exercise, relapse, substance use disorder, therapy Received 31 May 2016, revised 14 August 2016, accepted for publication 25 August 2016Substance use disorder (SUD) is a maladaptive pattern of drug use involving impaired control over drug-taking activities, social impairment, risky use and pharmacological indicators such as tolerance and withdrawal (American Psychiatric Association & DSM-5 Task Force 2013). Leaving aside the final point, these diagnostic criteria are clearly indicative of maladaptive cognition and behavior arising from suboptimal decision-making, poor executive function and inappropriate prioritization of goals. Drug seeking and drug taking has replaced normal social, work and leisure activities. Thus, the aim of addiction therapy is to inhibit and replace the maladaptive behaviors with others that will allow the individual to lead a more fulfilling lifestyle. A problem that arises with SUD is that the very cognitive impairments that define the disorder are to domains that need to be engaged in order to initiate and maintain the behavioral changes necessary for recovery. This creates a vicious cycle, which is no doubt a major contributory factor behind the poor retention rates and high incidence of relapse that are hallmarks of the disorder.Addiction or SUD is frequently conceptualized as a disorder of the brain and mind that is brought about by exposure to drugs of abuse -psychostimulants, opiates, barbiturates, alcohol, nicotine and cannabis -in combination with genetic and environmental influences (Leshner 1997). This description is somewhat contentious, partly because of the stigma implied, but perhaps more importantly because it may disempower those who are seeking to change their drug-taking patterns. If maladaptive drug seeking is seen as the result of a disordered mind, and not the free will of the subject, then perhaps that person will be less engaged or motivated to change those behavioral patterns (Kellogg & Tatarsky 2012). This, however, ...

“…In fact it is becoming increasingly evident that maturation of the PFC, and in particular changes to dopamine fiber innervation and relative receptor expression, results in divergent mechanisms of cue extinction between adolescents and adults (Zbukvic et al 2016;Zbukvic & Kim, 2018). Therefore it is possible that the discrepancy between current findings in adolescents and previous findings in adults may be mediated through age dependent changes in dopamine system.…”

Section: Discussionmentioning

confidence: 91%

Adolescent rats show estrous cycle-mediated sex-differences in extinction of conditioned fear

Ganella

Nguyen

et al. 2020

Preprint

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Anxiety disorders are more prevalent in females than males, and frequently emerge during adolescence. Despite this, preclinical research commonly focuses on adult males. Here we use Pavlovian fear conditioning and extinction in adolescent male and female rats to understand sexand age-dependent processes relevant to anxiety disorders. In experiment 1, 35-day-old male and female rats were exposed to 6 pairings of a conditioned stimulus (CS, a tone) with an aversive unconditioned stimulus (US, a footshock). The next day they were extinguished in a contextually distinct chamber, via 60 presentations of the CS without the US. Extinction recall was tested 24 hours later in the extinction context. Estrous phase was monitored by cytology on vaginal smears taken 1 hour after each behavioral session. In experiment 2, male and female rats were given sham surgery or gonadectomy at 21 days of age. They were then trained and tested as for experiment 1.We observed that females in proestrus or met/diestrus during extinction showed delayed extinction and impaired extinction recall the next day compared to males. Ovariectomy enhanced extinction for female rats, but orchidectomy delayed extinction for males. Plasma analyses showed that met/di/proestrus phases were associated with high estradiol levels. These findings suggest that high plasma estradiol levels impair extinction for adolescent females. While these results contradict what is observed in adult animals, they are consistent with the prevalence of anxiety disorders observed in females. Our findings have important implications for understanding and treating anxiety in adolescents, particularly where treatment involves extinction-based therapies.