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The posterior dorsomedial striatum (pDMS) is mainly composed of medium spiny neurons (MSNs) expressing either dopamine D1 receptors (D1Rs) or D2Rs. Activation of these two MSN types produces opposing effects on addictive behaviors. However, it remains unclear whether pDMS D1-MSNs or D2-MSNs receive afferent inputs from different brain regions or whether the extrastriatal afferents express distinct dopamine receptors. To assess whether these afferents also contained D1Rs or D2Rs, we generated double transgenic mice, in which D1R-expressing and D2R-expressing neurons were fluorescently labeled. We used rabies virus-mediated retrograde tracing in these mice to perform whole-brain mapping of direct inputs to D1-MSNs or D2-MSNs in the pDMS. We found that D1-MSNs preferentially received inputs from the secondary motor, secondary visual, and cingulate cortices, whereas D2-MSNs received inputs from the primary motor and primary sensory cortices, and the thalamus. We also discovered that the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) contained abundant D2R-expressing, but few D1R-expressing, neurons in a triple transgenic mouse model. Remarkably, although limited D1R or D2R expression was observed in extrastriatal neurons that projected to D1-MSNs or D2-MSNs, we found that cortical structures preferentially contained D1R-expressing neurons that projected to D1-MSNs or D2-MSNs, while the thalamus, substantia nigra pars compacta (SNc), and BNST had more D2R-expressing cells that projected to D2-MSNs. Taken together, these findings provide a foundation for future understanding of the pDMS circuit and its role in action selection and reward-based behaviors., (Copyright © 2021 Lu et al.)

Dopaminergic modulation of corticostriatal transmission is critically involved in reward-driven behaviors. This modulation is mainly mediated by dopamine D1 receptors (D1Rs) and D2Rs, which are highly expressed in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS), a brain region essential for goal-directed behaviors and addiction. D1Rs and D2Rs are also present at presynaptic cortical terminals within the DMS. However, it is not known how addictive substances alter the glutamatergic strength of striatal synapses expressing presynaptic dopamine receptors. Using cell type-specific Cre mice in combination with optogenetic techniques, we measured glutamatergic transmission at D1R- or D2R-expressing afferents to DMS MSNs. We found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1R-expressing MSNs (D2→D1), as compared with those observed at the other tested synapses (D1→D1, D1→D2, and D2→D2). Additionally, excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2→D1 synapse. Furthermore, we demonstrated that activation of postsynaptic, but not presynaptic, D2Rs inhibited corticostriatal transmission in an endocannabinoid-dependent manner. Taken together, these data provide detailed information on the mechanisms underlying dopamine receptor-mediated modulation of brain reward circuitry.

The present study evaluated the effects of psychiatric comorbidity on substance use disorder prevalence, HIV risk behavior, and other problem severity in male and female out-of-treatment injection drug users newly registered at a syringe exchange program. Participants (N = 338) were administered the Structured Clinical Interview for the DSM-IV, the Addiction Severity Index, and the Risk Assessment Battery, and classified into one of four diagnostic groups: (1) no antisocial personality disorder (APD) or Axis I psychiatric disorder (N = 162), (2) APD only (N = 74), (3) Axis I psychiatric disorder only (N = 55), or (4) APD plus Axis I psychiatric disorder (N = 47). Psychiatric comorbidity was associated with higher rates of substance use disorder and more HIV risk and other problem severity. In general, participants with both APD and an Axis I disorder exhibited the most problem severity. APD was uniquely associated with higher prevalence for each substance use disorder assessed in this study and with elevated HIV risk. These results support and extend studies conducted with opioid-dependent individuals recruited from treatment and community settings, and reinforce the need to develop interventions to encourage syringe exchange program participants to enroll in treatment.

Participants of syringe exchange programs (SEPs) exhibit high rates of substance use disorder but remain extremely ambivalent about seeking treatment. This study evaluated the effectiveness of motivational interviewing (MI) for encouraging SEP participants to enroll in substance abuse treatment. New opioid-dependent registrants to the Baltimore Needle Exchange Program (BNEP) (n =302) completed the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and the Addiction Severity Index (ASI) and were randomly assigned to one of three treatment referral conditions: (1) MI, (2) job readiness (JR) (attention control), or (3) standard referral. Participants in each condition who expressed interest in treatment were referred to a treatment readiness group that provided further encouragement and referral to programs that were accepting new admissions. Participants were observed for 1 year following the intervention. The results showed that 10.9% of study participants enrolled in substance abuse treatment, although no condition effects were observed. White participants and those diagnosed with major depression were most likely to enter treatment. The results suggest that a single motivational interview is insufficient to motivate changes in treatment seeking in this population, whereas the identification of predictors of treatment enrollment is worthy of further investigation.

Objective: The relationships of attention deficit hyperactivity disorder (ADHD), conduct disorder, and gender to substance abuse were studied in a large population-based sample of adolescent twins., Method: Structured interviews were administered to 626 pairs of 17-year-old twins (674 girls and 578 boys) and their mothers to generate lifetime psychiatric diagnoses, and computerized measures of current substance use were obtained. Hierarchical logit analyses were performed to assess the independent effects of ADHD, conduct disorder, and gender on current substance use, frequency of substance use, and DSM-III-R diagnoses of substance use disorders., Results: Conduct disorder was found to increase the risk of substance use and abuse in adolescents regardless of gender. In contrast, independent of its association with conduct disorder, an ADHD diagnosis did not significantly increase the risk of substance use problems., Conclusions: This study found no significant gender differences in the effects of ADHD and conduct disorder on substance use and abuse, although there was some suggestion that girls with ADHD might be at slightly higher risk than boys for substance abuse. In addition, increased risk of substance abuse among adolescents with conduct disorder may be primarily confined to those with persistent conduct disorder.

Background: We compared the prophylactic efficacy of lithium, carbamazepine, and the combination and identified possible clinical markers of response., Method: Fifty-two outpatients who met DSM-III-R criteria for bipolar illness were randomly assigned in a double-blind design for an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then a third year on the combination. Patients received monthly detailed evaluations, and daily life chart ratings of the degree of functional incapacity associated with mania or depression were completed., Results: For evaluable patients: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05)., Conclusion: These prospective, randomized data suggest a high incidence of inadequate response to either mood stabilizer or their combination despite use of adjunctive agents as needed. Additional novel treatment regimens are needed to better decrease affective morbidity in large numbers of bipolar outpatients.